WO2019114394A1 - Eb-1020的晶型及其制备方法和用途 - Google Patents

Eb-1020的晶型及其制备方法和用途 Download PDF

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WO2019114394A1
WO2019114394A1 PCT/CN2018/109908 CN2018109908W WO2019114394A1 WO 2019114394 A1 WO2019114394 A1 WO 2019114394A1 CN 2018109908 W CN2018109908 W CN 2018109908W WO 2019114394 A1 WO2019114394 A1 WO 2019114394A1
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crystal form
present
preparation
crystalline form
crystal
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PCT/CN2018/109908
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English (en)
French (fr)
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陈敏华
张炎锋
翟晓婷
张晓宇
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苏州科睿思制药有限公司
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Priority to US16/771,373 priority Critical patent/US11149004B2/en
Priority to CN201880075915.5A priority patent/CN111417624B/zh
Publication of WO2019114394A1 publication Critical patent/WO2019114394A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of medicinal chemistry. Specifically, it relates to a crystal form of EB-1020, a preparation method thereof and use thereof.
  • EB-1020 (Centanafadine Hydrochloride) is a triple reuptake inhibitor (TRI) that inhibits the reuptake of norepinephrine, serotonin and dopamine. Studies have shown that EB-1020 has potential relief or therapeutic effects on neurological disorders, especially attention deficit hyperactivity disorder (ADHD).
  • ADHD attention deficit hyperactivity disorder
  • EB-1020 (1R, 5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (hereinafter referred to as "compound (I)” ), its structural formula is as follows:
  • WO2016205762A discloses Form A, Form B and Form C of EB-1020. According to the paragraph [00232] of WO2016205762A, Form C is converted into a mixture of Forms A and B after two weeks at 40 ° C / 75% relative humidity, and the inventors have found that the existing Form C is placed at room temperature. After one month, it was changed to crystal form A. It can be seen that the existing crystal form C has poor stability and the risk of drug development is large.
  • WO2016205762A specification [00172] describes the diffraction peak of A in the XRPD pattern of Form B, indicating that Form A is easily mixed with Form A, and Form B is difficult to purify, which is not conducive to large-scale production and preparation.
  • Applications According to the specification of WO2016205762A [00179], the existing crystal forms A and B are needle-like crystals, and the compressibility and fluidity of the needle crystals are poor, which is not favorable for the tableting of the preparation, and the needle crystals are usually easy to be electrostatically charged, and the preparation of the needles is relatively easy. difficult.
  • the inventors have found a crystalline form CS1 of EB-1020 which is excellent in properties.
  • the crystalline form CS1 of EB-1020 of the invention has stability, melting point, solubility, in vitro and in vivo dissolution, moisture absorbing property, bioavailability, adhesion, compressibility, fluidity, processing property, purification effect, formulation development, and the like.
  • the main object of the present invention is to provide a crystal form of the compound (I), a process for its preparation and use.
  • the present invention provides the crystal form CS1 of the compound (I) (hereinafter referred to as "crystal form CS1").
  • the X-ray powder diffraction of the crystalline form CS1 has a diffraction angle 2 ⁇ value of 21.0° ⁇ 0.2°, 25.3° ⁇ 0.2°, 14.1° ⁇ 0.2°, and 16.1° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 17.8° ⁇ 0.2° and 20.6° ⁇ 0.2°; preferably, the crystal form CS1
  • the X-ray powder diffraction has characteristic peaks at two points in the diffraction angle 2 ⁇ value of 17.8° ⁇ 0.2° and 20.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 18.3° ⁇ 0.2° and 19.4° ⁇ 0.2°; preferably, the crystal form CS1
  • the X-ray powder diffraction has characteristic peaks at two points in the diffraction angle 2 ⁇ value of 18.3° ⁇ 0.2° and 19.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS1 has a diffraction angle 2 ⁇ value of 21.0° ⁇ 0.2°, 25.3° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.1° ⁇ 0.2°, Any 3, or 4, or 5, or 6, or 7 of 17.8 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, 19.4 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 ° , or at 8, or 9 or 10 with characteristic peaks.
  • the present invention also provides a method for preparing the crystal form CS1, which comprises: weighing a certain amount of the compound (I) raw material, heating and melting under the protection of an inert gas, and cooling to obtain a crystal form CS1.
  • the heating and melting temperature is 248 ⁇ 2 °C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form CS1 and a pharmaceutically acceptable carrier, diluent or excipient.
  • crystalline form CS1 of the present invention for the preparation of a serotonin, norepinephrine and dopamine triple reuptake inhibitor medicament.
  • the use of the crystalline form CS1 provided by the present invention for the preparation of a medicament for treating a nervous system disorder.
  • the crystal form CS1 provided by the invention has the following beneficial effects:
  • the crystalline bulk drug provided by the present invention has good physical and chemical stability.
  • the crystal form CS1 provided by the invention is openly placed at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the crystal form remains unchanged for at least 6 weeks, and preferably the crystal form remains at least for 4 months. change.
  • the crystal form remained unchanged at 80 ° C for at least 1 week.
  • the crystal form of the present invention has a chemical purity of 99% or more, more preferably 99.9% or more, and the chemical purity remains substantially unchanged during the standing.
  • the crystalline bulk drug of the present invention has a crystal form which remains unchanged after being pressed into tablets under different pressures, and has good physical stability.
  • the crystalline bulk drug has good physical and chemical stability.
  • the crystalline form CS1 does not change to other crystalline forms, and the chemical purity of the crystalline form CS1 remains substantially unchanged during storage, thereby ensuring consistent quality control of the drug substance and the formulation.
  • the crystal form CS1 of the present invention has higher solubility than the prior art. Particularly in FeSSIF, the solubility is about twice that of the prior art Form A and Form B.
  • the increase of solubility is beneficial to improve the bioavailability of the drug, thereby improving the drug-forming property and the drug effect of the drug; in addition, the improvement of the solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the drug. safety.
  • the crystal form CS1 of the present invention has better mechanical stability than the prior art.
  • the crystal form CS1 of the present invention did not change before and after the polishing, and the change in crystallinity was small, and the polishing stability was good.
  • the crystal form of the existing crystal form A is significantly reduced after grinding, and the existing crystal form B is partially converted into the crystal form A after grinding.
  • the grinding and pulverization of the raw material medicine is often required in the preparation process, and the better grinding stability of the crystalline form CS1 can reduce the risk of crystallinity change and crystal transformation of the raw material drug during the processing of the preparation.
  • the crystalline form CS1 has good stability in the formulation.
  • the crystal form CS1 of the present invention is mixed with an auxiliary material to form a pharmaceutical preparation, and is placed under the conditions of 25° C./60% relative humidity and 40° C./70% relative humidity, and the crystal form is left unchanged for at least one month, and the purity during the standing process. The amount of change is small.
  • the transformation of the crystal form in the preparation causes a change in the absorption of the drug, causing toxic side effects of the drug.
  • the crystalline form CS1 has good physical and chemical stability in the preparation, ensures that the quality of the raw material drug and the preparation is consistent and controllable, and minimizes the toxicity increase of the drug due to the change of the crystal form, and ensures the therapeutic effect of the drug.
  • the crystalline form CS1 of the present invention has good in vitro dissolution and dissolution rate.
  • Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
  • Good dissolution and high dissolution rate are important prerequisites for drug absorption.
  • Good in vitro dissolution results in higher absorption of the drug, better exposure characteristics in the body, thereby improving bioavailability and improving the efficacy of the drug; high dissolution rate allows the drug to reach the highest concentration in plasma quickly after administration. To ensure that the drug works quickly.
  • crystal form CS1 provided by the present invention has the following beneficial effects:
  • the crystal form CS1 of the present invention is non-needle-like, such as a spherical or short rod-like shape, and has better fluidity, and is more advantageous for processing and preparation of the preparation.
  • the existing crystal forms A and B are needle-like crystals, and the needle mold has poor compressibility and fluidity, which is disadvantageous for tableting of the preparation.
  • the crystal form CS1 provided by the present invention has good compressibility.
  • the good compressibility of the crystal form CS1 can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more stable, improve the appearance of the product, and improve the product quality.
  • Good compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
  • the crystal form CS1 of the present invention has excellent adhesion.
  • the adhesion evaluation results show that the crystalline form CS1 has a low adsorption amount and a low adhesion.
  • the low adhesion can effectively improve or avoid the phenomenon of sticky wheel and sticking caused by dry granulation and tablet tableting, which is beneficial to improve the appearance and weight difference of the product.
  • low adhesion can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the uniformity of the content of the final product. .
  • crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern characterization Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS1 of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Example 1 is an XRPD pattern of the crystal form CS1 obtained in Example 1.
  • Example 2 is a 1 H NMR chart of the crystal form CS1 obtained in Example 1.
  • Example 3 is a DSC chart of the crystal form CS1 obtained in Example 1.
  • Example 4 is a TGA chart of the crystal form CS1 obtained in Example 1.
  • Fig. 5 is an XRPD diagram of the crystal form CS1 of the present invention before and after being placed at 25 ° C / 60% relative humidity (the upper figure is before placement, and the lower figure is after placement).
  • Fig. 6 is an XRPD diagram of the crystal form CS1 of the present invention before and after being placed at 40 ° C / 75% relative humidity (the upper figure is before placement, and the lower figure is after placement).
  • Fig. 7 is an XRPD diagram of the crystal form CS1 of the present invention before and after being placed at 80 ° C (the upper figure is before placement, and the lower figure is after placement).
  • Fig. 8 is an XRPD diagram of the crystal form CS1 of the present invention before and after polishing (the figure above is before polishing, and the figure below is after grinding).
  • Fig. 9 is an XRPD diagram of the prior art crystal form A before and after polishing (the upper figure is before grinding, and the lower figure is after grinding).
  • Fig. 10 is an XRPD diagram of the prior art before and after the polishing of Form B (the figure above is before grinding, and the figure below is after grinding).
  • Figure 11 is a PLM diagram of a crystalline form CS1 of the present invention.
  • Fig. 12 is an XRPD diagram of the crystal form CS1 of the present invention before and after tableting under a pressure of 3 kN (the lower figure is before tableting, and the upper figure is after tableting).
  • Figure 13 is an XRPD diagram of the crystal form CS1 of the present invention before and after tableting at a pressure of 7 kN (the lower figure is before tableting, and the upper figure is after tableting).
  • Figure 14 is an XRPD diagram of the crystal form CS1 of the present invention before and after tableting under a pressure of 14 kN (the lower figure is before tableting, and the upper figure is after tableting).
  • Figure 15 is an in vitro dissolution profile of a crystalline CS1 formulation.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction according to the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the DSC according to the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the TGA of the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • IC ion chromatography
  • HPLC high performance liquid chromatography
  • the elution gradient is as follows:
  • Detection wavelength 226nm, reference wavelength is 500nm
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the compound (I) as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) as a raw material is in the form of a solid powder.
  • the EB-1020 used in the following examples was prepared according to the prior art, for example according to the preparation method disclosed in WO2016205762A.
  • the DSC of the crystalline form CS1 obtained in this example is as shown in FIG. 3, and an endothermic peak appears near the heating of 247 ° C, which is the melting endothermic peak of the crystalline form CS1.
  • the TGA of the crystal form CS1 obtained in the present example had a weight loss of about 1.1% when heated to around 200 °C.
  • the molar ratio of EB-1020 free base to chloride ion in the form CS1 was determined by ion chromatography.
  • the test data are shown in Table 2 below. The data indicates that Form CS1 is a monohydrochloride salt.
  • the crystal form CS1 of the present invention was weighed and left open for 6 weeks under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and placed open at 80 ° C for 1 week, and determined by HPLC and XRPD. The crystal form and chemical purity were changed, and the results are shown in Tables 3 and 4.
  • Placement condition Purity after 1 week of placement Purity after 2 weeks of placement Purity after 6 weeks of placement 25°C/60% relative humidity 99.93% 99.95% 99.94% 40 ° C / 75% relative humidity 99.95% 99.95% 99.97% 80 ° C 99.82% —— ———
  • the crystalline form CS1 can be stable for at least 6 weeks at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and can be stabilized for at least 1 week under severe conditions of 80 ° C, and the crystal form during standing.
  • the chemical purity of CS1 remains essentially unchanged. It can be seen that the crystalline form CS1 has good physical and chemical stability.
  • Example 3 Comparison of polishing stability of crystalline form CS1, existing form A and form B
  • the crystal form CS1, the existing crystal form A and the crystal form B of the present invention are respectively placed in a mortar and manually ground for 5 minutes.
  • the XRPD pattern before and after the crystal form CS1 of the present invention is as shown in FIG. 8 (the above figure is before grinding)
  • the following figure shows the XRPD pattern before and after the polishing of the existing crystal form A as shown in Fig. 9 (the upper figure is before grinding and the lower part is after grinding), and the XRPD pattern before and after the existing crystal form B is as shown in Fig. 10. Shown (above is before grinding, the figure below is after grinding).
  • the crystal form CS1 of the present invention does not change before and after the grinding, and the crystallinity remains substantially unchanged, and the polishing stability is good.
  • the crystal form of the existing crystal form A is significantly reduced after polishing, and a large amount of amorphous form appears, and the existing crystal form B is crystallized after grinding. It is shown that the crystal form CS1 of the present invention has better stability than the existing crystal forms A and B under a certain mechanical stress.
  • Example 4 Comparison of dynamic solubility of crystalline form CS1, existing form A and form B
  • Gastrointestinal fluids such as FaSSIF (simulated fasting intestinal fluid) and FeSSIF (simulated feeding intestinal fluid) are biologically relevant media that better reflect the effects of the intestinal physiological environment on drug release in such media.
  • the solubility of the test is closer to the solubility in the human environment.
  • the crystalline form CS1, the existing crystalline form A and the crystalline form B of the present invention were respectively weighed, and a saturated solution was prepared by using FaSSIF and FeSSIF, and the content of the sample in the saturated solution was measured by high performance liquid chromatography after equilibration for 4 hours (mg/mL). ), the results are shown in Table 5.
  • Example 5 Comparison of Morphology of Crystalline CS1 and Existing Form A and Form B
  • WO2016205762A specification [00179] has described that the existing crystal forms A and B are needle-like crystals, and the needle mold has poor compressibility and fluidity, which is not favorable for the tableting of the preparation, and the needle crystal is usually easy to carry static electricity, and the preparation of the needle is relatively high. difficult.
  • the crystal form CS1 prepared by the present invention was subjected to a polarizing microscope (PLM), and the PLM chart is shown in Fig. 11. It can be seen that the crystal form CS1 of the present invention is a non-acicular crystal, such as a spheroidal shape and a short rod shape, and has better fluidity, and is more favorable for processing and preparation of the preparation.
  • Example 6 Physical stability of crystalline CS1 under different pressure conditions
  • Crystal form Maximum adsorption amount (mg) Average adsorption amount (mg) Cumulative final adsorption amount (mg) Crystal form CS1 0.07 0* 0*
  • Example 8 Compressibility of Form CS1
  • Pressing with a manual tableting machine when pressing, select a circular flat punch that can be pressed into a cylindrical tablet (to ensure the isotropy of the tablet), add a certain amount of crystal form CS1, and press it with a certain pressure.
  • the round tablets were placed in a desiccator for 24 h.
  • the radial crushing force (hardness, H) was measured using a tablet hardness tester.
  • Example 9 Formulation preparation of crystalline form CS1
  • the crystal form CS1 and the auxiliary material were uniformly mixed, and the tablet was pressed by an ENERPAC type manual tableting machine.
  • ENERPAC ENERPAC type manual tableting machine.
  • a circular punch with a diameter of 7 mm was selected, and the pressure was 5 ⁇ 0.5 KN, which was pressed into a round tablet.
  • the tablets were packaged in HDPE bottles and placed at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 1 month.
  • Samples and impurities were sampled and the stability of the formulation of the crystalline form CS1 was examined.
  • the results are as follows Table 11 and Table 12 are shown. The results show that the crystalline CS1 preparation can be stable for at least one month under the conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the amount of purity change is small, and has good stability.
  • Placement condition Placement time Initial purity Purity after placement Purity change 25°C/60% relative humidity 1 month 99.79% 99.75% 0.04% 40 ° C / 75% relative humidity 1 month 99.79% 99.54% 0.25%
  • Example 10 In vitro dissolution of crystalline CS1 formulations
  • the CS1-containing tablets obtained in Example 9 were tested for in vitro dissolution, and the dissolution was measured according to the Chinese Pharmacopoeia 2015 edition 0931 dissolution and release assay conditions as follows:
  • Dissolution method paddle method
  • Fig. 15 shows that the tablet having the crystalline form CS1 of the present invention as an active ingredient has a good dissolution.

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Abstract

本发明涉及化合物(I)的晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备5-羟色胺、去甲肾上腺素和多巴胺三重再摄取抑制剂和/或治疗神经系统障碍药物制剂中的用途。本发明提供的化合物(I)的晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。 (I)

Description

EB-1020的晶型及其制备方法和用途 技术领域
本发明涉及药物化学领域。具体而言，涉及EB-1020的晶型及其制备方法和用途。
背景技术
去甲肾上腺素、5-羟色胺和多巴胺是与多种神经障碍有关的三种生物胺，抑制其重摄取可潜在治疗中枢神经系统障碍。EB-1020(Centanafadine Hydrochloride)是一种三重再摄取抑制剂(TRI)，可抑制去甲肾上腺素、5-羟色胺和多巴胺的重摄取。研究表明，EB-1020对于神经系统障碍，尤其是注意力缺陷多动障碍(ADHD)方面具有潜在的缓解或治疗效果。
EB-1020的化学名称为：(1R,5S)-1-(萘-2-基)-3-氮杂二环[3.1.0]己烷盐酸盐(以下称为“化合物(I)”)，其结构式如下：
Figure PCTCN2018109908-appb-000001
现有技术WO2016205762A公开了EB-1020的晶型A、晶型B和晶型C。根据WO2016205762A说明书[00232]段记载，晶型C在40℃/75％相对湿度条件下两周后转变为晶型A和B的混合物，且发明人经研究发现现有晶型C在室温下放置一个月后转变为晶型A，可见现有晶型C稳定性差，药物开发风险大。
WO2016205762A说明书[00172]段记载了晶型B的XRPD图谱中存在A的衍射峰，说明晶型B中易混有晶型A，可见晶型B较难纯化，不利于大规模生产和在制剂中的应用。根据WO2016205762A说明书[00179]段可知，现有晶型A和B为针状晶体，针状晶体的可压性和流动性差，不利于制剂压片，且针状结晶通常易带静电，制剂成型较为困难。
因此，本领域仍需要系统全面的开展化合物(I)的晶型筛选，寻找适合药用的优势晶型。本发明人发现了性质优良的EB-1020的晶型CS1。本发明EB-1020的晶型CS1，其在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提纯作用、制剂开发等方面中的至少一方面上存在优势，特别是稳定性好、溶解度高、制剂可加工性强，为含化合物(I)的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物(I)的晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的晶型CS1(以下称作“晶型CS1”)。
一方面，使用Cu-Kα辐射，所述晶型CS1的X射线粉末衍射在衍射角2θ值为21.0°±0.2°、25.3°±0.2°、14.1°±0.2°、16.1°±0.2°处有特征峰。
进一步地，所述晶型CS1的X射线粉末衍射在衍射角2θ值为17.8°±0.2°、20.6°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CS1的X射线粉末衍射在衍射角2θ值为17.8°±0.2°、20.6°±0.2°中的2处有特征峰。
进一步地，所述晶型CS1的X射线粉末衍射在衍射角2θ值为18.3°±0.2°、19.4°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CS1的X射线粉末衍射在衍射角2θ值为18.3°±0.2°、19.4°±0.2°中的2处有特征峰。
另一方面，所述晶型CS1的X射线粉末衍射在衍射角2θ值为21.0°±0.2°、25.3°±0.2°、13.9°±0.2°、14.1°±0.2°、16.1°±0.2°、17.8°±0.2°、20.6°±0.2°、18.3°±0.2°、19.4°±0.2°、21.3°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处有特征峰。
非限制性地，晶型CS1的X射线粉末衍射图如图1所示。
根据本发明的目的，本发明还提供所述晶型CS1的制备方法，所述制备方法包括:称取一定量化合物(I)原料，在惰性气体保护下加热熔融，冷却后得到晶型CS1。
进一步地，所述加热熔融温度为248±2℃。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CS1及药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提的晶型CS1在制备5-羟色胺、去甲肾上腺素和多巴胺三重再摄取抑制剂药物中的用途。
进一步地，本发明提供的晶型CS1在制备治疗神经系统障碍药物中的用途。
更进一步地，本发明提供的晶型CS1在制备治疗注意力缺陷多动障碍药物中的用途。
本发明提供的晶型CS1具有以下有益效果：
(1)本发明提供的晶型原料药具有良好的物理、化学稳定性。
本发明提供的晶型CS1在25℃/60％相对湿度和40℃/75％相对湿度下敞口放置，至少放置6周晶型保持不变，优选的可至少放置4个月晶型保持不变。在80℃条件下至少放置1周晶型保持不变。本发明晶型的化学纯度在99％以上，更优选的在99.9％以上，且在放置过程中化学纯度基本保持不变。此外，本发明的晶型原料药在不同的压力下压制成片后晶型保持不变，具有良好的物理稳定性。
晶型原料药具有良好的物理、化学稳定性。在存储和制剂工艺过程中，晶型CS1不会转 变成其它晶型，且在储存过程中，晶型CS1的化学纯度基本保持不变，从而保证原料药和制剂的质量一致可控。
(2)与现有技术相比，本发明晶型CS1具有更高的溶解度。特别是在FeSSIF中，溶解度是现有技术晶型A和晶型B的2倍左右。
溶解度的升高有利于提高药物的生物利用度，从而提高药物的成药性及药效；另外，溶解度的提高能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(3)与现有技术相比，本发明晶型CS1具有更好的机械稳定性。研磨前后本发明的晶型CS1未发生变化，且结晶度变化较小，具有良好的研磨稳定性。而现有晶型A研磨后结晶度下降明显，现有晶型B研磨后部分转变为晶型A。制剂加工过程中常需要原料药的研磨粉碎，晶型CS1更好的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
(4)晶型CS1在制剂中具有良好的稳定性。本发明晶型CS1与辅料混合做成药物制剂后，在25℃/60％相对湿度和40℃/70％相对湿度条件下放置，放置至少1个月晶型未发生变化，且放置过程中纯度变化量小。
制剂中晶型的转变会导致药物的吸收发生变化，引起药物的毒副作用。晶型CS1在制剂中具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。
(5)本发明晶型CS1具有良好的体外溶出度与溶出速率。晶型CS1制剂在pH＝5.0的醋酸缓冲溶液介质中，60分钟时的累积溶出度达95.29％。
不同的晶型可能导致制剂在体内有不同的溶出速率，直接影响制剂在体内的吸收、分布、排泄、代谢，最终因其生物利用度不同而导致临床药效的差异。良好的溶出度和高的溶出速率是药物被吸收的重要前提。良好的体外溶出度使得药物的吸收程度较高，在体内暴露特性更好，从而提高生物利用度，提高药物的疗效；高的溶出速率使得给药后药物在血浆中能够很快达到最高浓度值，进而确保药物快速起效。
进一步地，本发明提供的晶型CS1还具有以下有益效果：
(1)本发明的晶型CS1为非针状，如类球状或短棒状，流动性更好，更有利于制剂的加工和制备。而现有晶型A和B为针状晶体，针状晶体的可压性和流动性差，不利于制剂压片。
(2)本发明提供的晶型CS1具有良好的可压性。晶型CS1良好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为稳健，改善产品外观，提升 产品质量。良好的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。
(3)本发明晶型CS1具有优良的黏附性。黏附性评价结果表明，晶型CS1的吸附量较低，具有较低的黏附性。低的黏附性可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，低的黏附性还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品的含量均匀度。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线粉末衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CS1是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
附图说明
图1为实施例1所得晶型CS1的XRPD图。
图2为实施例1所得晶型CS1的 1HNMR图。
图3为实施例1所得晶型CS1的DSC图。
图4为实施例1所得晶型CS1的TGA图。
图5为本发明晶型CS1在25℃/60％相对湿度下放置前后的XRPD图(上图为放置前，下图为放置后)。
图6为本发明晶型CS1在40℃/75％相对湿度下放置前后的XRPD图(上图为放置前，下图为放置后)。
图7为本发明晶型CS1在80℃下放置前后的XRPD图(上图为放置前，下图为放置后)。
图8为本发明晶型CS1研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图9为现有技术晶型A研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图10为现有技术晶型B研磨前后的XRPD图(上图为研磨前，下图为研磨后)。
图11为本发明晶型CS1的PLM图。
图12为本发明晶型CS1在3kN压力下压片前后的XRPD图(下图为压片前，上图为压片后)。
图13为本发明晶型CS1在7kN压力下压片前后的XRPD图(下图为压片前，上图为压片后)。
图14为本发明晶型CS1在14kN压力下压片前后的XRPD图(下图为压片前，上图为压片后)。
图15为晶型CS1制剂的体外溶出曲线。
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热
TGA：热重分析
DVS：动态水分吸附
1HNMR：液态核磁氢谱
HPLC：高效液相色谱
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本 发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2018109908-appb-000002
1.540598；
Figure PCTCN2018109908-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的DSC的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的TGA的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
离子色谱(IC)数据采自于ThermoFisher ICS-1100，方法参数如下：
1、色谱柱：IonPac AS18(4×250mm)
2、流动相：25mM NaOH
3、流速：1.0mL/min
4、进样量：25μL
5、柱温：35℃
6、电流：80mA
7、运行时间：6min
本发明中测试纯度的高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)，方法参数如下：
色谱柱：L016#Waters Xbridge C18,150×4.6mm,5μm
流动相：A：25mM KH 2PO 4溶解在H 2O中，pH＝2.5
B：乙腈
洗脱梯度如下：
时间(min) ％B
0.0 10
20.0 40
30.0 80
35.0 80
35.1 10
40.0 10
流速：1.0ml/min
进样量：5μl
检测波长：226nm,参比波长为500nm
柱温：40℃
稀释剂：水:乙腈(体积比)＝1:1
本发明中测试溶解度的高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)，方法参数如下：
色谱柱：L016#Waters Xbridge C18,150×4.6mm,5μm
流动相：A：25mM KH 2PO 4溶解在H 2O中，pH＝2.5
B：乙腈
洗脱梯度如下：
时间(min) ％B
0.0 20
10.0 40
11.0 80
15.0 80
15.1 20
20.0 20
流速：1.0ml/min
进样量：5μl
检测波长：226nm
柱温：40℃
稀释剂：水:乙腈(体积比)＝1:1
核磁共振氢谱数据( 1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是精确的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述化合物(I)指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的化合物(I)为固体粉末形式。
以下实施例中所使用到的EB-1020是根据现有技术制备得到，例如根据WO2016205762A公开的制备方法得到。
具体实施方式
实施例1：制备晶型CS1
称取约15mg的化合物(I)原料，置于DSC中，以10℃/min的速度将其加热至248℃熔融后冷却至室温，得到白色固体。
经检测，所得固体为本发明的晶型CS1，其X射线粉末衍射数据如图1，表1所示。
1HNMR如图2所示，核磁数据为： 1HNMR{(400MHz,d 6-DMSO)δ9.73(s,2H),7.86(dd,J＝18.0,12.1Hz,4H),7.53–7.43(m,2H),7.38(dd,J＝8.6,1.2Hz,1H),3.77(d,J＝11.1Hz,1H),3.64–3.49(m,2H),3.42(d,J＝11.2Hz,1H),2.24(dt,J＝8.3,4.2Hz,1H),1.48(t,J＝5.3Hz,1H),1.28–1.15(m,1H).}
本实施例所得晶型CS1的DSC如图3所示，加热至247℃附近开始出现一个吸热峰，为晶型CS1的熔化吸热峰。
本实施例所得晶型CS1的TGA如图4所示，加热至200℃附近时，具有约1.1％的失重。
离子色谱测定晶型CS1中EB-1020游离碱和氯离子的摩尔比，测试数据如下表2所示。数据表明晶型CS1为单盐酸盐。
表1
衍射角2θ d值 强度％
13.86 6.39 28.78
14.12 6.27 21.15
15.62 5.67 5.26
16.11 5.50 8.54
17.84 4.97 34.58
18.32 4.84 14.82
19.44 4.57 13.74
20.06 4.43 9.30
20.28 4.38 15.31
20.60 4.31 28.24
20.98 4.23 100.00
21.33 4.17 14.90
24.31 3.66 5.19
25.25 3.53 36.57
25.58 3.48 4.66
25.87 3.44 6.17
26.94 3.31 4.48
27.87 3.20 14.89
28.18 3.17 3.27
28.56 3.13 5.59
29.19 3.06 2.47
29.78 3.00 2.35
30.03 2.98 4.03
30.90 2.89 8.31
31.70 2.82 5.88
32.56 2.75 2.87
34.30 2.61 5.47
35.11 2.56 3.46
表2
Figure PCTCN2018109908-appb-000004
实施例2：晶型CS1的稳定性
称取本发明的晶型CS1，分别在25℃/60％相对湿度和40℃/75％相对湿度条件下敞口放置6周，在80℃条件下敞口放置1周，采用HPLC和XRPD测定晶型与化学纯度的变化，结果如表3和表4所示。
表3
Figure PCTCN2018109908-appb-000005
Figure PCTCN2018109908-appb-000006
表4
放置条件 放置1周后纯度 放置2周后纯度 放置6周后纯度
25℃/60％相对湿度 99.93％ 99.95％ 99.94％
40℃/75％相对湿度 99.95％ 99.95％ 99.97％
80℃ 99.82％ —— ——
结果表明，晶型CS1在25℃/60％相对湿度和40℃/75％相对湿度条件下至少可稳定6周，在80℃的苛刻条件下放置至少可稳定1周，且放置过程中晶型CS1的化学纯度基本保持不变。可见，晶型CS1具有良好的物理、化学稳定性。
实施例3：晶型CS1、现有晶型A和晶型B的研磨稳定性对比
分别取本发明的晶型CS1、现有晶型A和晶型B置于研钵中，手动研磨5分钟，本发明晶型CS1研磨前后的XRPD图如图8所示(上图为研磨前，下图为研磨后)，现有晶型A研磨前后的XRPD图如图9所示(上图为研磨前，下图为研磨后)，现有晶型B研磨前后的XRPD图如图10所示(上图为研磨前，下图为研磨后)。
结果表明，研磨前后本发明的晶型CS1未发生变化，且结晶度基本保持不变，具有良好的研磨稳定性。而现有晶型A研磨后结晶度下降明显，出现大量无定形，现有晶型B研磨后发生转晶。表明在一定机械应力的作用下，本发明的晶型CS1相比现有晶型A和B具有更好的稳定性。
实施例4：晶型CS1、现有晶型A和晶型B的动态溶解度对比
胃肠道液体例如FaSSIF(模拟禁食状态肠液)和FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
分别称取本发明的晶型CS1、现有晶型A和晶型B，用FaSSIF和FeSSIF配制成饱和溶液，平衡4小时后用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表5所示。
表5
Figure PCTCN2018109908-appb-000007
结果表明，本发明的晶型CS1相比现有晶型A和晶型B明显具有更高的溶解度。
实施例5：晶型CS1和现有晶型A、晶型B的形貌对比
WO2016205762A说明书[00179]段已记载，现有晶型A和B为针状晶体，针状晶体的可压性和流动性差，不利于制剂压片，且针状结晶通常易带静电，制剂成型较为困难。对本发明制备得到的晶型CS1进行偏光显微镜(PLM)拍摄，PLM图如图11所示。可见本发明的晶型CS1为非针状晶体，如类球状和短棒状，流动性更好，更有利于制剂的加工和制备。
实施例6：晶型CS1在不同压力条件下的物理稳定性
取适量原料药晶型CS1，选择合适的压片模具，在不同压力下压制成形，压片前后进行XRPD测试，测试结果如表6所示。
表6
Figure PCTCN2018109908-appb-000008
结果表明，在不同的压力下，晶型CS1均具有良好的物理稳定性，有利于制剂的稳定制备。
实施例7：晶型CS1的黏附性
将30mg晶型CS1置于直径为8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录冲头累计的最终吸附量、压制过程中的最高吸附量和平均吸附量，实验结果如表7所示。结果表明，晶型CS1具有低的粘附性。
表7
晶型 最高吸附量(mg) 平均吸附量(mg) 累计的最终吸附量(mg)
晶型CS1 0.07 0* 0*
*表示在现有灵敏度条件下未检测出有吸附量。
实施例8：晶型CS1的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲(保证片剂的各向同性)，加入一定量的晶型CS1，采用一定的压力压制成圆形片剂，放置于干燥器中24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。采用下表8中的推荐参数进行测试。抗张强度的结果如表9所示，结果表明本发明的晶型CS1具有良好的可压性。
表8
模具 样品量 压力
Φ6mm圆形平冲 80mg 10kN
表9
晶型 厚度(mm) 直径(mm) 硬度(N) 抗张强度(MPa)
CS1 2.40 6.95 27.3 1.04
实施例9：晶型CS1的制剂制备
按表10的片剂处方用量，将晶型CS1与辅料混合均匀，采用ENERPAC型手动压片机进行压片。压片时，选择直径为7mm的圆形平冲，压力为5±0.5KN，压制成圆形片剂。
表10
Figure PCTCN2018109908-appb-000009
Figure PCTCN2018109908-appb-000010
将片剂用HDPE瓶封装，在25℃/60％相对湿度和40℃/75％相对湿度条件下放置1个月后，取样检测晶型及杂质，考察晶型CS1的制剂稳定性，结果如下表11和表12所示。结果表明，晶型CS1制剂在25℃/60％相对湿度和40℃/75％相对湿度条件下可以至少保持1个月稳定，且纯度变化量小，具有良好的稳定性。
表11晶型CS1在制剂中的物理稳定性
Figure PCTCN2018109908-appb-000011
表12晶型CS1在制剂中的化学稳定性
放置条件 放置时间 起始纯度 放置后纯度 纯度变化量
25℃/60％相对湿度 1个月 99.79％ 99.75％ 0.04％
40℃/75％相对湿度 1个月 99.79％ 99.54％ 0.25％
实施例10：晶型CS1制剂的体外溶出度
对实施例9获得的含CS1的片剂测试体外溶出情况，溶出度的测定按照中国药典2015年版0931溶出度与释放度测定法，条件如下：
溶出介质：pH＝5.0醋酸缓冲溶液
溶出方法：桨法
介质体积：900mL
转速：50rpm
介质温度：37℃
晶型CS1制剂的体外溶出情况如下表13，图15所示，表明以本发明晶型CS1为活性成分的片剂具有良好的溶出度。
表13
Figure PCTCN2018109908-appb-000012
Figure PCTCN2018109908-appb-000013
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (9)

  1. 一种化合物(I)的晶型CS1，其特征在于，其X射线粉末衍射在衍射角2θ值为21.0°±0.2°、25.3°±0.2°、14.1°±0.2°、16.1°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射在衍射角2θ值为17.8°±0.2°、20.6°±0.2°中的1处、或2处有特征峰。
  3. 根据权利要求1所述的晶型CS1，其特征还在于，其X射线粉末衍射在衍射角2θ值为18.3°±0.2°、19.4°±0.2°中的1处、或2处有特征峰。
  4. 一种式(I)化合物晶型CS1的制备方法，其特征在于，所述方法为：称取一定量化合物(I)原料，在惰性气体保护下加热熔融，冷却后得到。
  5. 根据权利要求4所述的制备方法，所述加热熔融温度为248±2℃。
  6. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型CS1及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1所述的晶型CS1在生产制备5-羟色胺、去甲肾上腺素和多巴胺三重再摄取抑制剂药物中的用途。
  8. 权利要求1所述的晶型CS1在制备用于治疗神经系统障碍药物中的用途。
  9. 权利要求1所述的晶型CS1在制备治疗注意力缺陷多动障碍药物中的用途。
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