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WO2016078587A1 - Lu ae58054 hydrochloride crystalline form a, and preparation method and application thereof - Google Patents

Lu ae58054 hydrochloride crystalline form a, and preparation method and application thereof Download PDF

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WO2016078587A1
WO2016078587A1 PCT/CN2015/094921 CN2015094921W WO2016078587A1 WO 2016078587 A1 WO2016078587 A1 WO 2016078587A1 CN 2015094921 W CN2015094921 W CN 2015094921W WO 2016078587 A1 WO2016078587 A1 WO 2016078587A1
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hydrochloride
hydrochloride salt
salt form
solvent
ray powder
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PCT/CN2015/094921
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
刘凯
张晓宇
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苏州晶云药物科技有限公司
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    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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

  • This invention relates to the field of pharmaceutical crystals, and more particularly to a novel crystalline form of Lu AE58054 hydrochloride and its preparation and use.
  • Lu AE58054 also known as Idalopirdine, was first developed by Lilly Pharmaceuticals of the United States and later developed by Lundbeck Pharmaceuticals of Japan and Otsuka Pharmaceuticals of Japan to treat Alzheimer's disease.
  • Lu AE58054 is a selective 5-HT6 receptor antagonist for the treatment of cognitive disorders.
  • 5-HT6 receptor mainly expressed in the human brain, especially in areas related to cognition, such as the hippocampus and frontal cortex. In animal models, 5-HT6 receptor antagonists can improve cognitive function.
  • the clinical phase II results of the drug show that Lu AE58054 helps to improve the cognitive function of patients with moderate Alzheimer's disease treated with donepezil.
  • Lu AE58054 N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, structure As follows:
  • the patent CN104619344 A discloses the preferred hydrochloride salt among the various pharmaceutically acceptable salts of Lu AE58054.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a crystal form of Lu AE58054 hydrochloride.
  • the invention also provides a method and use for the preparation of the crystal.
  • a first object of the present invention is to provide a Lu AE58054 hydrochloride crystal form, designated Lu AE58054 hydrochloride salt form A.
  • Lu AE58054 hydrochloride form A of the present invention has an X-ray powder diffraction pattern (Cu-K ⁇ radiation) at 25 ° C at a 2theta (2 ⁇ ) value of 17.1 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, 21.4 ° There is a characteristic peak at ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A has one or two or three of 2theta values of 12.8 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 ° Diffraction peaks.
  • the diffraction peak is at least two of the 2theta values of 12.8° ⁇ 0.2°, 19.2° ⁇ 0.2°, and 20.7° ⁇ 0.2°, and more preferably, the 2theta value is 12.8° ⁇ 0.2°, 19.2° ⁇
  • the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is also at one or two or three of the 2theta values of 15.3 ° ⁇ 0.2 °, 27.2 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °.
  • the diffraction peak is at least two of the 2theta values of 15.3° ⁇ 0.2°, 27.2° ⁇ 0.2°, 25.5° ⁇ 0.2°, and more preferably, the 2theta value is 15.3° ⁇ 0.2°, 27.2° ⁇
  • the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A has a characteristic peak at a 2theta value of 17.1 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, and at 12.8 ° ⁇ 0.2 ° There are diffraction peaks at 19.2 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 °, 15.3 ° ⁇ 0.2 °, 27.2 ° ⁇ 0.2 °, and 25.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is substantially identical to that of Figure 1.
  • the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is shown in Figure 1 and has peak positions as shown in Table 1 and peak intensities, wherein the peak position is ⁇ 0.2 Change within °.
  • a total of 19 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 2, wherein The peak position varies within ⁇ 0.2°.
  • a total of 16 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 3, wherein The peak position varies within ⁇ 0.2°.
  • a total of 22 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 4, wherein The peak position varies within ⁇ 0.2°.
  • Lu AE58054 hydrochloride form A began to exhibit an endothermic peak at 169 ⁇ 2 °C.
  • Lu AE58054 hydrochloride salt form A is an anhydride.
  • Lu AE58054 hydrochloride salt form A of the present invention is obtained by the following method:
  • Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. Saturating the solution, then cooling to below 10 ° C, until the solids are precipitated, separated, that is; or
  • a second object of the present invention is to provide a process for the preparation of Lu AE58054 hydrochloride salt Form A comprising the following steps a) or b):
  • Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. The solution is saturated, then cooled to below 10 ° C, and the solid is precipitated and separated.
  • the alcohol solvent includes ethanol or the like; and the ether solvent includes tetrahydrofuran or the like.
  • the alcohol solvent is ethanol and the ether solvent is tetrahydrofuran.
  • the stirring is carried out at room temperature, and the stirring time may be from 24 to 72 hours, preferably from 40 to 60 hours.
  • antisolvent as used in the above step a) includes a solvent in which Lu AE58054 hydrochloride is poorly soluble or insoluble at a temperature of from -10 °C to 110 °C.
  • the anti-solvent is an alkane, water, or a mixed solvent of an alkane and water.
  • alkanes are, for example, n-heptane and similar alkanes.
  • the mixed solvent is composed of tetrahydrofuran and water in a volume ratio of 1:5 to 30, preferably in a volume ratio of 1:6 to 20, more preferably in a volume ratio of 1 : 8 ⁇ 15 composition.
  • the molar ratio of Lu AE58054 to hydrochloric acid in Form A of Lu AE58054 hydrochloride is 1:0.95 to 1.05. That is, Lu AE58054 hydrochloride is a monohydrochloride salt.
  • a third object of the present invention is to provide a pharmaceutical preparation for treating Alzheimer's disease comprising the above-mentioned Lu AE58054 hydrochloride salt form A.
  • the pharmaceutical preparations of the invention can be prepared in a manner well known in the pharmaceutical art.
  • a fourth object of the present invention is to provide a use of Lu AE58054 hydrochloride salt Form A as a selective 5-HT6 receptor antagonist, particularly for the preparation of a medicament for the treatment of Alzheimer's disease. And a method of treating Alzheimer's disease using Lu AE58054 hydrochloride form A.
  • the Lu AE58054 hydrochloride salt form A provided by the invention has the following advantages:
  • the Lu AE58054 hydrochloride salt form A provided by the invention has excellent stability, can effectively avoid the occurrence of crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy;
  • the Lu AE58054 hydrochloride salt form A provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and facilitates long-term storage placement of the drug;
  • the crystal form A of Lu AE58054 hydrochloride provided by the invention has higher solubility than the existing hydrochloride salt, is beneficial to drug absorption, and has important significance for reducing drug loading;
  • the Lu AE58054 hydrochloride salt form A of the present invention has superior properties compared with the existing Lu AE58054 hydrochloride solid, which makes it more suitable for use as a selective 5-HT6 receptor. Antagonists and more suitable for the preparation of pharmaceutical preparations for the treatment of Alzheimer's disease.
  • Figure 1 is an XRPD pattern of Lu AE58054 hydrochloride salt form A
  • Figure 2 is a DSC chart of Lu AE58054 hydrochloride salt form A
  • Figure 3 is a TGA diagram of Lu AE58054 hydrochloride salt form A
  • Figure 4 is a DVS diagram of Lu AE58054 hydrochloride salt form A
  • Figure 5 is a comparison of XRPD of Lu AE58054 hydrochloride crystal form A before and after 15 days at 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity (a is the initial crystalline form XRPD, b is XRPD after 15 days at 5 ° C, c is XRPD after 15 days at 25 ° C / 60% relative humidity, and d is XRPD after 15 days at 40 ° C / 75% relative humidity);
  • Figure 6 is a comparison of XRPD of Lu AE58054 hydrochloride Form A placed at 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity for 30 days (a is the pre-placement hydrochloride) XRPD of Form A, e is XRPD placed after 30 days at 5 ° C, f is XRPD placed after 30 days at 25 ° C / 60% relative humidity, and g is placed at 40 ° C / 75% relative humidity for 30 days XRPD);
  • Figure 7 is a comparison of XRPD of Lu AE58054 hydrochloride crystal form A before and after 90 days at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity (a is the pre-placement hydrochloride) XRPD of Form A, h is XRPD placed after 90 days at 5 ° C, i is XRPD after 90 days of placement at 25 ° C / 60% relative humidity, j is placed at 40 ° C / 75% relative humidity for 90 days XRPD);
  • Figure 8 is a comparison of XRPD of Lu AE58054 hydrochloride Form A placed at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 1 year ago (a is pre-placement hydrochloride) XRPD of Form A, k is XRPD placed at 5 ° C for 1 year, m is XRPD placed at 25 ° C / 60% relative humidity for 1 year, and n is placed at 40 ° C / 75% relative humidity 1 XRPD after the year);
  • Figure 9 is a graph of Lu AE58054 hydrochloride salt form A and the hydrochloride salt obtained according to the method of patent CN1610547A.
  • the solids were tested for solubility comparison curves in SGF after 1 hour, 4 hours, and 24 hours respectively (the upper graph is the hydrochloride salt form A, and the lower graph is the hydrochloride solid in the patent CN1610547A);
  • Figure 10 is a graph comparing the solubility of Lu AE58054 hydrochloride Form A and the hydrochloride solid prepared according to the method of Patent CN1610547A in FaSSIF after 1 hour, 4 hours, and 24 hours, respectively.
  • A the figure below is the hydrochloride solid in the patent CN1610547A);
  • Figure 11 is a graph comparing the solubility of Lu AE58054 hydrochloride crystal form A and the hydrochloride solids prepared according to the method of patent CN1610547A in pure water after 1 hour, 4 hours, and 24 hours, respectively.
  • Type A the figure below is the hydrochloride solid in patent CN1610547A).
  • test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the existing Lu AE58054 hydrochloride solids are obtained according to the preparation method disclosed in Example 402 of Patent CN1610547A.
  • Solids of the hydrochloride salt include, but are not limited to, bulk or powdery solids.
  • 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 described in 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 differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in 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
  • Lu AE58054 hydrochloride solid 10.1 mg was dissolved in 0.05 mL of ethanol to give a clear solution. Under stirring, 0.4 mL of pure water was added dropwise until turbidity occurred, and stirring was continued for 48 hours at room temperature. The solid was collected to give Lu AE58054 hydrochloride salt form A.
  • the X-ray powder diffraction data of the obtained hydrochloride salt form A is shown in Table 1, and the XRPD pattern is shown in Fig. 1.
  • Table 1 The X-ray powder diffraction data of the obtained hydrochloride salt form A is shown in Table 1, and the XRPD pattern is shown in Fig. 1.
  • the diffraction peaks at 2theta values of 17.05°, 17.85° and 21.37° are characteristic peaks.
  • the diffraction peaks at 2theta values of 12.76°, 19.22°, and 20.73° are important peaks.
  • the 2theta values are the second most important peaks at 15.26°, 27.2, and 25.38°.
  • the DSC chart of the obtained hydrochloride salt form A is shown in Fig. 2, in which an endothermic peak is shown, indicating that the salt crystal form A has a melting point onset temperature of 169 ⁇ 2 °C.
  • the TGA chart of the obtained hydrochloride salt form A is shown in Fig. 3, which shows a 1.5% weight loss gradient when the hydrochloride salt form A is heated to the vicinity of 173 ° C.
  • the TGA test results show that the crystal form A has excellent thermal stability. .
  • hydrochloride salt form A was subjected to high performance liquid chromatography and ion chromatography. The results showed that the ratio of the free base to the chloride ion of Lu AE58054 was 1:0.96, indicating that the hydrochloride form A was a monohydrochloride.
  • Lu AE58054 hydrochloride salt form A A solid solution of 9.5 mg of Lu AE58054 hydrochloride was dissolved in 0.025 mL of tetrahydrofuran to give a clear solution. Under stirring, 0.3 mL of n-heptane was added dropwise until turbidity occurred, and stirring was continued for 48 hours at room temperature. The solid was collected to give Lu AE58054 hydrochloride salt form A.
  • the X-ray powder diffraction data of the hydrochloride salt form A obtained in this example is shown in Table 2.
  • Table 2 The X-ray powder diffraction data of the hydrochloride salt form A obtained in this example is shown in Table 2.
  • the diffraction peaks at 2theta values of 17.03°, 17.87° and 21.35° are characteristic peaks.
  • the diffraction peaks at 2theta values of 12.72°, 19.24°, and 20.77° are important peaks.
  • the 2theta values are the second most important peaks at 15.27°, 27.30°, and 25.41°.
  • the X-ray powder diffraction data of the hydrochloride salt form A obtained in this example is shown in Table 3. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 17.11°, 17.91° and 21.43° are characteristic peaks. The diffraction peaks at 2theta values of 12.82°, 19.29°, and 20.81° are important peaks. The 2theta values are the sub-significant peaks at 15.33°, 27.27°, and 25.47°.
  • Table 4 shows the wettability test of crystal form A
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the hydrochloride salt form A of the present invention has a weight gain of 0.29% after being equilibrated at 80% humidity, and is slightly hygroscopic according to the definition criteria of the wettability weight gain.
  • the hydrochloride salt form A prepared by the invention is placed at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 1 year, respectively, at 15 days, 30 days, 90 days and The crystal form stability was measured by sampling for 1 year, and the sample purity was measured at 15 days, 30 days, and 90 days. See Table 5 for the experimental results.
  • the XRPD of Form A after 15 days, 30 days, 90 days, 1 year and a week after being placed under the above three conditions is shown in Fig. 5, Fig. 6, Fig. 7, and Fig. 8, respectively.
  • Form A of the present invention has very excellent stability.
  • the hydrochloride salt form A prepared by the present invention and the hydrochloride solid prepared according to the patent CN1610547A are respectively prepared by using SGF (simulated artificial gastric juice) of pH 1.8, pH 6.5 FaSSIF (artificial intestinal juice under fasting state) and pure water.
  • SGF simulated artificial gastric juice
  • pH 1.8 pH 1.8
  • FaSSIF artificial intestinal juice under fasting state
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours in a saturated solution.
  • HPLC high performance liquid chromatography
  • the hydrochloride salt form A of the present invention has a significantly improved solubility compared to the hydrochloride solids of the patent CN1610547A.

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Abstract

The present invention relates to Lu AE58054 hydrochloride crystalline form A, and preparation method and application thereof, Lu AE58054 hydrochloride crystalline form A having a characteristic peak at a point where 2theta value is 17.1°±0.2°、17.8°±0.2°、21.4°±0.2° in an X-ray powder diffraction pattern (Cu-Kα radiation) under 25°C. Having a simple preparation process, a low cost, a good stability, a low moisture absorbance property, a high solubility, Crystalline form A is beneficial to absorption of drugs, and has a great significance in reducing drug load and preparing pharmaceutical formulation for curing Alzheimer disease.

Description

Lu AE58054的盐酸盐晶型A及其制备方法和用途Salt crystal form A of Lu AE58054 and preparation method and use thereof 技术领域Technical field
本发明涉及药物晶体领域，更具体地说，涉及一种Lu AE58054盐酸盐的新晶型及其制备方法和用途。This invention relates to the field of pharmaceutical crystals, and more particularly to a novel crystalline form of Lu AE58054 hydrochloride and its preparation and use.
背景技术Background technique
Lu AE58054，又名Idalopirdine，是由美国礼来(Lilly)制药首先研发，后由丹麦灵北(Lundbeck)制药和日本大冢(Otsuka)制药公司共同开发的治疗阿尔茨海默氏症的药物。Lu AE58054是一种选择性5-HT6受体拮抗剂，用于治疗认知障碍。5-HT6受体，主要表达于人体脑内，尤其与认知相关的区域，如海马、额叶皮层。在动物模型中，5-HT6受体拮抗剂能够改善认知功能。该药物的临床II期结果显示，Lu AE58054有助于改善药物多奈哌齐(donepezil)治疗的中度阿尔茨海默氏症患者的认知功能。目前灵北(Lundbeck)制药和大冢(Otsuka)制药公司已经启动了Lu AE58054的III期临床研究。Lu AE58054的化学名称为N-[2-(6-氟-1H-吲哚-3-基)乙基]-3-(2,2,3,3-四氟丙氧基)苄胺，结构如下所示：Lu AE58054, also known as Idalopirdine, was first developed by Lilly Pharmaceuticals of the United States and later developed by Lundbeck Pharmaceuticals of Japan and Otsuka Pharmaceuticals of Japan to treat Alzheimer's disease. Lu AE58054 is a selective 5-HT6 receptor antagonist for the treatment of cognitive disorders. 5-HT6 receptor, mainly expressed in the human brain, especially in areas related to cognition, such as the hippocampus and frontal cortex. In animal models, 5-HT6 receptor antagonists can improve cognitive function. The clinical phase II results of the drug show that Lu AE58054 helps to improve the cognitive function of patients with moderate Alzheimer's disease treated with donepezil. Currently, Lundbeck Pharmaceuticals and Otsuka Pharmaceuticals have launched Phase III clinical studies of Lu AE58054. The chemical name of Lu AE58054 is N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, structure As follows:
Figure PCTCN2015094921-appb-000001
Figure PCTCN2015094921-appb-000001
对于Lu AE58054来说，专利CN104619344 A公开了在Lu AE58054的多种可药用盐中优选盐酸盐。For Lu AE58054, the patent CN104619344 A discloses the preferred hydrochloride salt among the various pharmaceutically acceptable salts of Lu AE58054.
但是目前为止，尚未见任何关于Lu AE58054盐酸盐的晶型的相关报道，而根据CN1610547A报道的Lu AE58054盐酸盐的制备方法，所制得的Lu AE58054盐酸盐固体的各项性质特别是稳定性，溶解度等均不甚理想。However, so far, no relevant reports on the crystal form of Lu AE58054 hydrochloride have been reported, and the properties of the prepared Lu AE58054 hydrochloride solids are particularly according to the preparation method of Lu AE58054 hydrochloride reported by CN1610547A. Stability, solubility, etc. are not ideal.
发明内容Summary of the invention
本发明所要解决的技术问题是：克服现有技术的不足，提供一种Lu AE58054盐酸盐的晶体形式。The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a crystal form of Lu AE58054 hydrochloride.
本发明同时还提供所述晶体的制备方法和用途。The invention also provides a method and use for the preparation of the crystal.
因此，本发明的第一个目的是提供一种Lu AE58054盐酸盐晶型，命名为Lu  AE58054盐酸盐晶型A。Accordingly, a first object of the present invention is to provide a Lu AE58054 hydrochloride crystal form, designated Lu AE58054 hydrochloride salt form A.
其中，本发明的Lu AE58054盐酸盐晶型A在25℃下的X射线粉末衍射图(Cu-Kα辐射)在2theta(2θ)值为17.1°±0.2°、17.8°±0.2°、21.4°±0.2°处具有特征峰。Wherein the Lu AE58054 hydrochloride form A of the present invention has an X-ray powder diffraction pattern (Cu-Kα radiation) at 25 ° C at a 2theta (2θ) value of 17.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.4 ° There is a characteristic peak at ±0.2°.
进一步地，Lu AE58054盐酸盐晶型A的X射线粉末衍射图还在2theta值为12.8°±0.2°、19.2°±0.2°、20.7°±0.2°中的一处或二处或三处具有衍射峰。优选地，在2theta值为12.8°±0.2°、19.2°±0.2°、20.7°±0.2°中的至少二处具有衍射峰，更优选地，在2theta值为12.8°±0.2°、19.2°±0.2°、20.7°±0.2°这三处均具有衍射峰。Further, the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A has one or two or three of 2theta values of 12.8 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.7 ° ± 0.2 ° Diffraction peaks. Preferably, the diffraction peak is at least two of the 2theta values of 12.8°±0.2°, 19.2°±0.2°, and 20.7°±0.2°, and more preferably, the 2theta value is 12.8°±0.2°, 19.2°± There are diffraction peaks at all of 0.2°, 20.7°±0.2°.
更进一步地，Lu AE58054盐酸盐晶型A的X射线粉末衍射图还在2theta值为15.3°±0.2°、27.2°±0.2°、25.5°±0.2°中的一处或二处或三处具有衍射峰。优选地，在2theta值为15.3°±0.2°、27.2°±0.2°、25.5°±0.2°中的至少二处具有衍射峰，更优选地，在2theta值为15.3°±0.2°、27.2°±0.2°、25.5°±0.2°这三处均具有衍射峰。Further, the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is also at one or two or three of the 2theta values of 15.3 ° ± 0.2 °, 27.2 ° ± 0.2 °, 25.5 ° ± 0.2 °. Has a diffraction peak. Preferably, the diffraction peak is at least two of the 2theta values of 15.3°±0.2°, 27.2°±0.2°, 25.5°±0.2°, and more preferably, the 2theta value is 15.3°±0.2°, 27.2°± There are diffraction peaks at all of 0.2°, 25.5°±0.2°.
优选地，Lu AE58054盐酸盐晶型A的X射线粉末衍射图在2theta值为17.1°±0.2°、17.8°±0.2°、21.4°±0.2°处具有特征峰，且在12.8°±0.2°、19.2°±0.2°、20.7°±0.2°、15.3°±0.2°、27.2°±0.2°、25.5°±0.2°处均具有衍射峰。Preferably, the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A has a characteristic peak at a 2theta value of 17.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.4 ° ± 0.2 °, and at 12.8 ° ± 0.2 ° There are diffraction peaks at 19.2 ° ± 0.2 °, 20.7 ° ± 0.2 °, 15.3 ° ± 0.2 °, 27.2 ° ± 0.2 °, and 25.5 ° ± 0.2 °.
根据本发明的一个具体实施方案，Lu AE58054盐酸盐晶型A的X射线粉末衍射图基本上与图1一致。According to a particular embodiment of the invention, the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is substantially identical to that of Figure 1.
在本发明的一个具体实施例中，Lu AE58054盐酸盐晶型A的X射线粉末衍射图如图1所示且具有如表1所示的峰位置以及峰强度，其中，峰位置在±0.2°内变化。In a specific embodiment of the invention, the X-ray powder diffraction pattern of Lu AE58054 hydrochloride form A is shown in Figure 1 and has peak positions as shown in Table 1 and peak intensities, wherein the peak position is ± 0.2 Change within °.
在本发明的另一个具体实施例中，Lu AE58054盐酸盐晶型A的X射线粉末衍射图中显示了共19个衍射峰，这些特征峰的位置以及峰强度如表2所示，其中，峰位置在±0.2°内变化。In another embodiment of the present invention, a total of 19 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 2, wherein The peak position varies within ±0.2°.
在本发明的另一个具体实施例中，Lu AE58054盐酸盐晶型A的X射线粉末衍射图中显示了共16个衍射峰，这些特征峰的位置以及峰强度如表3所示，其中，峰位置在±0.2°内变化。In another embodiment of the present invention, a total of 16 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 3, wherein The peak position varies within ±0.2°.
在本发明的另一个具体实施例中，Lu AE58054盐酸盐晶型A的X射线粉末衍射图中显示了共22个衍射峰，这些特征峰的位置以及峰强度如表4所示，其中，峰位置在±0.2°内变化。In another embodiment of the present invention, a total of 22 diffraction peaks are shown in the X-ray powder diffraction pattern of Lu AE58054 hydrochloride salt form A, and the positions and peak intensities of these characteristic peaks are shown in Table 4, wherein The peak position varies within ±0.2°.
进一步地，当进行差示扫描量热分析时，所述Lu AE58054盐酸盐晶型A在169±2℃开始出现吸热峰。Further, when differential scanning calorimetry was performed, the Lu AE58054 hydrochloride form A began to exhibit an endothermic peak at 169 ± 2 °C.
进一步地，Lu AE58054盐酸盐晶型A为无水物。Further, Lu AE58054 hydrochloride salt form A is an anhydride.
进一步地，本发明所述的Lu AE58054盐酸盐晶型A通过如下方法制得： Further, the Lu AE58054 hydrochloride salt form A of the present invention is obtained by the following method:
a)将Lu AE58054盐酸盐固体溶解到醇类或醚类溶剂或二者的混合溶剂中，然后通过加入反溶剂进行搅拌析晶，即得；或a) dissolving Lu AE58054 hydrochloride solid in an alcohol or ether solvent or a mixed solvent of the two, and then stirring and crystallization by adding an anti-solvent;
b)在50℃～80℃的条件下，将Lu AE58054盐酸盐固体溶于水与选自醇类和醚类溶剂中的一种或多种的混合溶剂中，形成Lu AE58054盐酸盐的饱和溶液，然后降温至10℃以下，待固体析出，分离，即得；或b) Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. Saturating the solution, then cooling to below 10 ° C, until the solids are precipitated, separated, that is; or
本发明的第二个目的是提供一种Lu AE58054盐酸盐晶型A的制备方法，其包括如下步骤a)或b)：A second object of the present invention is to provide a process for the preparation of Lu AE58054 hydrochloride salt Form A comprising the following steps a) or b):
a)将Lu AE58054盐酸盐固体溶解到醇类或醚类溶剂或二者的混合溶剂中，然后通过加入反溶剂进行搅拌析晶，即得；或a) dissolving Lu AE58054 hydrochloride solid in an alcohol or ether solvent or a mixed solvent of the two, and then stirring and crystallization by adding an anti-solvent;
b)在50℃～80℃的条件下，将Lu AE58054盐酸盐固体溶于水与选自醇类和醚类溶剂中的一种或多种的混合溶剂中，形成Lu AE58054盐酸盐的饱和溶液，然后降温至10℃以下，待固体析出，分离，即得。b) Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. The solution is saturated, then cooled to below 10 ° C, and the solid is precipitated and separated.
上述步骤a)或b)中，醇类溶剂包括乙醇等；醚类溶剂包括四氢呋喃等。优选地，醇类溶剂为乙醇，醚类溶剂为四氢呋喃。In the above step a) or b), the alcohol solvent includes ethanol or the like; and the ether solvent includes tetrahydrofuran or the like. Preferably, the alcohol solvent is ethanol and the ether solvent is tetrahydrofuran.
根据本发明的一个具体实施方案，步骤a)中，在室温下进行搅拌，搅拌时间可以为24～72小时，优选为40～60个小时。According to a particular embodiment of the invention, in step a), the stirring is carried out at room temperature, and the stirring time may be from 24 to 72 hours, preferably from 40 to 60 hours.
上述步骤a)中所使用的术语“反溶剂”，包括在-10℃～110℃的温度条件下，Lu AE58054盐酸盐难溶或不溶的溶剂。优选地，步骤a)中，所述反溶剂为烷烃、水、或烷烃与水的混合溶剂。优选的烷烃为例如正庚烷和类似烷烃。The term "antisolvent" as used in the above step a) includes a solvent in which Lu AE58054 hydrochloride is poorly soluble or insoluble at a temperature of from -10 °C to 110 °C. Preferably, in step a), the anti-solvent is an alkane, water, or a mixed solvent of an alkane and water. Preferred alkanes are, for example, n-heptane and similar alkanes.
根据本发明的另一个具体实施方案，步骤b)中，所述混合溶剂由四氢呋喃与水按体积比1:5～30组成，优选按体积比1:6～20组成，更优选按体积比1:8～15组成。According to another embodiment of the present invention, in the step b), the mixed solvent is composed of tetrahydrofuran and water in a volume ratio of 1:5 to 30, preferably in a volume ratio of 1:6 to 20, more preferably in a volume ratio of 1 : 8 ~ 15 composition.
根据本发明的又一个具体实施方案，所述的Lu AE58054盐酸盐晶型A中Lu AE58054与盐酸的摩尔比为1：0.95～1.05。即，Lu AE58054盐酸盐为单盐酸盐。According to still another embodiment of the present invention, the molar ratio of Lu AE58054 to hydrochloric acid in Form A of Lu AE58054 hydrochloride is 1:0.95 to 1.05. That is, Lu AE58054 hydrochloride is a monohydrochloride salt.
本发明的第三个目的是提供一种用于治疗阿尔茨海默氏症的药物制剂，其包含上述的Lu AE58054盐酸盐晶型A。A third object of the present invention is to provide a pharmaceutical preparation for treating Alzheimer's disease comprising the above-mentioned Lu AE58054 hydrochloride salt form A.
本发明的药物制剂可通过制药领域中熟知的方式进行制备。The pharmaceutical preparations of the invention can be prepared in a manner well known in the pharmaceutical art.
本发明的第四个目的是提供一种Lu AE58054盐酸盐晶型A用作选择性5-HT6受体拮抗剂的用途，尤其是用于制备治疗阿尔茨海默氏症的药物中的用途，以及一种使用Lu AE58054盐酸盐晶型A治疗阿尔茨海默氏症的方法。A fourth object of the present invention is to provide a use of Lu AE58054 hydrochloride salt Form A as a selective 5-HT6 receptor antagonist, particularly for the preparation of a medicament for the treatment of Alzheimer's disease. And a method of treating Alzheimer's disease using Lu AE58054 hydrochloride form A.
本发明提供的Lu AE58054盐酸盐晶型A与现有技术相比，具有如下优点：Compared with the prior art, the Lu AE58054 hydrochloride salt form A provided by the invention has the following advantages:
(1)本发明提供的Lu AE58054盐酸盐晶型A具有优良的稳定性，能有效避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变； (1) The Lu AE58054 hydrochloride salt form A provided by the invention has excellent stability, can effectively avoid the occurrence of crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and efficacy;
(2)本发明提供的Lu AE58054盐酸盐晶型A引湿性低，不易受高湿度影响而潮解，方便药物的长期贮存放置；(2) The Lu AE58054 hydrochloride salt form A provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and facilitates long-term storage placement of the drug;
(3)本发明提供的Lu AE58054盐酸盐晶型A比已有的盐酸盐固体溶解度更高，有利于药物吸收，对减小载药量具有重要的意义；(3) The crystal form A of Lu AE58054 hydrochloride provided by the invention has higher solubility than the existing hydrochloride salt, is beneficial to drug absorption, and has important significance for reducing drug loading;
(4)本发明提供的Lu AE58054盐酸盐晶型A制备工艺简单，成本低廉，对未来该药物的优化和开发具有重要价值。(4) The preparation method of Lu AE58054 hydrochloride salt form A provided by the invention is simple and low in cost, and has great value for optimization and development of the drug in the future.
综上，本发明的Lu AE58054盐酸盐晶型A与已有的Lu AE58054盐酸盐固体相比，具有更优异的各项性能，这使得它更适于用作选择性5-HT6受体拮抗剂和更适于制备治疗阿尔茨海默氏症的药物制剂。In summary, the Lu AE58054 hydrochloride salt form A of the present invention has superior properties compared with the existing Lu AE58054 hydrochloride solid, which makes it more suitable for use as a selective 5-HT6 receptor. Antagonists and more suitable for the preparation of pharmaceutical preparations for the treatment of Alzheimer's disease.
附图说明DRAWINGS
图1为Lu AE58054盐酸盐晶型A的XRPD图；Figure 1 is an XRPD pattern of Lu AE58054 hydrochloride salt form A;
图2为Lu AE58054盐酸盐晶型A的DSC图；Figure 2 is a DSC chart of Lu AE58054 hydrochloride salt form A;
图3为Lu AE58054盐酸盐晶型A的TGA图；Figure 3 is a TGA diagram of Lu AE58054 hydrochloride salt form A;
图4为Lu AE58054盐酸盐晶型A的DVS图；Figure 4 is a DVS diagram of Lu AE58054 hydrochloride salt form A;
图5为Lu AE58054盐酸盐晶型A分别放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下15天前后的XRPD对比图(a为起始晶型的XRPD，b为放置在5℃下15天后的XRPD，c为放置在25℃/60％相对湿度下15天后的XRPD，d为放置在40℃/75％相对湿度下15天后的XRPD)；Figure 5 is a comparison of XRPD of Lu AE58054 hydrochloride crystal form A before and after 15 days at 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity (a is the initial crystalline form XRPD, b is XRPD after 15 days at 5 ° C, c is XRPD after 15 days at 25 ° C / 60% relative humidity, and d is XRPD after 15 days at 40 ° C / 75% relative humidity);
图6为Lu AE58054盐酸盐晶型A分别放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下30天前后的XRPD对比图(a为放置前盐酸盐晶型A的XRPD，e为放置在5℃下30天后的XRPD，f为放置在25℃/60％相对湿度下30天后的XRPD，g为放置在40℃/75％相对湿度下30天后的XRPD)；Figure 6 is a comparison of XRPD of Lu AE58054 hydrochloride Form A placed at 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity for 30 days (a is the pre-placement hydrochloride) XRPD of Form A, e is XRPD placed after 30 days at 5 ° C, f is XRPD placed after 30 days at 25 ° C / 60% relative humidity, and g is placed at 40 ° C / 75% relative humidity for 30 days XRPD);
图7为Lu AE58054盐酸盐晶型A分别放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下90天前后的XRPD对比图(a为放置前盐酸盐晶型A的XRPD，h为放置在5℃下90天后的XRPD，i为放置在25℃/60％相对湿度下90天后的XRPD，j为放置在40℃/75％相对湿度下90天后的XRPD)；Figure 7 is a comparison of XRPD of Lu AE58054 hydrochloride crystal form A before and after 90 days at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity (a is the pre-placement hydrochloride) XRPD of Form A, h is XRPD placed after 90 days at 5 ° C, i is XRPD after 90 days of placement at 25 ° C / 60% relative humidity, j is placed at 40 ° C / 75% relative humidity for 90 days XRPD);
图8为Lu AE58054盐酸盐晶型A分别放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下1年前后的XRPD对比图(a为放置前盐酸盐晶型A的XRPD，k为放置在5℃下1年后的XRPD，m为放置在25℃/60％相对湿度下1年后的XRPD，n为放置在40℃/75％相对湿度下1年后的XRPD)；Figure 8 is a comparison of XRPD of Lu AE58054 hydrochloride Form A placed at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 1 year ago (a is pre-placement hydrochloride) XRPD of Form A, k is XRPD placed at 5 ° C for 1 year, m is XRPD placed at 25 ° C / 60% relative humidity for 1 year, and n is placed at 40 ° C / 75% relative humidity 1 XRPD after the year);
图9为Lu AE58054盐酸盐晶型A和按照专利CN1610547A中方法制得的盐酸盐 固体分别在1小时、4小时、24小时后检测SGF中的溶解度对比曲线(上图为盐酸盐晶型A，下图为专利CN1610547A中的盐酸盐固体)；Figure 9 is a graph of Lu AE58054 hydrochloride salt form A and the hydrochloride salt obtained according to the method of patent CN1610547A. The solids were tested for solubility comparison curves in SGF after 1 hour, 4 hours, and 24 hours respectively (the upper graph is the hydrochloride salt form A, and the lower graph is the hydrochloride solid in the patent CN1610547A);
图10为Lu AE58054盐酸盐晶型A和按照专利CN1610547A方法制得的盐酸盐固体分别在1小时、4小时、24小时后检测FaSSIF中的溶解度对比曲线(上图为盐酸盐晶型A，下图为专利CN1610547A中的盐酸盐固体)；Figure 10 is a graph comparing the solubility of Lu AE58054 hydrochloride Form A and the hydrochloride solid prepared according to the method of Patent CN1610547A in FaSSIF after 1 hour, 4 hours, and 24 hours, respectively. A, the figure below is the hydrochloride solid in the patent CN1610547A);
图11为Lu AE58054盐酸盐晶型A和按照专利CN1610547A方法制得的盐酸盐固体分别在1小时、4小时、24小时后检测纯水中的溶解度对比曲线(上图为盐酸盐晶型A，下图为专利CN1610547A中的盐酸盐固体)。Figure 11 is a graph comparing the solubility of Lu AE58054 hydrochloride crystal form A and the hydrochloride solids prepared according to the method of patent CN1610547A in pure water after 1 hour, 4 hours, and 24 hours, respectively. Type A, the figure below is the hydrochloride solid in patent CN1610547A).
具体实施方式detailed description
以下结合具体的实施例对本发明做进一步详细的说明，但本发明不限于以下实施例。实施例中未注明的条件为常规条件。The present invention will be further described in detail below with reference to specific embodiments, but the invention is not limited to the following examples. Conditions not specified in the examples are conventional conditions.
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的已有的Lu AE58054盐酸盐固体是根据专利CN1610547A中实施例402公开的制备方法获得，所述盐酸盐的固体包括但不限于块状或粉末状固体。In the following examples, the test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the existing Lu AE58054 hydrochloride solids are obtained according to the preparation method disclosed in Example 402 of Patent CN1610547A. Solids of the hydrochloride salt include, but are not limited to, bulk or powdery solids.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric analysis
DVS：动态水分吸附DVS: Dynamic moisture adsorption
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：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 described in the present invention are as follows:
X射线反射参数：Cu-Kα辐射X-ray reflection parameters: Cu-Kα radiation
Kα1
Figure PCTCN2015094921-appb-000002
：1.540598；Kα2
Figure PCTCN2015094921-appb-000003
：1.544426Kα1
Figure PCTCN2015094921-appb-000002
:1.540598;Kα2
Figure PCTCN2015094921-appb-000003
:1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kV (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气 Protective gas: nitrogen
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
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：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:
温度：25℃Temperature: 25 ° C
载气，流速：N2,200毫升/分钟Carrier gas, flow rate: N 2 , 200 ml / min
单位时间质量变化：0.002％/分钟Unit time quality change: 0.002% / minute
相对湿度范围：0％RH-95％RHRelative humidity range: 0%RH-95%RH
实施例1Example 1
Lu AE58054盐酸盐晶型A的制备方法：Preparation method of Lu AE58054 hydrochloride salt form A:
将10.1mg Lu AE58054盐酸盐固体溶解于0.05mL乙醇中，得到澄清溶液。搅拌条件下，逐滴加入0.4mL纯水至出现浑浊，室温条件下继续搅拌48小时。收集固体得到Lu AE58054盐酸盐晶型A。10.1 mg of Lu AE58054 hydrochloride solid was dissolved in 0.05 mL of ethanol to give a clear solution. Under stirring, 0.4 mL of pure water was added dropwise until turbidity occurred, and stirring was continued for 48 hours at room temperature. The solid was collected to give Lu AE58054 hydrochloride salt form A.
所得盐酸盐晶型A的X射线粉末衍射数据如表1所示，XRPD图如图1所示。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为17.05°、17.85°、21.37°处的衍射峰为特征峰。2theta值为12.76°、19.22°、20.73°处的衍射峰为重要的峰。2theta值为15.26°、27.2、25.38°处的衍射峰为次重要的峰。The X-ray powder diffraction data of the obtained hydrochloride salt form A is shown in Table 1, and the XRPD pattern is shown in Fig. 1. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 17.05°, 17.85° and 21.37° are characteristic peaks. The diffraction peaks at 2theta values of 12.76°, 19.22°, and 20.73° are important peaks. The 2theta values are the second most important peaks at 15.26°, 27.2, and 25.38°.
表1晶型A的X射线粉末衍射数据Table 1 X-ray powder diffraction data of Form A
2theta2theta d间隔d interval 强度％strength%
17.0517.05 5.205.20 100.00100.00
21.3721.37 4.164.16 83.2483.24
17.8517.85 4.974.97 27.3327.33
15.2615.26 5.815.81 20.1320.13
19.2219.22 4.624.62 18.8518.85
20.7320.73 4.284.28 10.0410.04
12.7612.76 6.946.94 8.158.15
16.3816.38 5.415.41 7.757.75
25.3825.38 3.513.51 7.087.08
23.0223.02 3.863.86 5.405.40
25.1025.10 3.553.55 5.195.19
24.3324.33 3.663.66 4.974.97
8.478.47 10.4410.44 4.914.91
27.2027.20 3.283.28 4.824.82
25.7425.74 3.463.46 4.794.79
18.5418.54 4.784.78 4.254.25
30.1030.10 2.972.97 4.054.05
34.6234.62 2.592.59 1.771.77
所得盐酸盐晶型A的DSC图如图2所示，其中显示有一个吸热峰，显示盐酸盐晶型A的熔点起始温度为169±2℃。The DSC chart of the obtained hydrochloride salt form A is shown in Fig. 2, in which an endothermic peak is shown, indicating that the salt crystal form A has a melting point onset temperature of 169 ± 2 °C.
所得盐酸盐晶型A的TGA图如图3，显示加热盐酸盐晶型A至173℃附近时，有1.5％的重量损失梯度，TGA测试结果表明该晶型A具有优异的热稳定性。The TGA chart of the obtained hydrochloride salt form A is shown in Fig. 3, which shows a 1.5% weight loss gradient when the hydrochloride salt form A is heated to the vicinity of 173 ° C. The TGA test results show that the crystal form A has excellent thermal stability. .
所得盐酸盐晶型A的经高效液相色谱和离子色谱法检测，结果显示Lu AE58054的游离碱与氯离子的配比是1:0.96，表明盐酸盐晶型A为单盐酸盐。The obtained hydrochloride salt form A was subjected to high performance liquid chromatography and ion chromatography. The results showed that the ratio of the free base to the chloride ion of Lu AE58054 was 1:0.96, indicating that the hydrochloride form A was a monohydrochloride.
实施例2Example 2
Lu AE58054盐酸盐晶型A的制备方法：Preparation method of Lu AE58054 hydrochloride salt form A:
将9.5mg Lu AE58054盐酸盐固体溶解于0.025mL四氢呋喃中，得到的澄清溶液。搅拌条件下，逐滴加入0.3mL正庚烷至出现浑浊，室温条件下继续搅拌48小时。收集固体得到Lu AE58054盐酸盐晶型A。A solid solution of 9.5 mg of Lu AE58054 hydrochloride was dissolved in 0.025 mL of tetrahydrofuran to give a clear solution. Under stirring, 0.3 mL of n-heptane was added dropwise until turbidity occurred, and stirring was continued for 48 hours at room temperature. The solid was collected to give Lu AE58054 hydrochloride salt form A.
本实施例得到的盐酸盐晶型A的X射线粉末衍射数据如表2所示。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为17.03°、17.87°、21.35°处的衍射峰为特征峰。2theta值为12.72°、19.24°、20.77°处的衍射峰为重要的峰。2theta值为15.27°、27.30°、25.41°处的衍射峰为次重要的峰。The X-ray powder diffraction data of the hydrochloride salt form A obtained in this example is shown in Table 2. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 17.03°, 17.87° and 21.35° are characteristic peaks. The diffraction peaks at 2theta values of 12.72°, 19.24°, and 20.77° are important peaks. The 2theta values are the second most important peaks at 15.27°, 27.30°, and 25.41°.
表2晶型A的X射线粉末衍射数据Table 2 X-ray powder diffraction data of Form A
2theta2theta d间隔d interval 强度％strength%
19.2419.24 4.614.61 100.00100.00
21.3521.35 4.164.16 82.5282.52
17.0317.03 5.215.21 76.9376.93
17.8717.87 4.974.97 39.2639.26
25.4125.41 3.503.50 38.0338.03
20.7720.77 4.284.28 35.1835.18
25.1425.14 3.543.54 27.6427.64
15.2715.27 5.805.80 26.0026.00
18.5818.58 4.784.78 25.6525.65
22.0622.06 4.034.03 24.3424.34
27.3027.30 3.273.27 16.3416.34
23.1023.10 3.853.85 13.9013.90
24.3624.36 3.653.65 12.4412.44
28.6828.68 3.113.11 12.0212.02
16.3516.35 5.425.42 11.4711.47
30.0430.04 2.982.98 10.8710.87
12.7212.72 6.966.96 6.696.69
32.9532.95 2.722.72 5.395.39
30.5130.51 2.932.93 3.803.80
实施例3Example 3
Lu AE58054盐酸盐晶型A的制备方法：Preparation method of Lu AE58054 hydrochloride salt form A:
将10.0mg Lu AE58054的盐酸盐固体溶解于0.6mL四氢呋喃：水＝2：25(v:v，体积比)的混合溶剂中，在50℃条件下放置30分钟。过滤上述溶液，将所得滤液立即放入5℃的恒温箱中，搅拌48小时。收集固体得到Lu AE58054盐酸盐晶型A。The hydrochloride solid of 10.0 mg of Lu AE58054 was dissolved in a mixed solvent of 0.6 mL of tetrahydrofuran:water = 2:25 (v:v, by volume), and allowed to stand at 50 ° C for 30 minutes. The solution was filtered, and the resulting filtrate was immediately placed in an incubator at 5 ° C and stirred for 48 hours. The solid was collected to give Lu AE58054 hydrochloride salt form A.
本实施例得到的盐酸盐晶型A的X射线粉末衍射数据如表3所示。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为17.11°、17.91°、21.43°处的衍射峰为特征峰。2theta值为12.82°、19.29°、20.81°处的衍射峰为重要的峰。2theta值为15.33°、27.27°、25.47°处的衍射峰为次重要的峰。The X-ray powder diffraction data of the hydrochloride salt form A obtained in this example is shown in Table 3. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 17.11°, 17.91° and 21.43° are characteristic peaks. The diffraction peaks at 2theta values of 12.82°, 19.29°, and 20.81° are important peaks. The 2theta values are the sub-significant peaks at 15.33°, 27.27°, and 25.47°.
表3晶型A的X射线粉末衍射数据Table 3 X-ray powder diffraction data of Form A
2theta2theta d间隔d interval 强度％strength%
17.1117.11 5.185.18 100.00100.00
21.4321.43 4.154.15 74.6874.68
15.3315.33 5.785.78 16.2016.20
17.9117.91 4.954.95 14.7914.79
3.213.21 27.4927.49 13.6613.66
19.2919.29 4.604.60 11.4811.48
12.8212.82 6.906.90 7.687.68
8.548.54 10.3610.36 6.866.86
20.8120.81 4.274.27 6.026.02
28.7328.73 3.113.11 3.883.88
25.4725.47 3.503.50 3.813.81
23.0623.06 3.863.86 3.283.28
25.7925.79 3.453.45 3.043.04
27.2727.27 3.273.27 3.033.03
30.1930.19 2.962.96 2.732.73
34.6934.69 2.592.59 1.381.38
实施例4Example 4
Lu AE58054盐酸盐晶型A的引湿性实验：Lubricity test of Lu AE58054 hydrochloride crystal form A:
取本发明的盐酸盐晶型A约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表4所示。引湿性实验的DVS图如图4所示。About 10 mg of the hydrochloride salt form A of the present invention was tested for its wettability by a dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 4. The DVS pattern of the wettability experiment is shown in Figure 4.
表4晶型A的引湿性实验Table 4 shows the wettability test of crystal form A
Figure PCTCN2015094921-appb-000004
Figure PCTCN2015094921-appb-000004
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：Defining the characteristics of wettability and the definition of wettability weight gain (Chinese Pharmacopoeia 2010 edition Appendix XIX J drug wettability test guidelines, experimental conditions: 25 ° C ± 1 ° C, 80% relative humidity):
潮解：吸收足量水分形成液体Deliquescence: absorb enough water to form a liquid
极具引湿性：引湿增重不小于15％Very hygroscopic: the wetting weight gain is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Humidity: Wet weight gain is less than 15% but not less than 2%
略有引湿性：引湿增重小于2％但不小于0.2％Slightly wettability: wetting gain is less than 2% but not less than 0.2%
无或几乎无引湿性：引湿增重小于0.2％No or almost no wettability: wetting gain is less than 0.2%
结果表明，本发明的盐酸盐晶型A在80％湿度下平衡后增重0.29％，根据引湿性增重的界定标准，属于略有引湿性。The results show that the hydrochloride salt form A of the present invention has a weight gain of 0.29% after being equilibrated at 80% humidity, and is slightly hygroscopic according to the definition criteria of the wettability weight gain.
实施例5Example 5
Lu AE58054盐酸盐晶型A的稳定性实验：Stability test of Lu AE58054 hydrochloride crystal form A:
将本发明制备得到的盐酸盐晶型A放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下放置1年，分别于15天、30天、90天和1年取样测定其晶型稳定性，于15天、30天和90天取样测定其样品纯度。实验结果参见表5。晶型A在放置在上述三个条件下15天、30天、90天、1年前后的XRPD分别如图5、图6、图7、图8所示。The hydrochloride salt form A prepared by the invention is placed at 5 ° C, 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 1 year, respectively, at 15 days, 30 days, 90 days and The crystal form stability was measured by sampling for 1 year, and the sample purity was measured at 15 days, 30 days, and 90 days. See Table 5 for the experimental results. The XRPD of Form A after 15 days, 30 days, 90 days, 1 year and a week after being placed under the above three conditions is shown in Fig. 5, Fig. 6, Fig. 7, and Fig. 8, respectively.
表5晶型A的稳定性实验数据表Table 5 Stability Test Data Sheet for Form A
Figure PCTCN2015094921-appb-000005
Figure PCTCN2015094921-appb-000005
结合表6和图5-8可见，本发明的晶型A具有非常优异的稳定性。As can be seen in conjunction with Table 6 and Figures 5-8, Form A of the present invention has very excellent stability.
实施例6Example 6
Lu AE58054盐酸盐晶型A与专利CN1610547A中盐酸盐固体的溶解度对比实验：Comparison of the solubility of Lu AE58054 hydrochloride crystal form A with the hydrochloride solid in patent CN1610547A:
将本发明制备得到的盐酸盐晶型A和根据专利CN1610547A制备的盐酸盐固体分别用pH 1.8的SGF(模拟人工胃液)，pH6.5 FaSSIF(空腹状态下人工肠液)和纯水配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表6所示，盐酸盐晶型A和专利CN1610547A制备的盐酸盐固体在SGF、FaSSIF和纯水中的溶解度曲线分别如图9、图10、图11所示。The hydrochloride salt form A prepared by the present invention and the hydrochloride solid prepared according to the patent CN1610547A are respectively prepared by using SGF (simulated artificial gastric juice) of pH 1.8, pH 6.5 FaSSIF (artificial intestinal juice under fasting state) and pure water. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours in a saturated solution. The experimental results are shown in Table 6. The solubility curves of the hydrochloride solids prepared by the hydrochloride salt form A and the patent CN1610547A in SGF, FaSSIF and pure water are shown in Fig. 9, Fig. 10 and Fig. 11, respectively.
表6盐酸盐晶型A与专利CN1610547A中盐酸盐固体的溶解度数据对比 Table 6 Comparison of Solubility Data of Hydrochloride Salt Solids in Salt Form A and Patent CN1610547A
Figure PCTCN2015094921-appb-000006
Figure PCTCN2015094921-appb-000006
结合表6和图9-11可见，本发明的盐酸盐晶型A与专利CN1610547A中盐酸盐固体相比，溶解性有显著提高。As can be seen by combining Table 6 and Figures 9-11, the hydrochloride salt form A of the present invention has a significantly improved solubility compared to the hydrochloride solids of the patent CN1610547A.
上述实施例仅限于说明本发明的技术构思及特点，其目的在于让本领域技术人员能够了解本发明的内容并据以实施，应该理解，这些实施例并不能够用来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。 The above embodiments are only intended to illustrate the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the contents of the present invention and to implement them. It should be understood that these embodiments are not intended to limit the scope of the present invention. . Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (15)

  1. 一种如下结构式所示的Lu AE58054的盐酸盐的晶型A，a crystal form A of the hydrochloride salt of Lu AE58054 as shown in the following structural formula,
    Figure PCTCN2015094921-appb-100001
    Figure PCTCN2015094921-appb-100001
    其特征在于：使用Cu-Kα辐射，所述Lu AE58054盐酸盐晶型A在25℃下的X射线粉末衍射图在2theta值为17.1°±0.2°、17.8°±0.2°、21.4°±0.2°处具有特征峰。It is characterized in that the X-ray powder diffraction pattern of the Lu AE58054 hydrochloride crystal form A at 25 ° C is 17.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.4 ° ± 0.2 using Cu-Kα radiation. There is a characteristic peak at °.
  2. 根据权利要求1所述的Lu AE58054盐酸盐晶型A，其特征在于：所述Lu AE58054盐酸盐的晶型A的X射线粉末衍射图在2theta值为12.8°±0.2°、19.2°±0.2°、20.7°±0.2°中的一处或二处或三处具有衍射峰。The Lu AE58054 hydrochloride salt form A according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form A of the Lu AE58054 hydrochloride is 22.8 ° ± 0.2 °, 19.2 ° ± One or two or three of 0.2°, 20.7°±0.2° have diffraction peaks.
  3. 根据权利要求1或2所述的Lu AE58054盐酸盐晶型A，其特征在于：所述Lu AE58054盐酸盐的晶型A的X射线粉末衍射图在2theta值为15.3°±0.2°、27.2°±0.2°、25.5°±0.2°中的一处或二处或三处具有衍射峰。Lu AE58054 hydrochloride salt form A according to claim 1 or 2, characterized in that the X-ray powder diffraction pattern of the crystalline form A of the Lu AE58054 hydrochloride is at a value of 15.3 ° ± 0.2 °, 27.2 There are diffraction peaks at one or two or three of °±0.2° and 25.5°±0.2°.
  4. 根据权利要求1至3任一项所述的Lu AE58054盐酸盐晶型A，其特征在于：所述Lu AE58054盐酸盐的晶型A的X射线粉末衍射图在2theta值为17.1°±0.2°、17.8°±0.2°、21.4°±0.2°、12.8°±0.2°、19.2°±0.2°、20.7°±0.2°、15.3°±0.2°、27.2°±0.2°、25.5°±0.2°处具有衍射峰。Lu AE58054 hydrochloride salt form A according to any one of claims 1 to 3, characterized in that the X-ray powder diffraction pattern of the crystalline form A of the Lu AE58054 hydrochloride is at a 2theta value of 17.1 ° ± 0.2 °, 17.8 ° ± 0.2 °, 21.4 ° ± 0.2 °, 12.8 ° ± 0.2 °, 19.2 ° ± 0.2 °, 20.7 ° ± 0.2 °, 15.3 ° ± 0.2 °, 27.2 ° ± 0.2 °, 25.5 ° ± 0.2 ° Has a diffraction peak.
  5. 根据权利要求1至4中任一项所述的Lu AE58054盐酸盐晶型A，其特征在于：当进行差示扫描量热分析时，所述晶型A在169±2℃开始出现吸热峰。The Lu AE58054 hydrochloride salt form A according to any one of claims 1 to 4, characterized in that the crystal form A begins to absorb heat at 169 ± 2 ° C when subjected to differential scanning calorimetry. peak.
  6. 根据权利要求1至5中任一项所述的Lu AE58054盐酸盐晶型A，其特征在于，所述晶型A通过如下方法制得：The Lu AE58054 hydrochloride salt form A according to any one of claims 1 to 5, wherein the crystal form A is obtained by the following method:
    a)将Lu AE58054盐酸盐固体溶解到醇类或醚类溶剂或二者的混合溶剂中，优选乙醇或四氢呋喃中，然后通过加入反溶剂进行搅拌析晶，即得；或a) dissolving Lu AE58054 hydrochloride solids in an alcohol or ether solvent or a mixed solvent of the two, preferably in ethanol or tetrahydrofuran, and then stirring and crystallization by adding an anti-solvent;
    b)在50℃～80℃的条件下，将Lu AE58054盐酸盐固体溶于水与选自醇类和醚类溶剂中的一种或多种的混合溶剂中，形成Lu AE58054盐酸盐的饱和溶液，然后降温至10℃以下，待固体析出，分离，即得。b) Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. The solution is saturated, then cooled to below 10 ° C, and the solid is precipitated and separated.
  7. 一种Lu AE58054盐酸盐晶型A的制备方法，其特征在于：所述方法包括步骤a)或b)： A method for preparing Lu AE58054 hydrochloride salt form A, characterized in that the method comprises the steps a) or b):
    a)将Lu AE58054盐酸盐固体溶解到醇类或醚类溶剂或二者的混合溶剂中，然后通过加入反溶剂进行搅拌析晶，即得；或a) dissolving Lu AE58054 hydrochloride solid in an alcohol or ether solvent or a mixed solvent of the two, and then stirring and crystallization by adding an anti-solvent;
    b)在50℃～80℃的条件下，将Lu AE58054盐酸盐固体溶于水与选自醇类和醚类溶剂中的一种或多种的混合溶剂中，形成Lu AE58054盐酸盐的饱和溶液，然后降温至10℃以下，待固体析出，分离，即得。b) Lu AE58054 hydrochloride solid is dissolved in a mixed solvent of water and one or more selected from the group consisting of alcohols and ether solvents at 50 ° C to 80 ° C to form Lu AE58054 hydrochloride. The solution is saturated, then cooled to below 10 ° C, and the solid is precipitated and separated.
  8. 根据权利要求7所述的制备方法，其特征在于：步骤a)或b)中，所述的醇类溶剂包括乙醇；所述醚类溶剂包括四氢呋喃。The preparation method according to claim 7, wherein in the step a) or b), the alcohol solvent comprises ethanol; and the ether solvent comprises tetrahydrofuran.
  9. 根据权利要求7所述的制备方法，其特征在于：步骤a)中，在室温下进行搅拌，搅拌时间为24～72小时，优选为40～60个小时。The production method according to claim 7, wherein in the step a), the stirring is carried out at room temperature, and the stirring time is 24 to 72 hours, preferably 40 to 60 hours.
  10. 根据权利要求7至9中任一项所述的制备方法，其特征在于：步骤a)中，所述反溶剂为烷烃、水、或烷烃与水的混合溶剂。The preparation method according to any one of claims 7 to 9, wherein in the step a), the anti-solvent is an alkane, water, or a mixed solvent of an alkane and water.
  11. 根据权利要求10所述的制备方法，其特征在于：所述烷烃为正庚烷。The process according to claim 10, wherein the alkane is n-heptane.
  12. 根据权利要求7或8所述的制备方法，其特征在于：步骤b)中，所述混合溶剂由四氢呋喃与水按体积比1:5～30组成，优选按体积比1:6～20组成，更优选按体积比1:8～15组成。The preparation method according to claim 7 or 8, wherein in the step b), the mixed solvent is composed of tetrahydrofuran and water in a volume ratio of 1:5 to 30, preferably in a volume ratio of 1:6 to 20, More preferably, it is composed of a volume ratio of 1:8 to 15.
  13. 权利要求1至6中任一项所述的Lu AE58054盐酸盐晶型A用作选择性5-HT6受体拮抗剂的用途。Use of Lu AE58054 hydrochloride salt form A according to any one of claims 1 to 6 as a selective 5-HT6 receptor antagonist.
  14. 根据权利要求13所述的用途，其特征在于，所述选择性5-HT6受体拮抗剂用作治疗阿尔茨海默氏症的药物。The use according to claim 13, wherein the selective 5-HT6 receptor antagonist is used as a medicament for the treatment of Alzheimer's disease.
  15. 一种用于治疗阿尔茨海默氏症的药物制剂，其特征在于：包含权利要求1至6中任一项所述的Lu AE58054盐酸盐晶型A。 A pharmaceutical preparation for the treatment of Alzheimer's disease, characterized by comprising the Lu A AE58054 hydrochloride salt form A according to any one of claims 1 to 6.
PCT/CN2015/094921 2014-11-18 2015-11-18 Lu ae58054 hydrochloride crystalline form a, and preparation method and application thereof WO2016078587A1 (en)

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WO2018013686A1 (en) * 2016-07-12 2018-01-18 Concert Pharmaceuticals, Inc. Deuterated idalopirdine
EP3333154A1 (en) 2016-12-07 2018-06-13 Sandoz Ag Crystalline form of a selective 5-ht6 receptor antagonist
US10071963B2 (en) 2014-07-04 2018-09-11 H. Lundbeck A/S Polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the treatment of Alzheimer's disease

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CN102656146A (en) * 2009-12-23 2012-09-05 H.隆德贝克有限公司 Processes for the manufacture of a pharmaceutically active agent

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CN102656146A (en) * 2009-12-23 2012-09-05 H.隆德贝克有限公司 Processes for the manufacture of a pharmaceutically active agent

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10071963B2 (en) 2014-07-04 2018-09-11 H. Lundbeck A/S Polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the treatment of Alzheimer's disease
WO2018013686A1 (en) * 2016-07-12 2018-01-18 Concert Pharmaceuticals, Inc. Deuterated idalopirdine
EP3333154A1 (en) 2016-12-07 2018-06-13 Sandoz Ag Crystalline form of a selective 5-ht6 receptor antagonist

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