`
`Digital Access Service
`(DAS)
`
`WIPO
`WORLD
`INTELLECTUAL PROPENTY
`ORGANIZATION
`
`CERTIFICATE OF AVAILABILITY OF A CERTIFIED PATENT DOCUMENT IN A
`DIGITAL LIBRARY
`
`The International Bureau certifies that a copy of the patent application indicated
`below has been available to the WIPO Digital Access Service since the date of
`availability indicated, and that the patent application has been available to the
`indicated Office(s) as of the date specified following the relevant Office code:
`
`Document details: Country/Office: CN
`
`Filing date: 07 Aug 2017 (01.08.2017)
`
`Application number: 2017106481352
`
`Date of availability of document:
`
`05 Mar 2020 (05.03.2020)
`
`The following Offices can retrieve this document by using the access code:
`AR, AU, BR, CA, CL, CN, DK, EA, EE, EP, ES, Fl, GB, GE, IB, IL, IN,
`JP, KR, MA, NL, NO, NZ, SE, US
`
`Date of issue of this certificate:
`
`09 Mar 2020 (09.03.2020)
`
`
`
`Page 1 of 28
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`04, chemin des Colombeties
`12171 (geneva 20, Seettentand
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`
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`EISAI EXHIBIT 1008
`
`Page 1 of 28
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`EISAI EXHIBIT 1008
`
`

`

`
`
`NATIONAL INTELLECTUAL PROPERTY ADMINISTRATION, PRC
`
`
`
`
`
`
`
`CERTIFICATE
`
`
`Attachment to the Certificate is a copy of the patent application submitted to the Bureau.
`
`201710648135.2
`Application No.:
`Application Type: Patent for Invention
`Title of Invention: A Crystal Form of Orexin Receptor Antagonist, Its Preparation Method and Use
`Application Date: August 1, 2017
`Applicant:
`Crystal Pharmaceutical (Suzhou) Co., Ltd.
`Inventors/Designers: Chen Minhua, Zhang Yanfeng, Huang Chunxiang, Zhang Xiaoyu
`
`
`
`
`
`
`
`
`
`Bureau Director
`Shen Changyu
`March 5, 2020
`
`[signature]
`
`
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`Page 2 of 28
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`

`

`Claims
`
`
`
`1. A crystal form of CS2 of E-2006, is characterized in that its X-ray powder diffraction (XRPD) presents a
`characteristic peak at the places whose diffraction angle 2θ value is 7.8°±0.2°, 15.6°±0.2° or 11.4°±0.2°.
`2. The crystal form of CS2 as stated in Claim 1, is also characterized in that its XRPD presents a characteristic
`peak at one or several places whose diffraction angle 2θ value is 12.5°±0.2°, 21.3°±0.2° or 27.3°±0.2°.
`3. The crystal form of CS2 as stated in Claim 1, is also characterized in that its XRPD presents a characteristic
`peak at one or several places whose diffraction angle 2θ value is 24.0°±0.2°, 19.4°±0.2° or 22.3°±0.2°.
`4. Preparation methods for the crystal form of CS2 of E2006, are characterized in and comprise:
`(1) Dissolve E-2006 into ketone, haloalkane or amide solvents, and evaporate slowly to get the crystal
`form of CS2; or
`(2) Dissolve E-2006 into nitrile solvent, add ionic liquid for induction, and evaporate slowly to get the
`crystal form of CS2; or
`(3) Dissolve E-2006 into the positive solvent to make an E-2006-containing solution, then drip
`anti-solvent slowly into the positive solvent solution or drip the positive solvent solution into anti-solvent, and
`stir and crystallize to get the crystal form of CS2; or
`(4) Dissolve E-2006 into ketone solvent, ketone and water mixed solvent, ketone and normal heptane
`mixed solvent, cyclic ether and water mixed solvent or haloalkane solvent, and heat to accelerate evaporation to
`get the crystal form of CS2.
`5. According to the preparation methods as stated in Claim 4, as stated in Method (1), the ketone solvent is
`acetone,
`the haloalkane solvent
`is chloroform and
`the amide solvent
`is dimethylformamide or
`dimethylacetamide; as stated in Method (2), the nitrile solvent is acetonitrile, the ionic liquid is
`1-ethyl-3-methylimidazolium methylsulfate,
`1-ethyl-3-methylimidazolium
`hexafluorophosphate
`or
`1,3-dimethyl-methylimidazole phosphate salt; as stated in Method (3), if anti-solvent is normal heptane, the
`positive solvent can be haloalkane or arene solvent, and if anti-solvent is water, the positive solvent can be
`alcohol or amide solvent; as stated in Method (4), the ketone solvent is butanone, the ketone and water mixed
`solvent refers to acetone and water mixed, the ketone and normal heptane mixed solvent refers to acetone and
`normal heptane mixed, the cyclic ether and water mixed solvent refers to tetrahydrofuran and water mixed, the
`haloalkane solvent is dichloromethane, and the heating temperature is 40(cid:31)~100(cid:31).
`
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`Claims
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`6. According to the preparation methods as stated in Claim 5, as stated in Method (3), the haloalkane solvent is
`dichloromethane, the arene solvent is methylbenzene, the alcohol solvent is methanol and the amide solvent is
`dimethylformamide; as stated in Method (4), the volume ratio of acetone to water, acetone to normal heptane
`and tetrahydrofuran to water are 1:1, and the heating temperature is 100(cid:31).
`7. A pharmaceutical composition, comprising the crystal form of CS2 of curative dose as stated in Claim 1 and a
`pharmaceutically acceptable carrier, diluents or excipient.
`8. Use of the crystal form of CS2 as stated in Claim 1 in producing the agents adopted to prepare orexin
`receptor antagonist.
`9. Use of the crystal form of CS2 as stated in Claim 1 in producing the agents adopted to prepare the drugs for
`prevention and treatment of insomnia and/or sleep disorder and/or irregular sleep-wake rhythm disorder
`(ISWRD).
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`Specification
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`A Crystal Form of Orexin Receptor Antagonist, Its Preparation Method and Use
`
`Technical Field
`This invention refers to the field of crystal technology of drugs, specifically, involving a crystal form of
`orexin receptor antagonist, its preparation method and use.
`
`Background Art
`Polymorphism or heteromorphism is an exclusive characteristic of certain molecules and molecular
`compounds. Even the same molecule may have different crystal forms due to different spread spectrums, and
`these crystal forms may have different crystal structures and physical properties, such as solubility, stability,
`mobility, thermal property, mechanical nature, purifying ability, X-ray diffraction spectrum, infrared absorption
`spectrum, Raman spectrum and solid-state NMR (referring to P. Di Martino et al, J. Thermal Anal.,
`48:447-458(1997)). One or some analysis and detection methods can be adapted to distinguish different crystal
`forms of the same molecule or molecular compound.
`Different crystal forms of a solid chemical may bring differences in solubility, stability, mobility,
`compressibility and some other properties to affect the safety and efficacy of such chemical-contained drug
`products (referring to K. Knapman, Modern Drug Discovery, 3,53-54,57,2000.), resulting in different clinical
`drug efficacies. Finding of new crystal forms (including anhydride, hydrate, solvate, etc.) of APIs (Active
`Pharmaceutical Ingredients) may bring the substances owning more processing advantages or providing better
`physicochemical properties, such as better bioavailability, storage stability, easy processing, easy purification or
`acting as the intermediate crystal form for the transformation of other crystal forms. New crystal forms of
`pharmaceutical compounds can help to improve the performance of drugs and to expand the forms of APIs that
`can be chosen from pharmaceutically.
`Researched by EISAI, E-2006 (Lemborexant) is used for the clinical treatment of insomnia. Insomnia is a
`commonly seen sleep disorder featured on difficult to fall asleep and maintain sleep. Research shows that orexin
`is the key regulator of the sleep-wake cycle, and orexin receptor antagonist owns the potential of avoiding
`improperly timed night waking and boosting normal sleep-wake cycle. E-2006 is an orexin receptor antagonist.
`In the clinical trial, E-2006 can obviously improve insomniacs’ sleep efficiency, including faster asleep and
`shorter night waking. Besides, E-2006 also presents a huge potential in curing ISWRD of patients with
`Alzheimer’s disease. Different from common insomnia symptoms, some medical demands of ISWRB are not
`satisfied in this field until now.
`
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`Specification
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`Chemical name of E-2006:
`(1R,2S)-2-{[(2,4-dimethylpyrimidine-5-group)oxygroup]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridine-2-gro
`up)cyclopropanecarboxamide, its structural formula is shown as Formula (I) below:
`
`
`
`Formula (I)
`Patent CN103153963B has published the preparation methods of E-2006, but not the information related
`to its crystal form. No information on the crystal form of E-2006 is published at present. Thus, the crystal form
`of E-2006 as shown in Formula (I) needs to be systematically and fully developed in this art, to realize its
`pharmaceutical development and release its potential and to promote the preparation of the better prescription
`that contains this API.
`After the study, the crystal form of CS2 of E-2006 is found by the inventors. The crystal form of CS2
`provided in the present invention possesses good stability and low hygroscopicity. Besides, it is superior in at
`least one solubility, melting point, dissolution rate, bioavailability, processing performance and purification
`function. This provides a new and better choice for the preparation of crystal structure of CS2 with E-2006
`containing agents and it is significant to the development of drugs.
`
`Summary of the Invention
`To fill in the technological gap, this invention aims at providing a crystal form of E-2006, its preparation
`methods and use.
`
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`Specification
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`
`
`For this invention, the crystal form of CS2 of the compound as shown in Formula (I) (hereinafter referred
`to as the “crystal form of CS2”) is provided here in this invention.
`With Cu-Kα radiation, XRPD of the crystal form of CS2 presents a characteristic peak at the places whose
`diffraction angle 2θ value is 7.8°±0.2°, 15.6°±0.2° or 11.4°±0.2°.
`Further, XRPD of the crystal form of CS2 presents a characteristic peak at one or several places whose
`diffraction angle 2θ value is 12.5°±0.2°, 21.3°±0.2° or 27.3°±0.2°. Preferably, XRPD of the CS2 presents a
`characteristic peak at all the places whose diffraction angle 2θ value is 12.5°±0.2°, 21.3°±0.2° and 27.3°±0.2°.
`Further, XRPD of the crystal form of CS2 presents a characteristic peak at one or several places whose
`diffraction angle 2θ value is 24.0°±0.2°, 19.4°±0.2° and 22.3°±0.2°. Preferably, XRPD of the crystal form of
`CS2 presents a characteristic peak at all the places whose diffraction angle 2θ value is 24.0°±0.2°, 19.4°±0.2°
`and 22.3°±0.2°.
`In a preferable embodiment, XRPD of the crystal form of CS2 presents a characteristic peak at the places
`whose diffraction angle 2θ value is 7.8°±0.2°, 15.6°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 21.3°±0.2°, 27.3°±0.2°,
`24.0°±0.2°, 19.4°±0.2° or 22.3°±0.2°.
`Non-restrictively, in an embodiment of the present invention, the XRPD spectrum of the crystal form of
`CS2 is shown as Fig.1.
`According to the purpose of this invention, it also provides preparation methods of the crystal form of CS2,
`characterized in and comprising:
`(1) Dissolve E-2006 into ketone, haloalkane or amide solvents, and evaporate slowly to get the crystal
`form of CS2; or
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`Specification
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`(2) Dissolve E-2006 into nitrile solvent, add ionic liquid for induction, and evaporate slowly to get the
`crystal form of CS2; or
`(3) Dissolve E-2006 into the positive solvent to make an E-2006-containing solution, then drip
`anti-solvent slowly into the positive solvent solution or drip the positive solvent solution into anti-solvent, and
`stir and crystallize to get the crystal form of CS2; or
`(4) Dissolve E-2006 into ketone solvent, ketone and water mixed solvent, ketone and normal heptane
`mixed solvent, cyclic ether and water mixed solvent or haloalkane solvent, and heat to accelerate evaporation to
`get the crystal form of CS2.
`Further, as stated in Method (1), the ketone solvent contains acetone, the haloalkane solvent contains
`chloroform and the amide solvent contains dimethylformamide or dimethylacetamide.
`Further, as stated in Method (2), the nitrile solvent contains acetonitrile, the ionic liquid contains
`1-ethyl-3-methylimidazolium methylsulfate,
`1-ethyl-3-methylimidazolium
`hexafluorophosphate
`and
`1,3-dimethyl-methylimidazole phosphate salt.
`Further, as stated in Method (3), if anti-solvent is normal heptane, the positive solvent can be haloalkane
`or arene solvent; if anti-solvent is water, the positive solvent can be alcohol or amide solvent;
`Even further, as stated in Method (3), the haloalkane solvent contains dichloromethane, the arene solvent
`contains methylbenzene,
`the alcohol solvent contains methanol and
`the amide solvent contains
`dimethylformamide.
`Further, as stated in Method (4), the ketone solvent contains butanone, the ketone and water mixed solvent
`contains acetone and water mixed, the ketone and normal heptane mixed solvent contains acetone and normal
`heptane mixed, the cyclic ether and water mixed solvent contains tetrahydrofuran and water mixed, the
`haloalkane solvent contains dichloromethane, and the heating temperature is 40(cid:31)~100(cid:31);
`Even further, as stated in Method (4), the volume ratio (v:v) of acetone to water, acetone to normal
`heptane and tetrahydrofuran to water is 1:1, and the heating temperature is 100(cid:31).
`
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`Stability of drugs is vital, especially for keeping good stability within the validity of the sale, which could
`avoid the changes in drug dissolution rate and bioavailability caused by the change of crystal form, and it is
`significant to ensure the curative effect and safety of drugs. Meanwhile, a more stable crystal form is more
`controllable during the crystalline process to prevent mixed crystal. During the preparation process and storage,
`it is uneasy to transform into other crystal forms, so as to ensure the consistent and controllable quality of
`samples and to ensure dissolution curve of preparation products not to change with the storage time as well. The
`crystal form of CS2 of E-2006 provided in the present invention owns good stability, as it can be stored for one
`month under a relative humidity of 25(cid:31)/60% and 40(cid:31)/75% and two weeks under 60(cid:31)/75%, with crystal form
`remaining unchanged.
`Hygroscopicity is one of the key properties of crystal form. As the crystal form of high hygroscopicity
`may change in weight because of absorbing much water, the constituent content of the crystal form of API is
`difficult to determine. Moreover, the crystal form of API also may absorb water and cake due to high
`hygroscopicity and it will affect the particle size distribution of samples in the preparation process and also the
`uniformity of APIs in preparation, so as to affect the dissolution and bioavailability of samples. APIs of high
`hygroscopicity require much for package and storage conditions, leading to an increase in drug production cost.
`Thus, preparation of the crystal form of low hygroscopicity is crucial to drug production. The crystal form of
`CS2 provided in the present invention owns a low hygroscopicity. After reaching a balance under a relative
`humidity of 80%, it becomes 0.10% heavier compared with the initial condition, and thus the crystal form of
`CS2 can be regarded as almost no hygroscopicity. This could solve the problems brought by high
`hygroscopicity of crystal form as stipulated above.
`Besides, the crystal form of CS2 also owns at least one of the following favorable properties: high
`solubility, easy preparation and less toxic solvents applied, good crystallinity, good particle morphology, better
`mobility and better apparent density.
`Concerned with the preparation methods of the crystal form of CS2 provided in the present invention:
`The “evaporation” stated can be completed in conventional ways. For example, slow evaporation refers to
`sealing the vessel with film, pricking the film and still standing for evaporation; fast evaporation refers to
`keeping the vessel open to the air for evaporation.
`According to the present invention, the E-2006, as an API, can be solid (crystalline or amorphous),
`semisolid, waxy or oily. Preferably, the compound as shown in Formula (I), as an API, is solid powder.
`
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`Specification
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`
`
`In the present invention, “crystal” or “polymorphism” refers to being characterized by the XRPD spectrum.
`Persons skilled in the art could understand that the physicochemical properties discussed herein can be
`characterized, and the experimental error depends on instrument conditions, sample preparation and sample
`purity. Particularly, all the persons skilled in the art know that the XRPD spectrum will change with the
`conditions of the instrument. Specifically, the relative intensity of the XRPD spectrum also may change with
`experimental conditions, and thus, the sequence of peak intensity cannot be used as the only or decisive factor.
`In fact, the relative intensity of the diffraction peaks shown in the XRPD spectrum has something to do with the
`preferred orientation of the crystal, and the peak intensity stated herein is illustrative, but not for absolute
`comparison. Besides, the experimental error of peak angles is often 5% or less and such error also should be
`considered, and it generally allows an error of ±0.2°. Moreover, affected by such experimental factors as sample
`height, angles of the peak may offset in general, and it often allows certain offset. Therefore, the persons skilled
`in the art could understand that, the XRPD spectrum of a crystal form doesn’t need to be totally the same as the
`XRPD spectrums provided in the embodiments. The “same XRPD spectrum” stated herein doesn’t mean
`absolutely the same, and the same peak is allowed to have a position offset of ±0.2° and peak intensity is
`allowed to have certain change. Any crystal form whose XRPD spectrum has the same or similar characteristic
`peaks with the stated spectrum is included in the present invention. Persons skilled in the art could compare the
`XRPD spectrum provided in the present invention with the spectrum of an unknown crystal form to prove
`whether the two spectrums present the same or different crystal forms.
`“Crystal form”, “polymorphism” and other related words stated herein refer to that solid compound exists
`in a crystal structure with a specific crystal state. Differences in the physicochemical properties of
`polymorphism can be embodied by storage stability, compressibility, density, dissolution rate, etc. In extreme
`circumstances, the difference in solubility or dissolution rate could bring low efficacy and even toxicity to
`drugs.
`What needs illustration is that the numbers and numerical ranges mentioned herein shouldn’t be narrowly
`understood as the numbers or numerical ranges themselves. Persons skilled in the art should understand that
`these numbers and numerical ranges could fluctuate roughly not deviating from the spirits and principles of this
`invention. In the present invention, most of the fluctuation ranges that could be foreseen by the persons skilled
`in the art are noted with “around”.
`
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`Specification
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`
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`Besides, a pharmaceutical composition is provided in the present invention, comprising the crystal form of
`CS2 of curative dose for treatment and/or prevention and also at least one pharmaceutically acceptable carrier,
`diluent or excipient.
`Further, the use of the crystal form of CS2 in producing the agents adopted to prepare the orexin receptor
`antagonist is provided in the present invention.
`Even further, the use of the crystal form of CS2 in producing the agents adopted to prepare the drugs for
`prevention and treatment of insomnia and/or sleep disorder and/or irregular sleep-wake rhythm disorder
`(ISWRD) is provided in the present invention.
`
`Brief Description of the Drawings
`Fig.1 shows the XRPD spectrum of the crystal form of CS2 got according to Embodiment 1 of the present
`invention.
`Fig.2 shows the DSC spectrum of the crystal form of CS2 got according to Embodiment 1 of the present
`invention.
`Fig.3 shows the TGA spectrum of the crystal form of CS2 got according to Embodiment 1 of the present
`invention.
`Fig.4 shows the 1H NMR spectrum of the crystal form of CS2 got according to Embodiment 1 of the
`present invention.
`Fig.5 shows the XRPD spectrum of the crystal form of CS2 got according to Embodiment 7 of the present
`invention.
`Fig.6 shows the XRPD spectrum of the crystal form of CS2 got according to Embodiment 8 of the present
`invention.
`Fig.7 shows the XRPD spectrum of the crystal form of CS2 got according to Embodiment 17 of the
`present invention.
`Fig.8 shows the DVS spectrum of the crystal form of CS2 provided in the present invention.
`Fig.9 shows the XRPD spectrums of the crystal form of CS2 before and after DVS (the spectrum above is
`before DVS and the spectrum below is after DVS).
`Fig.10 shows a comparison of the XRPD spectrums of crystal form of CS2 before and after being placed
`for one month under a relative humidity of 25(cid:31)/60% (the spectrum above is before and the spectrum below is
`after).
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`Specification
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`Fig.11 shows a comparison of the XRPD spectrums of crystal form of CS2 before and after being placed
`for one month under a relative humidity of 40(cid:31)/75% (the spectrum above is before and the spectrum below is
`after).
`Fig.12 shows a comparison of the XRPD spectrums of crystal form of CS2 before and after being placed
`for one month under a relative humidity of 60(cid:31)/75% (the spectrum above is before and the spectrum below is
`after).
`
`Specific Embodiments
`Further referring to the embodiments below, the embodiments provided in the present invention elaborate
`on how to prepare and use the crystal form as described herein. It is obvious to the persons skilled in the art that
`many changes in both materials and methods are allowed without separating from the scope of the present
`invention.
`Instruments and methods used by data collection:
`The XRPD spectrums as stated in the present invention are collected on Bruker D2 PHASER X-ray Power
`Diffractometer. XRPD-related parameters are shown as follows:
`XRPD parameters: Cu, Kα
`
`
`
`Kα1/ Kα2 intensity scale: 0.50
`Voltage: 30kV
`Current: 10mA
`Scan range: 3.0-40.0°
`The DSC (Differential Scanning Calorimetry) spectrums as stated in the present invention are collected on
`TA Q2000. DSC-related parameters are shown as follows:
`Scanning rate: 10(cid:31)/min without special request
`Protective gas: N2
`The TGA (Thermogravimetric Analysis) spectrums as stated in the present invention are collected on TA
`Q500. TGA-related parameters are shown as follows:
`
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`Specification
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`Scanning rate: 10(cid:31)/min
`Protective gas: N2
`The DVS (Dynamic Vapor Sorption) spectrums as stated in the present invention are collected on an
`Intrinsic DVS meter manufactured by SMS (Surface Measurement Systems Ltd.). DVS-related parameters are
`shown as follows:
`Temperature: 25(cid:31)
`The flow rate of carrier gas: N2, 200ml/min
`Mass change per unit time: 0.002%/min
`Range of relative humidity: 0%RM-95%RH
`Abbreviations:
`XRPD: X-Ray Powder Diffraction
`DSC: Differential Scanning Calorimetry
`TGA: Thermogravimetric Analysis
`DVS: Dynamic Vapor Sorption
`1H NMR: Nuclear Magnetic Resonance
`Unless otherwise stipulated, the following embodiments are all operated under room temperature.
`E-2006 applied in the following embodiments is prepared according to existing technologies, such as the
`preparation methods published in CN103153963B.
`Embodiments 1~2: Preparation of crystal form of CS2 by slow evaporation
`Weigh a certain mass of E-2006, dissolve it into the solvent of a certain volume as shown in Table 1, and
`then filter and evaporate slowly under room temperature to get the solids. Mark the solids got from
`Embodiments 1~4 as Samples 1~4, and all of them are crystal forms of CS2 upon detection. Choose Sample 1
`for testing and characterizing, and the data concerned with XRPD are shown as Fig.1 and Table 2.
`
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`DSC of the crystal form of CS2 got from Embodiment 1 is shown as Fig.2. When heating to around 177(cid:31),
`an endothermic peak appears and this is the melting endothermic peak of the crystal form of CS2.
`TGA of the crystal form of CS2 got from Embodiment 1 is shown as Fig.3. When heating to around 170(cid:31),
`it suffers a mass loss of about 0.6%.
`1H NMR spectrum of the crystal form of CS2 got from Embodiment 1 is shown as Fig.4, providing data:
`1H NMR (400
`
`Embodiment Mass of E-2006 (mg)
`
`
`
`Table 1
`
`Solvent
`Acetone
`Chloroform
`Dimethylformamide
`Dimethylacetamide
`
`Table 2
`
`Solvent Volume (mL)
`
`
`
`
`
`Sample
`Sample 1
`Sample 2
`Sample 3
`Sample 4
`
`Diffraction Angle 2θ
`Value
`
`Value d
`
`Intensity %
`
`
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`Embodiments 5~7: Preparation of the crystal form of CS2 by induction with ionic liquid and evaporation
`Weigh about 31.5mg E-2006, add 1.0mL acetonitrile solvent to dissolve and filter, then add a small
`amount of the ionic liquid as shown in Table 3 and evaporate slowly under room temperature to get the solids.
`Mark the solids got from Embodiments 5~7 as Samples 5~7, and all of them are crystal forms of CS2 upon
`detection. Choose Sample 7 for testing and characterizing, and the data concerned with XRPD are shown as
`Fig.5 and Table 4.
`
`Table 3
`
`Embodiment
`5
`6
`7
`
`Ionic Liquid
`1-ethyl-3-methylimidazolium methylsulfate
`1-ethyl-3-methylimidazolium hexafluorophosphate
`1,3-dimethyl-methylimidazole phosphate salt
`
`Sample
`Sample 5
`Sample 6
`Sample 7
`
`Table 4
`
`Diffraction Angle 2θ
`Value
`
`Value d
`
`Intensity %
`
`
`
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`Embodiments 8~11: Preparation of crystal form of CS2 by anti-solvent addition or inverted anti-solvent
`addition
`Weigh a certain mass of E-2006, dissolve it into the positive solvent of a certain volume as shown in
`Tables 5 and 6, and then filter to get the E-2006-containing positive solvent solution. Drip anti-solvent into the
`positive solvent solution (anti-solvent addition) or drip the positive solvent solution into anti-solvent (inverted
`anti-solvent addition), keep stirring until a large number of solids separate, and then centrifuge, collect and dry
`the solids received. Mark the solids got from Embodiments 8~15 as Samples 8~15, and all of them are crystal
`form of CS2 upon detection. Choose Sample 8 for testing and characterizing, and the data concerned with
`XRPD are shown as Fig.6 and Table 7.
`Table 5: Preparation of crystal form of CS2 by Anti-solvent Addition
`
`Mass of
`E-2006
`(mg)
`20.2
`19.6
`20.5
`20.5
`
`Positive Solvent
`
`Dichloromethane
`Methylbenzene
`Methanol
`Dimethylformamide
`
`Volume of
`Positive
`Solvent (mL)
`0.5
`1.0
`0.5
`0.5
`
`Anti-solvent
`
`Normal heptane
`Normal heptane
`Water
`Water
`
`Volume of
`Anti-solvent
`(mL)
`1.0
`2.0
`0.2
`0.3
`
`Sample
`
`8
`9
`10
`11
`
`Embodiment
`
`8
`9
`10
`11
`
`
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`Specification
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`Table 6: Preparation of crystal form of CS2 by Inverted Anti-solvent Addition
`
`Embodiment
`
`12
`13
`14
`15
`
`Mass of
`E-2006
`(mg)
`20.2
`19.6
`20.5
`20.5
`
`Positive Solvent
`
`Dichloromethane
`Methylbenzene
`Methanol
`Dimethylformamide
`
`Volume of
`Positive
`Solvent (mL)
`0.5
`1.0
`0.5
`0.5
`
`Table 7
`
`Anti-solvent
`
`Normal heptane
`Normal heptane
`Water
`Water
`
`Volume of
`Anti-solvent
`(mL)
`2.0
`2.0
`2.0
`2.0
`
`Sample
`
`12
`13
`14
`15
`
`Diffraction Angle 2θ
`Value
`
`Value d
`
`Intensity %
`
`
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`Specification
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`Embodiments 16~20: Preparation of crystal form of CS2 by fast evaporation
`Weigh a certain mass of E-2006, dissolve it into the solvent of a certain volume as shown in Table 8, open
`to the air under 100(cid:31) after filtering and evaporate fast to get the solids. Mark the solids got from Embodiments
`16~20 as Samples 16~20, and all of them are crystals form of CS2 upon detection. Choose Sample 17 for
`testing and characterizing, and the data concerned with XRPD are shown as Fig.7 and Table 9.
`Table 8
`
`Embodiment Mass of E-2006 (mg)
`
`
`
`Solvent
`Dichloromethane
`Butanone
`Normal heptanes/Acetone
`v:v=1:1
`Water/Acetone v:v=1:1
`Tetrahydrofuran/Water v:v=1:1
`
`Table 9
`
`Solvent Volume (mL)
`
`Sample
`
`
`
`Diffraction Angle 2θ
`Value
`
`Value d
`
`Intensity %
`
`
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`Embodiment 21: Study on hygroscopicity
`Hygroscopicity is one of the key properties of crystal form. As the crystal form of high hygroscopicity
`may change in weight because of absorbing much water, the constituent content of the crystal form of API is
`difficult to determine. Moreover, the crystal form of API also may absorb water and cake due to high
`hygroscopicity and it will affect the particle size distribution of samples in the preparation process and also the
`uniformity of APIs in preparation, so as to affect the dissolution and bioavailability of samples. APIs of high
`hygroscopicity require much for package and storage conditions, leading to an increase in drug production cost.
`Thus, preparation of the crystal form of low hygroscopicity is crucial to drug production.
`Based on the importance of hygroscopicity, investors take about 15mg of the crystal form of CS2 provided
`in the present invention under 25(cid:31) and make DVS test its hygroscopicity. Results show that:
`After reaching a balance under a relative humidity of 80%, it becomes 0.10% heavier compared with the
`initial condition, and thus the crystal form of CS2 can be regarded as almost no hygroscopicity. This could solve
`the problems brought by high hygroscopicity of crystal form as stipulated above. It is convenient for long-term
`storage and could greatly reduce the cost of material storage and quality control, owning very high economic
`value. DVS spectrum of the crystal form of CS2 is shown in Fig.8. Besides, XRPD spectrums of the crystal
`form of CS2 are got before and after DVS, shown in Fig.9 (the spectrum above is before DVS and the spectrum
`below is after DVS), indicating that no change occurs to the crystal form of CS2 before and after DVS.
`Concerning the description of hygroscopicity and the determination of hygroscopicity-caused weight gain
`(General Rules of Chinese Pharmacopoeia 2015: 9103 Guiding Principles for the Test on Drug Hygroscopicity,
`experimental conditions: 25(cid:31)±1(cid:31), the relative humidity of 80%):
`Deliquescence: absorb enough water to become a kind of liquid
`
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`Extreme hygroscopicity: hygroscopicity-caused weight gain is not smaller than 15%
`Moderate hygroscopicity: hygroscopicity-caused weight gain is smaller than 15% but not smaller than 2%
`A little hygroscopicity: hygroscopicity-caused weight gain is smaller than 2% but not smaller than 0.2%
`No or almost no hygroscopicity: hygroscopicity-caused weight gain is smaller than 0.2%
`Embodiment 22: Study on stability
`Put the crystal form of CS2 prepared in the present invention under a relative humidity of 25(cid:31)/60% and
`40(cid:31)/75% respectively to the open air for one month; and put the crystal form of CS2 under a relative humidity
`of 60(cid:31)/75% for two weeks. The results are shown in Table 10.
`Table 10
`
`Purity
`afterward
`
`Purity
`Change
`
`Initial Purity
`
`Conditions
`
`Duration
`
`Relative humidity
`25(cid:31)/60%
`
`1 month
`
`Relative humidity
`40(cid:31)/75%
`
`1 month
`
`Relative humidity
`60(cid:31)/75%
`
`2 weeks
`
`Crystal Form
`afterward
`Crystal form of
`CS2 (the one
`below in
`Fig.10)
`Crystal form of
`CS2 (the one
`below in
`Fig.11)
`Crystal form of
`CS2 (the one
`below in
`Fig.12)
`
`Initial Crystal
`Form
`Crystal form of
`CS2 (the one
`below in
`Fig.10)
`Crystal form of
`CS2 (the one
`below in
`Fig.11)
`Crystal form of
`CS2 (the one
`below in
`Fig.12)
`
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`All the persons skilled in the art know that the chemical stability of a drug directly correlates to its purity
`and impurities. The purity of crystal form is significant in ensuring the efficacy and safety of drugs and in
`preventing adverse reactions as well. Meanwhile, the purity of crystal form is higher and the yield is relatively
`more stable, making for industrial production. Besides, impurities contained in crystal form can be considered
`as a key factor that affects the pur