WO2015180680A1 - 一种环肽类化合物的结晶粉末及其制备方法和用途 - Google Patents

一种环肽类化合物的结晶粉末及其制备方法和用途 Download PDF

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WO2015180680A1
WO2015180680A1 PCT/CN2015/080224 CN2015080224W WO2015180680A1 WO 2015180680 A1 WO2015180680 A1 WO 2015180680A1 CN 2015080224 W CN2015080224 W CN 2015080224W WO 2015180680 A1 WO2015180680 A1 WO 2015180680A1
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crystalline powder
formula
compound
solid
cyclic peptide
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PCT/CN2015/080224
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English (en)
French (fr)
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刘石东
王修胜
唐志军
季晓铭
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上海天伟生物制药有限公司
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Priority to JP2016546139A priority Critical patent/JP6437004B2/ja
Priority to US15/314,799 priority patent/US10138275B2/en
Priority to EP15799703.2A priority patent/EP3150622B1/en
Publication of WO2015180680A1 publication Critical patent/WO2015180680A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K1/00General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Definitions

  • the present invention relates to a crystalline powder of a compound, and more particularly to a crystalline powder of a cyclic peptide compound, a process for the preparation thereof and use thereof.
  • Micafungin is a new type of echinocandin antifungal drug that destroys the structure of fungal cells and dissolves them by inhibiting the ⁇ -1,3-D-glucan synthase, a component of the fungal cell wall. Micafungin is widely used to treat various infections, especially those caused by Aspergillus, Candida, Cryptococcus, Mucor, Actinomycetes, Histoplasma, Dermatophytes and Fusarium.
  • Micafungin Sodium (also known as FK463) is the active pharmaceutical ingredient of the drug Mycamine.
  • the chemical structure of micafungin sodium salt is shown in formula I:
  • the compound of the formula I is a polypeptide compound with poor stability, and the degradation product formation may affect its quality and efficacy during transportation or long-term storage. Further, the compound of the formula I is difficult to be crystallized, and is usually in an amorphous state.
  • the compound of formula I is degraded and the quality is degraded.
  • WO 03/018615 of Fujisawa Pharmaceutical Co., Ltd. discloses a novel crystal form of the compound of the formula I and a preparation method thereof.
  • WO03/018615 is prepared by dissolving an amorphous compound of the formula I in an aqueous alcoholic solution or an aqueous acetone solution, and adding a solvent such as ethyl acetate, dichloromethane, acetone and acetonitrile to obtain a needle-like crystal of the compound B82 of the formula I.
  • the crystal was crystallized in an organic solvent, and the morphology under the microscope was needle-like crystals.
  • X-ray powder diffraction had peaks at 2 ⁇ angles of 4.6°, 5.5°, 9.0°, 9.8°, and 16.9°.
  • the inventors performed the B82 type needle crystal according to the method of Example 1 of the patent WO03/018615. Preparation, observation of the obtained crystal using an optical microscope, the size of about 1 um, using a Malven particle size analyzer to determine d50 in the range of 0.2-1.0 um, is a fine needle-like crystal.
  • the inventors found in the process of subsequent filtration, drying and the like of the B82 type crystal that since the B82 type crystal is substantially in the form of a fine needle, the crystal of the compound of the formula I is difficult to filter and the operation time is long.
  • the solvent content of the compound of formula I has a Dry/Wet (dry to wet weight ratio) of about 0.25 before the crystals are dried, and the crystals enclose a large amount of organic solvent.
  • the drying process it is necessary to increase the drying temperature or prolong the drying time so that the solvent content meets the requirements of the drug substance.
  • the use of the above drying process increases the degradation products of the compound of formula I, which seriously affects the quality and stability of the drug substance.
  • the inventors found that the bulk density of B82 needle crystals is about 0.8g/mL, which is denser, which is not conducive to the evaporation of solvent in the drying process, which directly affects the crystal powder.
  • the B82 type crystal is exposed to the environment, it is easy to absorb moisture and has poor stability.
  • Another object of the present invention is to provide a process for the preparation of the crystalline powder.
  • Yet another object of the invention is to provide the use of the crystalline powder.
  • the present invention provides a crystalline powder of a compound of formula I.
  • the crystalline powder has a bulk density of less than 0.6 g/mL.
  • the crystalline powder has a bulk density of less than 0.5 g/mL.
  • the crystalline powder has a d50 of from 10 to 100 um.
  • the crystalline powder has a d50 of from 20 to 50 um.
  • the crystalline powder has a d10 of from 1 to 9 um.
  • the crystalline powder has a d10 of from 1 to 5 um.
  • the crystalline powder has a d50 of 10-100 um before solid-liquid separation.
  • the crystalline powder has a d50 of 20 to 50 um before solid-liquid separation.
  • the crystalline powder has a d10 of from 1 to 9 um prior to solid-liquid separation.
  • the crystalline powder has a d10 of 3-6 um before solid-liquid separation.
  • the B82 type needle crystal disclosed in WO03/018615 has a fine needle-like morphology, is difficult to filter, is difficult to dry, and has poor stability.
  • the inventors screened the crystallization solvent system using a different solvent combination in a three-phase system. After a long period of research, the inventors have unexpectedly discovered that a regular columnar crystal can be obtained in a specific three-phase solvent system. Subsequently, we conducted a large number of solvent screening tests to finally obtain a crystalline powder of a compound of formula I with better stability and better morphology, and determined the preparation process.
  • the crystal of the present invention has a columnar shape, a large crystal particle, a small bulk density, easy filtration, and easy removal of a solvent in the crystal.
  • the inventors have surprisingly found through research that the compound of the formula I is cooled or added poorly in an aqueous solution of methanol/isobutanol, methanol/isopropanol or methanol/n-propanol, ie a three-phase system solution or a four-phase solvent system.
  • a solvent or the like which lowers the solubility of the compound of the formula I in a solution, a columnar crystal of a compound of the formula I, which is a crystalline powder of the compound of the formula I.
  • the compound of the formula I obtained after filtration after crystallization has a high Dry/Wet (dry to wet weight ratio) before drying, a small organic solvent content, and a small bulk density after drying, and the organic solvent is easily removed.
  • Powder bulk density by comparing the bulk and tightness of the powder, can be seen as a measure of the relative importance of the interaction of the particles.
  • Methods for measuring the bulk density of a powder are known in the art, for example, using a cylinder measurement method, a volume measurement method, a container measurement method, or the like.
  • the invention The crystalline powder of the compound of formula I is determined by a cylinder measurement having a bulk density of less than 0.7 g/mL, more preferably less than 0.6 g/mL; optimally less than 0.5 g/mL.
  • Particle size distribution was determined using a Malvern particle sizer 2600C to analyze the size distribution (including d10 and d50) of the crystal before solid-liquid separation of the crystallizing liquid.
  • d10 and d50 are known ways of indicating the particle size distribution
  • d50 means a certain particle size value such that the size of 50 vol/% of the particles is smaller than the value.
  • D10 means a certain particle size value such that the size of 10 vol/% of the particles is smaller than the stated value.
  • a preferred method of determining d10 and d50 is laser diffraction.
  • the crystalline powder of the compound of formula I of the present invention has a d50 of from 10 to 100 um and a d10 of from 1 to 9 um.
  • d50 is at 20-50 um and d10 is at 1-5 um.
  • the crystalline powder of the compound of formula I has a d50 of 10-100 um and a d10 of 1-9 um before solid-liquid separation. More preferably, its d50 is at 20-50 um and d10 is at 3-6 um.
  • the crystalline powder of the compound of the formula I of the present invention is a columnar crystal under an optical microscope.
  • the crystalline powder of the compound of formula I of the present invention has a shape substantially identical to that of Figure 1 prior to solid-liquid separation.
  • HPLC High Performance Liquid Chromatography
  • Diluent phosphate buffer of water
  • Detection wavelength 210 nm
  • Injection volume 10 ⁇ l.
  • GC Gas chromatography separation and detection of trace impurities in compounds is an accurate, qualitative and quantitative analytical method.
  • the content of the organic solvent in the crystalline powder of the compound of the formula I obtained by the preparation of the present invention is determined by gas chromatography (GC).
  • X-ray powder diffraction also known as “X-ray polycrystalline diffraction (XRD or XRPD)
  • XRD X-ray polycrystalline diffraction
  • An X-ray powder diffractometer is used to generate a series of diffraction patterns when X-rays are transmitted through the crystal, in which different diffraction lines and their intensity are determined by a certain atomic group, thereby determining the crystal structure.
  • Methods for determining X-ray powder diffraction of crystals are known in the art. For example, a copper radiation target is used to acquire a map using an X-ray powder diffractometer of the RIGAKU D/max 2550VB/PC model at a scanning speed of 2° per minute.
  • the crystalline powder of the compound of the formula I of the present invention has a specific crystal form and has a specific characteristic peak in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the crystalline powder of the compound of the present invention has characteristic peaks at the following 2 theta angles: 4.4 ⁇ 0.2 °, 5.2 ⁇ 0.2 °, 8.5 ⁇ 0.2 °, 9.6 ⁇ 0.2 °;
  • the map also has characteristic peaks at the following 2 theta angles: 7.5 ⁇ 0.2°, 8.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 13.7 ⁇ 0.2°, 22.5 ⁇ 0.2°; in another preferred embodiment
  • the map also has characteristic peaks at the following 2 theta angles: 12.6 ⁇ 0.2 °, 14.9 ⁇ 0.2 °, 15.6 ⁇ 0.2 °, 25.1 ⁇ 0.2 °.
  • the crystalline powder of the compound of formula I of the present invention has characteristic peaks on the X-ray powder diffraction pattern at the following 2 theta angles: 4.4 ⁇ 0.1 °, 5.2 ⁇ 0.1 °, 8.5 ⁇ 0.1 °, 9.6 ⁇ 0.1 °;
  • the map also has characteristic peaks at the following 2 theta angles: 7.5 ⁇ 0.1 °, 8.8 ⁇ 0.1 °, 16.6 ⁇ 0.1 °, 13.7 ⁇ 0.1 °, 22.5 ⁇ 0.1 °;
  • the map also has characteristic peaks at the following 2 theta angles: 12.6 ⁇ 0.1 °, 14.9 ⁇ 0.1 °, 15.6 ⁇ 0.1 °, 25.1 ⁇ 0.1 °.
  • the crystalline powder of the compound of formula I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.
  • the present invention provides a process for the preparation of a crystalline powder of a compound of formula I, the process comprising the steps of:
  • step (c) The solid obtained in the step (b) is vacuum dried together with the aqueous system to obtain the crystalline powder.
  • the alcohol mixed solution in the step (a) is selected from the group consisting of methanol/isobutanol, methanol/isopropanol, and methanol/n-propanol.
  • the volume ratio of the two alcohols is 0.01-100. It is preferably 0.05-20, more preferably 0.1-10.
  • the total volume ratio of the alcohol to water is from 0.1 to 100, preferably from 0.5 to 10, more preferably from 1 to 7.
  • the temperature of dissolution in the step (a) is from 10 to 50 ° C, preferably from 20 to 40 ° C.
  • step (a) comprises from 1 to 500 mg/ml, preferably from 5 to 100 mg/ml, more preferably from 10 to 50 mg/ml, based on the total volume of the solution.
  • organic solvent (i) in the step (b) is selected from the group consisting of n-propanol, isopropanol, isobutanol, methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate.
  • the temperature of the cooling described in the step (b) is -40 to 35 ° C, preferably -20 to 35 ° C, more preferably -10 to 30 ° C, and most preferably -5 to 15 ° C.
  • volume ratio of the organic solvent (i) in the step (b) to the mixed alcohol solution in the step (a) is from 0.1 to 50, preferably from 0.1 to 10, more preferably from 1 to 5.
  • the crystalline powder of the compound of formula I provided by the present invention can also be used directly for the preparation of a medicament for the treatment of fungal infections.
  • a pharmaceutical composition comprising a crystalline powder of a compound of formula I, and a pharmaceutically acceptable carrier can be provided.
  • crystal refers to a solid in which a molecule or atomic complex is in a particular arrangement.
  • solid-liquid separation refers to the process of separating a solid and a liquid by filtration or the like after the compound of the formula I is crystallized in a solvent.
  • “Dry/Wet” and “dry to wet weight ratio” are used interchangeably and refer to the ratio of the weight of the solvent free of the compound to the weight of the solvent.
  • the wet weight of the crystal in the present invention is obtained by filtering the solid obtained by crystallization until no significant droplets flow out and weighing.
  • the compound of formula I can be obtained using methods conventional in the art, such as, but not limited to, the preparation of the compound as reported in patent WO 96/11210; it is also commercially available, such as, but not limited to, such as Fujisawa Corporation of Japan.
  • the term "pharmaceutically acceptable carrier” refers to a carrier for the administration of a therapeutic agent, including various excipients and diluents.
  • the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which are not excessively toxic after administration. Suitable carriers are well known to those of ordinary skill in the art. A thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991).
  • Pharmaceutically acceptable carriers in the compositions can include liquids such as water, saline, glycerol and ethanol.
  • auxiliary substances such as disintegrants, wetting agents, emulsifiers, pH buffering substances and the like may also be present in these carriers.
  • a crystalline powder of a compound of formula I which is excellent in morphology and which is easy to filter and dry.
  • a method for preparing a crystalline powder of the compound of the formula I is provided, and the method is easy to solid-liquid separation and easy to dry to remove residual solvent, which is very suitable for industrial production.
  • Figure 1 is a photomicrograph of a crystal of a compound of formula I before solid-liquid separation.
  • Figure 2 shows an X-ray powder diffraction (XRPD) pattern of a crystalline powder of a compound of formula I.
  • the units in the weight percent by volume in the present invention are well known to those skilled in the art and, for example, refer to the weight of the solute in a 100 ml solution.
  • a solid amorphous powder of the compound of formula I is prepared according to the method of U.S. Patent No. 7,199,248.
  • Example 1 of the patent WO03/018615 a needle crystal was obtained, which was a B82 type crystal.
  • the wet crystals were weighed after filtration, and the dry-wet weight ratio was calculated to be 0.25.
  • the wet solid was weighed to calculate a dry-wet weight ratio of 0.45.
  • the filtered solid is placed in a vacuum drying oven, and a tray of tap water is placed in the bottom of the drying box, and dried in a vacuum to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a disk of ice water mixture was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying oven to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying cabinet, and dried in a vacuum to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a disk of ice water mixture was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying oven to obtain a crystalline powder.
  • the filtered solid was placed in a vacuum drying oven, and a disk of pure water was placed in the bottom of the drying oven, and dried in a vacuum to obtain a crystalline powder.
  • the filtered solid is placed in a vacuum drying oven, and a tray of tap water is placed in the bottom of the drying box, and dried in a vacuum to obtain a crystalline powder.
  • Examples 2-10 A crystalline powder of a compound of formula I was prepared using 1-4 g of a compound of formula I, with a filtration time of up to only 27 min, while 0.5 g of a compound of formula I was used in Comparative Example 1 to prepare a B82 type crystal with a small scale. However, the filtration time is much longer than that of Examples 2-10. It can be seen that the crystalline powder of the compound of the formula I prepared by the present invention has obvious advantages in the filtration process.
  • the comparative examples were compared with the drying process of the samples obtained in the examples.
  • the precipitated 5 g solids were prepared according to the methods of Examples 2-10 and Comparative Examples 1-3, and placed at 25 ° C, and dried under vacuum with an aqueous system until detected by GC. The results showed that the organic solvent was not contained, and the drying time was compared. Analyze sample purity. The specific results are shown in the following table:
  • Example 2 0.45 99.68% 99.68% 7h
  • Example 3 0.43 99.63% 99.61% 6.5h
  • Example 4 0.55 99.64% 99.64% 9h
  • Example 5 0.6 99.52% 99.47% 10h
  • Example 6 0.49 99.61% 99.6% 8.5h
  • Example 7 0.6 99.65% 99.57% 9.5h
  • Example 8 0.38 99.52% 99.46% 6h
  • Example 9 0.54 99.42% 99.38% 8.5h
  • Example 10 0.56 99.5% 99.43% 9h
  • Comparative example 1 0.85 99.26% 97.96% 25h Comparative example 2 / 98.82% 96.21% 30h Comparative example 3 / 98.74% 96.17% 32h
  • Crystal powder of formula I lactose Anhydrous citric Sodium hydroxide 2.5g 20g Moderate amount Moderate amount
  • Example 2 0.2 g of the crystalline powder of the compound of the formula I obtained by the method of Example 2 was prepared, and an eye drop was prepared in accordance with Example 2 of US2007249546A1.

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Abstract

本发明公开了一种环肽类化合物的结晶粉末,其结构如式I所示,并且公开了它们的制备方法和用途。

Description

一种环肽类化合物的结晶粉末及其制备方法和用途 技术领域
本发明涉及化合物结晶粉末,更具体地涉及一种环肽类化合物的结晶粉末及其制备方法和用途。
背景技术
米卡芬净(Micafungin)是一种新型棘白菌素类抗真菌药物,通过抑制真菌细胞壁的组成成分β-1,3-D-葡聚糖合成酶,破坏真菌细胞结构,使之溶解。米卡芬净广泛用于治疗各种感染,尤其是曲霉菌、念珠菌、隐球菌、毛霉菌、放线菌、组织胞浆菌、皮肤癣菌和镰刀菌等引起的感染。
米卡芬净钠(Micafungin Sodium,又称FK463)是药品Mycamine(米开民)的活性药物成分。米卡芬净钠盐的化学结构如式I所示:
Figure PCTCN2015080224-appb-000001
5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(R)-2-氨甲酰基-1-羟乙基]-11,20,21,25-四羟基-15-[(R)-1-羟乙基]-26-甲基-2,5,8,14,17,23-六氧-18-[4-[5-(4-戊氧基苯基)异恶唑-3-基]苯甲酰氨基]-1,4,7,13,16,22-六氮杂三环[22.3.0.09,13]二十七-6-基]-1,2-二羟乙 基]-2-羟苯基硫酸钠。
式I化合物为多肽类化合物,稳定性差,在运输或长期保存时,会有降解产物生成影响其质量和药效。且式I化合物难于被结晶,通常情况下为无定形状态。
美国专利6,107,458和7,199,248以及WO96/11210公开了制备和提纯式I化合物的方法。其中,美国专利7,199,248将米卡芬净DIPEA(二异丙基乙基胺)盐通过过滤和色谱分离提纯后,再使用丙酮和乙酸乙酯沉淀,得到无定型的式I化合物。
Atsushi Ohigashi等人在Journal of Synthesit Organic Chemistry(合成有机化学杂志)2006年第64卷第12期上发表的论文“Process Development of Micafungin,a Novel Lipopeptide Antifungal Agent”中介绍,在式I化合物的离子交换洗脱溶液中加入丙酮和乙酸乙酯混合液使式I化合物沉淀,能够得到无定型的式I化合物。式I化合物沉淀物干燥前溶剂含量高(Dry/Wet=0.25),式I化合物沉淀物中含有约75%的溶剂,需要延长干燥时间才能使溶剂含量低于标准值,然而延长干燥时间会使式I化合物降解物增加,质量下降。
此外,藤泽药品工业株式会社的专利申请WO03/018615公开了一种式I化合物的新晶型及其制备方法。WO03/018615使用无定型的式I化合物溶解在含水的醇类溶液或含水的丙酮溶液中,加入乙酸乙酯、二氯甲烷、丙酮和乙腈等溶剂,得到式I化合物B82型针状晶体。该晶体在有机溶剂中结晶得到,显微镜下形态为针状晶体,X-射线粉末衍射在2θ角4.6°、5.5°、9.0°、9.8°、16.9°有峰。
藤泽药品工业株式会社,YAMASHITA等人在生物工学杂志2005年第83卷发表的论文“Study of Industrial Manufacturing Methods for Micafungin(FK463)中提到FK463通过溶剂的优化和PH的控制成功得到针状晶体,没有具体的实施方式和晶体数据。由于该公司在先的专利申请WO03/018615公开了式I化合物的B82型针状晶体,可见YAMASHITA等人获得的也是B82型针状晶体
本发明人按照专利WO03/018615实施例1的方法进行了B82型针状晶体的 制备,使用光学显微镜观察所获得的晶体,尺寸约为1um,使用Malven粒径分析仪分析测得d50在0.2-1.0um,为细小针状晶体。本发明人在对B82型晶体进行后续过滤、干燥等工艺步骤操作时发现,由于B82型晶体基本上为细小针状形态,导致式I化合物晶体过滤困难,操作时间长。晶体干燥前,式I化合物的溶剂含量Dry/Wet(干湿重比)约为0.25,晶体包裹大量有机溶剂。干燥过程中需要通过提高干燥温度或延长干燥时间才能使溶剂含量符合原料药要求。但采用上述的干燥过程会使式I化合物的降解产物增加,严重影响原料药的质量和稳定性。发明人通过对B82型针状晶体干燥得到的结晶粉末研究后发现,B82型针状晶体堆积密度约为0.8g/mL,较为密实,不利于结晶粉末在干燥过程中溶剂的挥发,直接影响其干燥过程,且B82型晶体暴露在环境中,容易吸湿,稳定性差。
因此本领域迫切需要获得一种形态规则、更容易过滤、堆积密度小容易干燥的式I化合物的稳定形式,以便能够更好的实现商业化生产。
发明内容
本发明的一个目的在于提供一种式I化合物的结晶粉末。
本发明的另一个目的是提供所述结晶粉末的制备方法。
本发明的又一个目的是提供所述结晶粉末的用途。
式I化合物的结晶粉末
本发明提供了式I化合物的一种结晶粉末。
一种环肽类化合物的结晶粉末,其结构如式I所示,所述晶型粉末的堆积密度小于0.7g/mL。
在本发明的另一优选例中,所述结晶粉末的堆积密度小于0.6g/mL。
在本发明的另一优选例中,所述结晶粉末的堆积密度小于0.5g/mL。
在本发明的另一优选例中,所述结晶粉末的d50在10-100um。
在本发明的另一优选例中,所述结晶粉末的d50在20-50um。
在本发明的另一优选例中,所述结晶粉末的d10在1-9um。
在本发明的另一优选例中,所述结晶粉末的d10在1-5um。
在本发明的另一优选例中,所述结晶粉末在固液分离前,d50在10-100um。
在本发明的另一优选例中,所述结晶粉末在固液分离前,d50在20-50um。
在本发明的另一优选例中,所述结晶粉末在固液分离前,d10在1-9um。
在本发明的另一优选例中,所述结晶粉末在固液分离前,d10在3-6um。
WO03/018615公开的B82型针状晶体为细小针状形态,过滤困难、难于干燥且稳定性较差。发明人为了能够获得稳定性更好、形态更优的式I化合物,发明人在三相体系中利用不同的溶剂组合筛选结晶溶剂体系。经过很长一段时间的研究,本发明人意外的发现,在特定的三相的溶剂体系中,能得到形态规则的柱状晶体。随后我们有进行了大量的溶剂筛选试验,最终得到一种稳定性更好、形态更优的式I化合物的结晶粉末,并且确定了制备工艺。与WO03/018615公开的B82型针状晶体相比,本发明的晶体为柱状,晶体颗粒大,其堆积密度小,易于过滤且晶体中的溶剂容易去除。
发明人经过研究惊奇地发现,式I化合物在甲醇/异丁醇、甲醇/异丙醇、甲醇/正丙醇的水溶液,即三相体系溶液或四相溶剂体系中,通过降温或添加难溶性溶剂等降低式I化合物在溶液中溶解度的手段,式I化合物形态优异的柱状晶体,即式I化合物的结晶粉末。结晶后过滤获得的式I化合物干燥前Dry/Wet(干湿重比)高,包裹的有机溶剂含量少,且干燥后堆积密度小易于除去有机溶剂。
式I化合物的结晶粉末的鉴定和性质
本发明人在获得式I化合物的结晶粉末后,进一步采用多种方式和仪器对其性质进行了研究。
“粉末堆积密度”,通过粉末的松密度和紧密度的比较,可以看出微粒的相互作用的相对重要性的量度标准。测量粉末堆积密度的方法是本领域已知的,例如使用量筒测量法、体积计测量法、容器测量法等方法测定。本发明的 式I化合物的结晶粉末采用量筒测量法测定其堆积密度小于0.7g/mL,更佳地小于0.6g/mL;最佳地小于0.5g/mL。
“颗粒尺寸分布”,使用Malvern颗粒尺寸仪2600C确定来分析结晶液固液分离前晶体的尺寸分布(包括d10和d50)。其中,d10和d50是标示颗粒尺寸分布的已知方式,d50是指某一颗粒尺寸值,要使得50vol/%颗粒的尺寸小于所述值。d10是指某一颗粒尺寸值,要使得10vol/%颗粒的尺寸小于所述值。确定d10和d50的优选方法是激光衍射。本发明的式I化合物的结晶粉末测定其d50在10-100um,d10在1-9um。更佳地,其d50在20-50um,d10在1-5um。式I化合物的结晶粉末固液分离前其d50在10-100um,d10在1-9um。更佳地,其d50在20-50um,d10在3-6um。
“显微分析技术”,通过光学显微镜对晶体外形识别达到晶型分析的目的。本发明的式I化合物的结晶粉末在光学显微镜下为柱状晶体。优选本发明的式I化合物的结晶粉末固液分离前具有与图1基本一致的形状。
“高效液相色谱法”(HPLC)是用于检测化合物纯度的常用方法,是以液体为流动相,采用高压输液系统,将具有不同极性的单一溶剂或不同比例的混合溶剂、缓冲液等流动相泵入装有固定相的色谱柱,在柱内各成分被分离后,进入检测器进行检测,从而实现对试样的分析。本发明中采用HPLC测定式I化合物纯度以及用于样品的稳定性研究,所述的HPLC检测条件如下:
分析柱:YMC-ODS 250×4.6mm,5μm;
流动相:乙腈∶磷酸盐缓冲液(pH 3.0)=45∶70;
流速:1ml/min;
柱温:35℃;
稀释液:水的磷酸盐缓冲液;
检测波长:210nm;
进样量:10μl。
采用气相色谱法(GC)分离检测化合物中的微量杂质,是一种准确、定性定量的分析方法。本发明中使用气相色谱(GC)对本发明制备获得的式I化合物的结晶粉末中的有机溶剂含量进行测定。
“X射线粉末衍射”又称“X射线多晶衍射(XRD或XRPD)”是目前用于测定晶体构造(即晶型)的常用试验方法。采用X射线粉末衍射仪,在X射线透过晶体时产生一系列衍射图谱,该图谱中不同的衍射线及其强度有一定结构的原子团所决定,由此确定晶体结构。测定晶体的X射线粉末衍射的方法在本领域是已知的。例如使用RIGAKU D/max 2550VB/PC型号的X射线粉末衍射仪,以2°每分钟的扫描速度,采用铜辐射靶获取图谱。
本发明的式I化合物的结晶粉末具有特定的晶体形态,在X射线粉末衍射图中有特定的特征峰。具体而言,本发明的式I化合物的结晶粉末的X射线粉末衍射图上在下述2θ角有特征峰:4.4±0.2°,5.2±0.2°,8.5±0.2°,9.6±0.2°;在一个优选的实施方式中,该图谱还在下述2θ角有特征峰:7.5±0.2°,8.8±0.2°,16.6±0.2°,13.7±0.2°,22.5±0.2°;在另一个优选的实施方式中,该图谱还在下述2θ角有特征峰:12.6±0.2°,14.9±0.2°,15.6±0.2°,25.1±0.2°。在一个优选的实施方式中,本发明的式I化合物的结晶粉末的X射线粉末衍射图上在下述2θ角有特征峰:4.4±0.1°,5.2±0.1°,8.5±0.1°,9.6±0.1°;在另一个优选的实施方式中,该图谱还在下述2θ角有特征峰:7.5±0.1°,8.8±0.1°,16.6±0.1°,13.7±0.1°,22.5±0.1°;在另一个优选的实施方式中,该图谱还在下述2θ角有特征峰:12.6±0.1°,14.9±0.1°,15.6±0.1°,25.1±0.1°。更佳地,所述式I化合物的结晶粉末具有与图2基本一致所示的X-射线粉末衍射(XRPD)图。
式I化合物的结晶粉末的制备
本发明提供式I所示化合物结晶粉末的制备方法,所述方法包含以下步骤:
(a)将如式I所示化合物溶解在含水的醇类混合溶液中;
(b)通过降温和/或添加有机溶剂(i),得到固体;
(c)步骤(b)中得到的固体与水体系一起进行真空干燥,得到所述结晶粉末。
其中,步骤(a)中所述醇类混合溶液选自:甲醇/异丁醇、甲醇/异丙醇、甲醇/正丙醇。
其中,步骤(a)中所述含水的醇类混合溶液中,两种醇体积比为0.01-100, 优选0.05-20,更优选0.1-10。
其中,步骤(a)中所述含水的醇类混合溶液中,醇总体积与水体积比为0.1-100,优选0.5-10,更优选1-7。
其中,步骤(a)中所述溶解的温度为10至50℃,优选20至40℃。
其中,步骤(a)中以所述溶解液的总体积计,其中含有式I化合物1-500mg/ml,优选5-100mg/ml,更优选10-50mg/ml。
其中,步骤(b)中所述有机溶剂(i)选自:正丙醇、异丙醇、异丁醇、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯。
其中,步骤(b)中所述的降温的温度为-40至35℃,优选-20至35℃,更优选-10至30℃,最优选-5至15℃。
其中,步骤(b)中所述有机溶剂(i)与步骤(a)中含水的醇类混合溶液的体积比为0.1-50,优选0.1-10,更优选1-5。
式I化合物的结晶粉末的用途及其组合物
本发明提供的式I化合物的结晶粉末也可以直接用于制备治疗真菌感染的药物。可以提供一种含有式I化合物的结晶粉末,和药学上可接受的载体的药物组合物。
相关术语
如本文所用,术语“晶体”是指分子或原子复合物呈特定排列形式的固体。
如本文所用,术语“固液分离”是指式I化合物在溶剂中结晶析出后,通过过滤等方式将固体和液体分开的过程。
如本文所用,“Dry/Wet”和“干湿重比”可以互换使用,都是指化合物不含溶剂的重量与含溶剂重量的比值。本发明中晶体湿重是通过将结晶得到的固体过滤至无明显液滴流出,称重得到。
如本文所用,“式I化合物”,“化合物I”和“如式I所示化合物”可以互换使用,都是指具有以下结构式的化合物:
Figure PCTCN2015080224-appb-000002
式I化合物可以使用本领域常规的方法获得,例如但不限于,专利WO96/11210报道的该化合物的制备方法;也可以通过商业渠道获得,例如但不限于,如日本藤泽公司。
如本文所用,术语“药学上可接受的载体”指用于治疗剂给药的载体,包括各种赋形剂和稀释剂。该术语指这样一些药剂载体:它们本身并不是必要的活性成分,且施用后没有过分的毒性。合适的载体是本领域普通技术人员所熟知的。在Remington’s Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。在组合物中药学上可接受的载体可包括液体,如水、盐水、甘油和乙醇。另外,这些载体中还可能存在辅助性的物质,如崩解剂、润湿剂、乳化剂、pH缓冲物质等。
本发明的主要优点在于:
1.提供一种形态优异的式I化合物的结晶粉末,该晶体粉末易于过滤及干燥。
2.提供了式I化合物结晶粉末的制备方法,且所述方法容易固液分离、易于干燥去除残留溶剂非常适合工业化生产。
附图说明
图1所示为式I化合物晶体固液分离前显微镜观察照片。
图2所示为式I化合物结晶粉末的X射线粉末衍射(XRPD)图谱。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的,例如是指在100毫升的溶液中溶质的重量。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
制备化合物I
按照美国专利7,199,248中方法制备得到式I化合物的固体无定型粉末。
比较例1
制备B82型晶体
按照专利WO03/018615实施例1方法制备得到针状晶体,为B82型晶体。粒径分布测定得d10=0.3um,d50=0.96um。过滤后将湿晶体称重,计算得到干湿重比为0.25。干燥后的堆积密度为0.85g/mL,粒径为d10=0.25um,d50=0.7um。
实施例2
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物1g,25℃下溶解于50ml甲醇/异丁醇水溶液(异丁醇∶水∶甲醇=8∶2∶1)中,缓慢降温至8℃,溶液中有固体析出,并保持此温度继续搅拌3.5h固体大量析出,慢慢加入90ml乙酸乙酯,过滤得到固体。过滤前取样在15×40倍的显微镜下观察固体照片见附图1, 过滤前取样进行粒径分布测定得d10=3.3um,d50=32.6um。过滤后将湿固体称重,计算得到干湿重比为0.45。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘自来水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.45g/mL,粒径为d10=3um,d50=31.9um。其XRPD见图2。
实施例3
制备式I化合物结晶粉末
将由对比例1制备得到的B82型晶体2.5g,30℃下溶解于50ml甲醇/异丁醇水溶液(异丁醇∶水∶甲醇=1∶1∶1)中,慢慢加入50ml乙酸甲酯,过滤得到固体。过滤前取样进行粒径分布测定得d10=4.2um,d50=43.9um。过滤后将湿固体称重,计算得到干湿重比为0.52。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘纯水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.43g/mL,粒径为d10=3.7um,d50=43.1um。
实施例4
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物3g,10℃下溶解于600ml甲醇/异丁醇水溶液(异丁醇∶水∶甲醇=5∶1∶2)中,降温至-20℃,溶液中有固体析出,继续搅拌约12h固体大量析出,过滤得到固体。过滤前取样进行粒径分布测定得d10=5.7um,d50=54.3um。过滤后将湿固体称重,计算得到干湿重比为0.61。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘冰水混合物,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.55g/mL,粒径为d10=5.1um,d50=50um。
实施例5
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物3g,50℃下溶解于120ml甲醇/异丙醇水溶液(异丙醇∶水∶甲醇=1∶4∶1)中,降温至30℃,溶液中有固 体析出,继续搅拌30min固体大量析出,慢慢加入200ml异丙醇,过滤得到固体。过滤前取样进行粒径分布测定得d10=9um,d50=98.3um。过滤后将湿固体称重,计算得到干湿重比为0.66。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘自来水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.6g/mL,粒径为d10=9um,d50=97.7um。
实施例6
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物1g,20℃下溶解于20ml甲醇/异丙醇水溶液(异丙醇∶水∶甲醇=10∶2∶1)中,慢慢加入200ml乙酸正丙酯,过滤得到固体。过滤前取样进行粒径分布测定得d10=5.8um,d50=50um。过滤后将湿固体称重,计算得到干湿重比为0.6。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘自来水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.49g/mL,粒径为d10=5um,d50=48.7um。
实施例7
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物1.0g,18℃下溶解于100ml甲醇/异丙醇水溶液(异丙醇∶水∶甲醇=1∶2∶20)中,降温至-5℃,溶液中有固体析出,继续搅拌4h固体大量析出,过滤得到固体。过滤前取样进行粒径分布测定得d10=1um,d50=10um。过滤后将湿固体称重,计算得到干湿重比为0.69。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘冰水混合物,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.6g/mL,粒径为d10=1um,d50=10um。
实施例8
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物2g,30℃下溶解于20ml甲 醇/正丙醇水溶液(正丙醇∶水∶甲醇=1∶15∶10)中,降温至15℃,溶液中有固体析出,继续搅拌2h固体大量析出,慢慢加入100ml乙酸异丙酯,过滤得到固体。过滤前取样进行粒径分布测定得d10=3um,d50=20um。过滤后将湿固体称重,计算得到干湿重比为0.45。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘自来水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.38g/mL,粒径为d10=2.6um,d50=18.7um。
实施例9
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物4g,25℃下溶解于300ml甲醇/正丙醇水溶液(正丙醇∶水∶甲醇=20∶2∶1)中,慢慢加入30ml异丁醇,过滤得到固体。过滤前取样进行粒径分布测定得d10=1.8um,d50=23.9um。过滤后将湿固体称重,计算得到干湿重比为0.62。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘纯水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.54g/mL,粒径为d10=1.3um,d50=20um。
实施例10
制备式I化合物结晶粉末
将由实施例1制备得到的无定型的式I化合物2.7g,40℃下溶解于80ml甲醇/正丙醇水溶液(正丙醇∶水∶甲醇=10∶3∶1)中,降温至-10℃,溶液中有固体析出,继续搅拌1h固体大量析出,过滤得到固体。过滤前取样进行粒径分布测定得d10=8.7um,d50=100um。过滤后将湿固体称重,计算得到干湿重比为0.63。将过滤后固体放入真空干燥箱中,在干燥箱内底部放一盘自来水,真空干燥得到结晶粉末,所得结晶粉末的堆积密度为0.56g/mL,粒径为d10=8.3um,d50=100um。
比较例2
将由实施例1制备得到的无定型的式I化合物0.8g,25℃下溶解于5ml甲 醇水溶液(甲醇∶水=3∶2),缓慢降温至约0℃,溶液中有固体析出,并保持此温度继续搅拌3h,过滤得到固体无定型粉末,计算得到干湿重比为0.13。
比较例3
将由实施例1制备得到的无定型的式I化合物2.1g,32℃下溶解于50ml乙醇水溶液(乙醇∶水=5∶1)中,降温至10℃,溶液中有固体析出,并保持此温度继续搅拌5h,过滤得到固体无定型粉末,计算得到干湿重比为0.1。
比较例4
将由实施例1制备得到的无定型的式I化合物3g,20℃下溶解于55ml正丙醇水溶液(正丙醇∶水=1∶1)中,降温至0℃,溶液中有固体析出,并保持此温度继续搅拌5h,过滤得到固体无定型粉末,计算得到干湿重比为0.19。
比较例5
将由实施例1制备得到的无定型的式I化合物2.5g,45℃下溶解于32ml异丙醇水溶液(异丙醇∶水=2∶3)中,降温至15℃,溶液中有固体析出,并保持此温度继续搅拌1h,过滤得到固体无定型粉末,计算得到干湿重比为0.18。
比较例6
将由实施例1制备得到的无定型的式I化合物1.7g,32℃下溶解于90ml异丁醇水溶液(异丁醇∶水=4∶1)中,降温至10℃,溶液中有固体析出,并保持此温度继续搅拌2h,慢慢加入20ml乙酸乙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.21。
比较例7
将由实施例1制备得到的无定型的式I化合物1g,28℃下溶解于50ml正丁醇水溶液(正丁醇∶水=9∶1)中,降温至0℃,慢慢加入50ml乙酸甲酯,过滤得到固体无定型粉末,计算得到干湿重比为0.2。
比较例8
将由实施例1制备得到的无定型的式I化合物1.2g,17℃下溶解于45ml丙酮水溶液(丙酮∶水=4∶1)中,降温至-5℃,溶液中有固体析出,并保持此温度继续搅拌3.5h,过滤得到固体无定型粉末,计算得到干湿重比为0.15。
比较例9
将由实施例1制备得到的无定型的式I化合物5g,25℃下溶解于150ml乙腈水溶液(乙腈∶水=3∶1)中,降温至8℃,溶液中有固体析出,并保持此温度继续搅拌2h,慢慢加入200ml乙酸异丙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.09。
比较例10
将由实施例1制备得到的无定型的式I化合物1.7g,30℃下溶解于100ml甲醇/乙醇水溶液(甲醇∶乙醇∶水=8∶2∶1)中,降温至11℃,溶液中有固体析出,并保持此温度继续搅拌6h,慢慢加入100ml乙酸乙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.23。
比较例11
将由实施例1制备得到的无定型的式I化合物1.7g,23℃下溶解于100ml丙醇/丁醇水溶液(丙醇∶丁醇∶水=6∶5∶3)中,降温至-5℃,溶液中有固体析出,并保持此温度继续搅拌7h,过滤得到固体无定型粉末,计算得到干湿重比为0.11。
比较例12
将由实施例1制备得到的无定型的式I化合物4g,45℃下溶解于28ml甲醇/正丁醇水溶液(甲醇∶正丁醇∶水=1∶7∶2)中,降温至11℃,溶液中有固体析出,并保持此温度继续搅拌6h,过滤得到固体无定型粉末,计算得到干湿 重比为0.18。
比较例13
将由实施例1制备得到的无定型的式I化合物1g,20℃下溶解于70ml乙醇/丁醇水溶液(乙醇∶丁醇∶水=2∶2∶5)中,慢慢加入100ml乙酸乙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.2。
比较例14
将由实施例1制备得到的无定型的式I化合物3g,50℃下溶解于20ml甲醇/乙腈水溶液(甲醇∶乙腈∶水=4∶1∶2)中,降温至25℃,溶液中有固体析出,并保持此温度继续搅拌2h,慢慢加入70ml乙酸乙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.19。
比较例15
将由实施例1制备得到的无定型的式I化合物2g,30℃下溶解于10ml甲醇/丙酮水溶液(甲醇∶丙酮∶水=9∶2∶2)中,降温至5℃,溶液中有固体析出,并保持此温度继续搅拌4h,慢慢加入50ml乙酸乙酯,过滤得到固体无定型粉末,计算得到干湿重比为0.15。
实施例11
本实施例中,将实施例2-10与比较例1-3析出固体,使用布氏漏斗过滤至无明显液滴流出,并比较过滤过程。具体结果见下表:
样品 粒径分布 过滤时间
实施例2 d10=3.3um,d50=32.6um 10min
实施例3 d10=4.2um,d50=43.9um 20min
实施例4 d10=5.7um,d50=54.3um 17min
实施例5 d10=9um,d50=98.3um 18min
实施例6 d10=5.8um,d50=50um 9min
实施例7 d10=1um,d50=10um 23min
实施例8 d10=3um,d50=20um 20min
实施例9 d10=1.8um,d50=23.9um 27min
实施例10 d10=8.7um,d50=100um 16min
比较例1 d10=0.3um,d50=0.96um 90min
比较例2 / 150min
比较例3 / 300min
实施例2-10使用1-4g式I化合物制备式I化合物结晶粉末,过滤时间最长仅为27min,而比较例1中使用0.5g式I化合物制备B82型晶体,规模小。但过滤所需时间远多于实施例2-10,可见本发明制备得到的式I化合物结晶粉末在过滤过程中有明显优势。
实施例12
本实施例中,将比较例与实施例所得样品的干燥过程进行比较。
按实施例2-10,比较例1-3方法分别制备析出的5g固体,置于25℃下,与水体系一起真空干燥至使用GC检测,结果显示不含有有机溶剂,比较其干燥时间,并分析样品纯度。具体结果见下表:
样品 堆积密度(g/mL) 干燥前纯度 干燥后纯度 所需时间
实施例2 0.45 99.68% 99.68% 7h
实施例3 0.43 99.63% 99.61% 6.5h
实施例4 0.55 99.64% 99.64% 9h
实施例5 0.6 99.52% 99.47% 10h
实施例6 0.49 99.61% 99.6% 8.5h
实施例7 0.6 99.65% 99.57% 9.5h
实施例8 0.38 99.52% 99.46% 6h
实施例9 0.54 99.42% 99.38% 8.5h
实施例10 0.56 99.5% 99.43% 9h
比较例1 0.85 99.26% 97.96% 25h
比较例2 / 98.82% 96.21% 30h
比较例3 / 98.74% 96.17% 32h
实施例13
药物组合物的制备
式I化合物结晶粉末 乳糖 无水柠檬酸 氢氧化钠
2.5g 20g 适量 适量
将20g乳糖在低于50℃加热下溶于纯水(200ml)。冷却至20℃以下后,向乳糖溶液中加入按实施例2的方法获得的式I化合物结晶粉末2.5g,在温和搅拌下避免产生气泡。在加入2%柠檬酸水溶液(0.95ml)后,向溶液中加入0.4%氢氧化钠水溶液(约24ml),以调节pH5.5,然后用纯水稀释,定容至250ml。将所得的溶液分装到100个10ml体积的小瓶中,每个小瓶2.5ml。用常规方法,用冻干机将各个小瓶中的溶液冻干,以获得各含25mg式I化合物结晶粉末的冻干组合物。
实施例14
药物组合物的制备
取按实施例2的方法获得的式I化合物的结晶粉末0.2g,按照US2007249546A1实施例2制备成滴眼液。
以上所述仅为本发明的较佳实施例而已,并非用以限定本发明的实质技术内容范围,本发明的实质技术内容是广义地定义于申请的权利要求范围中,任何他人完成的技术实体或方法,若是与申请的权利要求范围所定义的完全相同,也或是一种等效的变更,均将被视为涵盖于该权利要求范围之中。

Claims (17)

  1. 一种环肽类化合物的结晶粉末,其结构如式I所示,所述结晶粉末的堆积密度小于0.7g/mL;
    Figure PCTCN2015080224-appb-100001
  2. 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的堆积密度小于0.6g/mL,优选小于0.5g/mL。
  3. 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的d50在10-100um,优选d50在20-50um。
  4. 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末的d10在1-9um,优选d10在1-5um。
  5. 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末在固液分离前,d50在10-100um,优选d50在20-50um。
  6. 如权利要求1所述的环肽类化合物的结晶粉末,其特征在于,所述结晶粉末在固液分离前,d10在1-9um,优选d10在3-6um。
  7. 一种制备如权利要求1-6任一所述的环肽类化合物的结晶粉末的方法,其特征在于,所述的方法包含以下步骤:
    (a)将如式I所示化合物溶解在含水的醇类混合溶液中;
    (b)通过降温和/或添加有机溶剂(i),得到固体;
    (c)步骤(b)中得到的固体与水体系一起进行真空干燥,得到如权利要 求1-6任一所述的结晶粉末。
  8. 如权利要求7所述的制备方法,其特征在于,步骤(a)中所述醇类混合溶液选自:甲醇/异丁醇、甲醇/异丙醇、甲醇/正丙醇。
  9. 如权利要求8所述的制备方法,其特征在于,步骤(a)中所述含水的醇类混合溶液中,两种醇体积比为0.01-100,优选0.05-20,更优选0.1-10。
  10. 如权利要求7所述的制备方法,其特征在于,步骤(a)中所述含水的醇类混合溶液中,醇总体积与水体积比为0.1-100,优选0.5-10,更优选1-7。
  11. 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述有机溶剂(i)选自:正丙醇、异丙醇、异丁醇、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯。
  12. 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述的降温的温度为-40至35℃,优选-20至35℃,更优选-10至30℃,最优选-5至15℃。
  13. 如权利要求7所述的制备方法,其特征在于,步骤(b)中所述有机溶剂(i)与步骤(a)中含水的醇类混合溶液的体积比为0.1-50,优选0.1-10,更优选1-5。
  14. 如权利要求7所述的制备方法,其特征在于,步骤(c)中所述水体系选自:自来水、纯水、冰水混合物或其他能释放水蒸汽的物质。
  15. 一种如权利要求1-6任一所述的环肽类化合物结晶粉末的用途,其特征在于,用于制备治疗真菌感染的药物。
  16. 一种药物组合物,其特征在于,所述的药物组合物中含有如权利要求1-6任一所述的环肽类化合物结晶粉末和药学上可接受的载体。
  17. 一种如权利要求16所述的药物组合物的制备方法,其特征在于,所述的方法包含以下步骤:
    将如权利要求1-6任一所述的环肽类化合物结晶粉末和药学上可接受的载体混合,得到如权利要求16所述的药物组合物
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