WO2015180682A1 - 一种环肽类化合物的溶剂合物及其制备方法和用途 - Google Patents

一种环肽类化合物的溶剂合物及其制备方法和用途 Download PDF

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WO2015180682A1
WO2015180682A1 PCT/CN2015/080232 CN2015080232W WO2015180682A1 WO 2015180682 A1 WO2015180682 A1 WO 2015180682A1 CN 2015080232 W CN2015080232 W CN 2015080232W WO 2015180682 A1 WO2015180682 A1 WO 2015180682A1
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solvate
formula
compound
water
preparation
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PCT/CN2015/080232
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English (en)
French (fr)
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刘石东
王修胜
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 EP15800267.5A priority Critical patent/EP3150623B1/en
Priority to JP2017514773A priority patent/JP6491325B2/ja
Priority to US15/314,458 priority patent/US10183973B2/en
Publication of WO2015180682A1 publication Critical patent/WO2015180682A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/30—Extraction; Separation; Purification by precipitation
    • C07K1/306—Extraction; Separation; Purification by precipitation by crystallization
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • the invention relates to a micafungin sodium solvate and a preparation method 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 formula I is a polypeptide compound with poor stability and degradation during transport or long-term storage. Product formation affects its quality and efficacy. 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.
  • the patent application WO 03/018615 of Fujisawa Pharmaceutical Co., Ltd. discloses a crystal form of a compound of the formula I and a preparation method thereof, using an amorphous compound of the formula I dissolved in an aqueous single alcohol solution or an aqueous acetone solution, A solvent such as ethyl acetate, dichloromethane, acetone or acetonitrile is added 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°, 5.4°, 9.0°, 9.8°, and 16.9°.
  • the inventors carried out the preparation of the B82-type needle crystal according to the method of Example 1 of the patent WO03/018615, and observed the crystal obtained by an optical microscope, and the size was about 1 ⁇ m, which was a fine needle crystal.
  • the inventors found in the process steps of subsequent filtration, drying, etc. of the crystal, due to the B82 crystal
  • the body is substantially in the form of a fine needle, which results in difficulty in filtering the crystal of the compound of formula I, and has a long operation time; before the crystal is dried, the solvent content of the compound of formula I is Dry/Wet of about 0.25, and the crystal encapsulates a large amount of organic solvent.
  • micafungin sodium solid stability is poor, can only be stored at low temperature or a large number of excipients freeze-dried to ensure its stability, which greatly restricts the development of micafungin sodium drug use. If a more stable micafungin sodium solid form can be found, it can be prepared into a variety of different dosage forms, such as lyophilized powder injections, tablets, capsules, ointments, etc., to facilitate the use of different patients.
  • Another object of the present invention is to provide a process for the preparation of the solvate.
  • Yet another object of the invention is to provide the use of the solvate.
  • the present invention provides a solvate of a compound of formula I, wherein the solvate of the compound of formula I contains 2 molecules of water of crystallization and 0.5 molecule of methanol.
  • the X-ray powder diffraction (XRPD) pattern of the solvate of the compound of the formula I has a peak at the following 2 theta angle: 3.6 ⁇ 0.2 °, 6.4 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 9.5 ⁇ 0.2 °.
  • the X-ray powder diffraction (XRPD) pattern of the solvate of the compound of the formula I has a peak at the following 2 theta angle: 7.5 ⁇ 0.2 °, 11 ⁇ 0.2 °, 12.4 ⁇ 0.2°.
  • the X-ray powder diffraction (XRPD) pattern of the solvate of the compound of formula I has a peak at the following 2 theta angle: 13.4 ⁇ 0.2 °, 20.2 ⁇ 0.2 °.
  • the solvate of the compound of formula I has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the solvate of the compound of formula I has the following crystal parameters:
  • the compounds of the formula I disclosed in the amorphous and crystalline forms disclosed in the prior art are less stable.
  • the inventors have studied the compounds of the formula I, and found that the two-phase system is simply utilized. For example, methanol/water, ethanol/water, n-propanol/water, isopropanol/water, isobutanol/water, n-butanol/water, acetonitrile/water, acetone/water, by cooling and/or adding organic solvents
  • the compound I precipitated, and the obtained solids were all amorphous and had poor stability.
  • the inventors conducted extensive research on the ratio of the above two systems of water and the crystallization pH, but finally found that the product was still amorphous.
  • the inventors did not give up the effort to continue to screen the solvent system in a three-phase system using different solvent combinations. After a long period of research, the inventors have unexpectedly discovered that a solvate of a compound of formula I having a regular morphology and columnar crystals can be obtained in a specific three-phase solvent system. After a large number of solvent screening tests were carried out, a solvate of a compound of formula I with better stability and better morphology was finally obtained, and its preparation process was determined. The obtained solvate of the compound of the formula I is more regular than the B82-type needle crystal disclosed in WO03/018615, and is a columnar crystal (Fig. 12).
  • the particles are large, easy to filter and the solvent in the crystal is easily removed. It is important that the stability is significantly better than the B82 type crystal.
  • the solvent in the solvate of the compound of the formula I is removed, it is possible to form a solvent-free crystal of the compound of the formula I.
  • the inventors further studied the solvate structure of the compound of formula I and found that the water molecule and the methanol molecule combine with the sodium atom of the compound of formula I to form a eutectic composition, and the solvate of the compound of formula I contains two molecules of water of crystallization. And 0.5 molecule of methanol, in addition, may also contain free (not bound to the molecule of the compound of formula I) solvent or water. This is due to the fact that during the preparation of the solvate from the crystallization of the compound, the compound molecule is combined with a crystalline solvent molecule or a water molecule to form a stable structure solvate.
  • the compound molecules also encapsulate or adsorb a certain amount of solvent molecules or water molecules. These solvent molecules and water molecules are not combined with the compound molecules, so they do not participate in the structure of the structure, and their content and presence do not affect the structure, and the content thereof is not definite.
  • the inventors further studied the properties of the compound of formula I after solvating it in a variety of ways and instruments.
  • 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 solvates of the compounds of formula I according to the invention have a specific crystal form with specific characteristic peaks in the X-ray powder diffraction pattern.
  • the solvate of the compound of the formula I of the present invention has a characteristic peak at the following 2 theta angle on the X-ray powder diffraction pattern: 3.6 ⁇ 0.2 °, 6.4 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 9.5 ⁇ 0.2 °;
  • the map also has characteristic peaks at the following 2 theta angles: 7.5 ⁇ 0.2°, 11 ⁇ 0.2°, 12.4 ⁇ 0.2°; in another preferred embodiment, the map also has the following 2 ⁇ angles. Characteristic peak: 13.4 ⁇ 0.2 °, 20.2 ⁇ 0.2 °. More preferably, the solvate of the compound of formula I has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.
  • XRPD X-ray powder diffraction
  • Single-crystal X-ray diffraction analysis is a direct, independent, accurate and quantitative method for determining the crystal form of a drug. It is also an internationally recognized authoritative method for studying the polymorphic problem of solid chemical drugs.
  • the crystal structure of the solvate of the compound of the formula I of the present invention is passed through a German Bruker single crystal diffractometer (SMART APEX-II (DUO)) at a temperature of 140 (2) K. Conduct testing and data collection.
  • the solvate used for the single crystal test had a crystal size of 0.230 x 0.080 x 0.030 mm.
  • a unit cell of a solvate of a compound of the formula I contains 1/2 molecule of methanol and 2 molecules of water.
  • the inventors analyzed the cell packing pattern of the solvate of the compound of the formula I shown in Fig. 4 and found that the figure also contained some isobutanol and water used in the free crystallization process.
  • the moisture content of the composition of the compound of formula I is determined using a method commonly employed in the art, for example using Karl Fischer (KF).
  • GC Gas chromatography
  • a solvent compound of the compound of the formula I prepared by the present invention is used as a raw material by gas chromatography (GC), and the methanol content in the crystal of the obtained solvent-free compound of the formula I is determined to confirm whether or not methanol has been effectively removed.
  • HPLC High Performance Liquid Chromatography
  • Diluent phosphate buffer of water
  • Detection wavelength 210 nm
  • Injection volume 10 ⁇ l.
  • the present invention provides a process for the preparation of a solvate of a compound of formula I.
  • the inventors not only screened the solvent system during the study, but also studied the effect of pH on the solvate of the compound of formula I.
  • a large number of experiments have shown that pH is not a decisive factor in the solvate of the compound of formula I.
  • a two-phase or three-phase system solvent is used to obtain an amorphous form I compound, even if the pH is changed, an amorphous solid is obtained.
  • a solvate of a compound of formula I is obtained by solvent crystallization using a three-phase system, a solvate of the compound of formula I can be obtained, even if the pH is changed, while ensuring that the compound of formula I is stable.
  • 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 from 0.01 to 100, preferably from 0.05 to 20, more preferably from 0.1 to 10.
  • the total volume of the alcohol to the volume ratio of 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, acetic acid Methyl ester, ethyl acetate, n-propyl acetate, 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.
  • solvates of the compounds of formula I provided herein can be used to prepare crystals of the compound of formula I which are free of solvents.
  • the solvate of the compound of formula I provided by the present invention provides a solvent-free method of crystallizing a compound of formula I comprising the steps of:
  • the solvate of the compound of formula I provided herein is dried under vacuum with an aqueous system to provide a solvent-free crystal of the compound of formula I.
  • the water system is selected from the group consisting of tap water, pure water, ice water mixture or other substances capable of releasing water vapor.
  • drying of a solvate of a compound of formula I with an aqueous system means placing the solvate of the compound of formula I in a vacuum dried place where the sample is normally placed and surrounding the solvate of the compound of formula I.
  • An open container containing a substance that releases water vapor is placed.
  • solvates of the compounds of formula I provided herein can also be used directly to prepare medicaments for the treatment of fungal infections.
  • the invention also provides pharmaceutical compositions comprising a solvate of a compound of formula I and a pharmaceutically acceptable carrier.
  • solvate of a compound of formula I is a substance formed by the interaction of a compound of formula I with an organic solvent or water by hydrogen bonding or salt bonding.
  • crystal refers to a solid in which a molecule or atomic complex is in a particular arrangement.
  • 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.
  • Figure 1 shows an X-ray powder diffraction (XRPD) pattern of a solvate of a compound of formula I;
  • Figure 2 is a diagram showing the single crystal structure of a solvate of the compound of formula I.
  • Figure 3 is a graph showing the unit cell packing of the solvate of the compound of formula I.
  • Figure 4 is a partial enlarged view of the single crystal structure of the solvate of the compound of formula I.
  • Figure 5 is a partial enlarged view of the single crystal structure of the solvate of the compound of formula I.
  • Figure 6 shows an X-ray powder diffraction (XRPD) pattern of a solvent-free crystal of a compound of formula I.
  • Figure 7 shows an X-ray powder diffraction (XRPD) pattern of a solvent-free crystal of a compound of formula I.
  • Figure 8 shows an amorphous X-ray powder diffraction (XRPD) pattern of a compound of formula I.
  • Figure 9 is a HPLC chromatogram of the solvate of the compound of formula I obtained in Example 2 after 30 days at 25 °C.
  • Figure 10 is a HPLC chart of the B82 type crystal obtained in Comparative Example 1 at 25 ° C for 30 days.
  • Figure 11 is a photograph of the crystal obtained in Comparative Example 1 under a microscope.
  • Fig. 12 is a photograph of the crystal obtained in Example 2 under a microscope.
  • 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.
  • the moisture content of the crystal is determined by a detection method generally used in the art. For example using Karl Fischer (KF) Determine the moisture content.
  • Example 1 to Example 8 of the patent WO03/018615 needle-like crystals were obtained, which were B82-type crystals.
  • the samples were observed under a microscope of 15 ⁇ 40 times before filtration, and the photographs of the crystals are shown in Fig. 11.
  • the B82 crystal was analyzed by single crystal X-ray diffraction to confirm that the unit cell contained no solvent methanol and crystal water, and was an unsolvate.
  • a solid amorphous powder of the compound of formula I is prepared according to the method of U.S. Patent No. 7,199,248, the X-ray powder diffraction pattern of which is shown in Figure 8.
  • the tap water was removed, vacuum drying was continued, and the moisture content was controlled to 3.7% to obtain a solvent-free crystal of the compound of the formula I.
  • the XRPD is shown in Fig. 7, and it was detected by GC, and no methanol or other organic solvent was detected.
  • the solvate of the compound of the formula I obtained in Example 2 was measured by an X-ray powder diffractometer, and its X-ray powder diffraction pattern had characteristic peaks at the following 2 ⁇ angles: 3.6 ⁇ 0.2 °, 6.4 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 7.5 ⁇ 0.2 °, 9.5 ⁇ 0.2 °, 11.0 ⁇ 0.2 °, 12.4 ⁇ 0.2 °, 13.4 ⁇ 0.2 °, 20.2 ⁇ 0.2 °, X-ray powder diffraction pattern shown in Figure 1.

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Abstract

本发明提供一种环肽类化合物的溶剂合物，其环肽类化合物结构如式I所示，并且公开了其制备方法和用途。

Description

一种环肽类化合物的溶剂合物及其制备方法和用途 技术领域
本发明涉及一种米卡芬净钠溶剂合物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 PCTCN2015080232-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化合物的晶型及制备方法，使用无定型的式I化合物溶解在含水的单一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°、5.4°、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，但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，为细小针状晶体。本发明人在对晶体进行后续过滤、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。
目前所公开的米卡芬净钠固体稳定性较差，只能在低温下保存或添加大量赋形剂冻干保证其稳定性，大大制约了米卡芬净钠药品用途的发展。如果能够找到一种更稳定的米卡芬净钠固体形式，就能够将其制备成多种不同剂型，例如冻干粉针剂、片剂、胶囊、软膏剂等，方便不同的患者使用。
因此本领域迫切需要获得一种稳定性更好的式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化合物的溶剂合物。
本发明的另一个目的是提供所述溶剂合物的制备方法。
本发明的又一个目的是提供所述溶剂合物的用途。
式I化合物的溶剂合物
本发明提供了式I化合物的溶剂合物，所述1分子式I化合物的溶剂合物中含有2分子结晶水和0.5分子甲醇。
在本发明的另一优选例中，所述式I化合物的溶剂合物的X-射线粉末衍射(XRPD)图上在下述2θ角有峰：3.6±0.2°，6.4±0.2°，6.8±0.2°,9.5±0.2°。
在本发明的另一优选例中，所述式I化合物的溶剂合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：7.5±0.2°，11±0.2°，12.4±0.2°。
在本发明的另一优选例中，所述式I化合物的溶剂合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：13.4±0.2°，20.2±0.2°。
在本发明的另一优选例中，所述式I化合物的溶剂合物有如图1所示的X-射线粉末衍射(XRPD)图谱。
在本发明的另一个优选例中，所述式I化合物的溶剂合物具有下列晶体参数：
Figure PCTCN2015080232-appb-000002
现有技术公开的无定形和结晶形式的式I化合物稳定性较差，为了能够获得稳定性好的式I化合物，发明人对式I化合物进行了研究，研究发现：单纯的利用两相体系，例如甲醇/水，乙醇/水，正丙醇/水，异丙醇/水,异丁醇/水,正丁醇/水，乙腈/水，丙酮/水，通过降温和/添加有机溶剂使得式I化合物析出，得到的固体均为无定型且稳定性很差。在进一步研究过程中，发明人对上述两项体系水的比例以及结晶pH进行了大量的研究，但最终发现获得仍是无定型态的产物。
为了能够获得稳定性好的式I化合物，发明人没有放弃努力，继续在三相体系中利用不同的溶剂组合筛选溶剂体系。经过很长一段时间的研究后，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、柱状晶体的式I化合物的溶剂合物。在进行了大量的溶剂筛选试验后，最终得到稳定性更好、形态更优的式I化合物的溶剂合物，并且确定了其制备工艺。所获得的式I化合物的溶剂合物与WO03/018615公开的B82型针状晶体相比，形态规则，为柱状晶体(附图12)，颗粒大，易于过滤且晶体中的溶剂容易去除，更重要的是稳定性明显优于B82型晶体。而当式I化合物的溶剂合物中的溶剂脱去后，能够生成不含溶剂的式I化合物晶体。
发明人进一步对式I化合物的溶剂合物结构进行研究后发现，水分子和甲醇分子与式Ⅰ化合物中钠原子结合形成共晶组合物，每分子式I化合物的溶剂合物中含有2分子结晶水和0.5分子甲醇，此外，还可能含有游离的(未与式I化合物分子结合的)溶剂或水。这是由于化合物结晶制备溶剂合物的过程中，化合物分子除了与结晶溶剂分子或水分子结合形成稳定结构的溶剂合物外，在 化合物分子间还会包裹或吸附一定量的溶剂分子或水分子，这些溶剂分子和水分子未与化合物分子结合，因此不参与结构构成，其含量和存在与否并不影响结构，其含量也是不确定的。
式I化合物的溶剂合物的鉴定和性质
本发明人在获得式I化合物溶剂合物后进一步采用多种方式和仪器对其性质进行了研究。
“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化合物的溶剂合物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化合物的溶剂合物的X射线粉末衍射图上在下述2θ角有特征峰：3.6±0.2°，6.4±0.2°，6.8±0.2°,9.5±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°，11±0.2°，12.4±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：13.4±0.2°，20.2±0.2°。更佳地，所述式I化合物的溶剂合物具有与图1基本一致所示的X-射线粉末衍射(XRPD)图。
“单晶X射线衍射分析(SXRD)”是一种直接、独立、准确、定量的确定药物晶型的分析方法，也是目前国际上公认研究固体化学药物多晶型问题的权威方法。本发明式I化合物的溶剂合物的晶体结构式通过德国布鲁克单晶衍射仪(SMART APEX-Ⅱ(DUO)),在140(2)K温度下
Figure PCTCN2015080232-appb-000003
进行检测和数据收集。用于单晶测试的溶剂合物的晶体大小为0.230×0.080×0.030mm的晶体。
根据单晶X射线衍射数据对式I化合物的溶剂合物的结构进行解析发现，式I化合物的溶剂合物为每两分子式I化合物结合一分子甲醇，且每一分子式I化合物结合两分子水，并具有下列晶体学参数：
Figure PCTCN2015080232-appb-000004
由上述数据可知，一分子式I化合物的溶剂合物的晶胞中含1/2分子甲醇和2分子水。
此外，发明人在对图4所示的式I化合物溶剂合物的晶胞堆积图进行解析后发现，图中还含有一些游离的结晶过程中所用的异丁醇和水。
测定式I化合物的组合物的水分含量，采用本领域通用的检测方法，例如使用Karl Fischer(KF)测定水分含量。
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)对由本发明制备的式I化合物的溶剂化合物作为原料，制备获得的不含溶剂的式I化合物晶体中的甲醇含量进行测定，以确认甲醇是否已被有效去除。
“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。
式I化合物溶剂合物的制备
本发明提供式I所示化合物溶剂合物的制备方法。
发明人在研究过程中不仅对溶剂体系进行了筛选，还研究了pH对式I化合物的溶剂合物的影响。经过大量实验证明，pH并不是式I化合物的溶剂合物获得的决定性因素。当使用两相或三相体系溶剂结晶得到无定形式I化合物时，即使改变pH，获得的仍然是无定型固体。而当使用三相体系溶剂结晶获得式I化合物的溶剂合物后，在保证式I化合物稳定的前提下，即使改变pH，仍然能够得到式I化合物的溶剂合物。
发明人最终确定了下述获得式I化合物的溶剂合物的制备方法，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)，得到所述的溶剂合物。
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，醇的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化合物溶剂合物的用途及其组合物
本发明提供的式I化合物的溶剂合物可以用来制备不含溶剂的式I化合物晶体。
由本发明提供的式I化合物的溶剂合物制备不含溶剂的式I化合物晶体方法包含以下步骤：
将本发明提供的式I化合物的溶剂合物与水体系一起进行真空干燥，得到不含溶剂的式I化合物晶体。
其中，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。
其中，所述将式I化合物的溶剂合物与水体系一起进行真空干燥，是指将式I化合物的溶剂合物放置在真空干燥通常放置样品的地方，并在式I化合物的溶剂合物周围放置盛着能释放水蒸汽的物质的敞开的容器。
本发明提供的式I化合物的溶剂合物也可以直接用于制备治疗真菌感染的药物。
本发明还提供了含有式I化合物的溶剂合物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“式I化合物的溶剂合物”，又称“式I化合物的溶剂化物”，是式I化合物与有机溶剂或水通过氢键、盐键相互作用而形成的物质。
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，“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 PCTCN2015080232-appb-000005
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.提供稳定性优越的式I化合物的溶剂合物，方便运输和存储，解决了现有技术中亟待解决的技术问题。
2.提供了式I化合物的溶剂合物的制备方法，且所述方法非常适合规模化生产。
附图说明
图1所示为式I化合物溶剂合物的X射线粉末衍射(XRPD)图谱；其中
峰号 2-θ d(A) I％(相对强度)
1 3.6 24.7974 100.0
2 6.4 13.7127 84.0
3 6.8 12.9885 42.9
4 7.5 11.7774 14.0
5 9.4 9.3605 42.8
6 10.8 8.1551 15.5
7 12.4 7.1206 15.8
8 13.6 6.5156 16.7
9 20.4 4.3580 24.6
图2所示为式I化合物溶剂合物的单晶结构图。
图3所示为式I化合物溶剂合物的晶胞堆积图。
图4所示为式I化合物溶剂合物的单晶结构局部放大图。
图5所示为式I化合物溶剂合物的单晶结构局部放大图。
图6所示为不含溶剂的式I化合物晶体的X射线粉末衍射(XRPD)图谱。
图7所示为不含溶剂的式I化合物晶体的X射线粉末衍射(XRPD)图谱。
图8所示为式I化合物无定型的X射线粉末衍射(XRPD)图谱。
图9所示为实施例2获得的式I化合物溶剂合物在25℃,30天后的HPLC图谱。
图10所示为对比例1获得的B82型晶体在25℃,30天后的HPLC图谱。
图11所示为比较例1获得的晶体在显微镜下的照片。
图12所示为实施例2获得的晶体在显微镜下的照片。
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。
测定晶体的水分含量采用本领域通用的检测方法。例如使用Karl Fischer (KF)测定水分含量。
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。
比较例1
制备B82型晶体
按照专利WO03/018615实施例1至实施例8方法制备均得到针状晶体，为B82型晶体，过滤前取样在15×40倍的显微镜下观察晶体照片见附图11。B82晶体经单晶X射线衍射分析，确认晶胞中不含有溶剂甲醇和结晶水，属于非溶剂化物。
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，其X射线粉末衍射图谱见附图8。
实施例2
制备式I化合物溶剂合物
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℃，溶液中有晶体析出，并保持此温度继续搅拌3.5h晶体大量析出，慢慢加入90ml乙酸乙酯。过滤前取样在15×40倍的显微镜下观察晶体照片见附图12。过滤得到式I化合物溶剂合物，其XRPD见附图1。
实施例3
制备式I化合物溶剂合物
将由比较例1制备得到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，过滤得到式I化合物溶剂合物。
实施例4
制备式I化合物溶剂合物
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℃，溶液中有晶体析出，继续搅拌2h晶体大量析出，过滤得到式I化合物溶剂合物。
实施例5
制备式I化合物溶剂合物
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＝4:2:1)中，降温至30℃，溶液中有晶体析出，继续搅拌30min晶体大量析出，慢慢加入200ml异丙醇，过滤得到式I化合物溶剂合物。
实施例6
制备式I化合物溶剂合物
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，过滤得到式I化合物溶剂合物。
实施例7
制备式I化合物溶剂合物
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℃，溶液中有晶体析出，继续搅拌4h晶体大量析出，过滤得到式I化合物溶剂合物。
实施例8
制备式I化合物溶剂合物
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℃，溶液中有晶体析出，继续搅拌2h晶体大量析出，慢慢加入100ml乙酸异丙酯，过滤得到式I化合物溶剂合物。
实施例9
制备式I化合物溶剂合物
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，过滤得到式I化合物溶剂合物。
实施例10
制备式I化合物溶剂合物
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℃，溶液中有晶体析出，继续搅拌1h晶体大量析出，过滤得到式I化合物溶剂合物。
实施例11
制备式I化合物溶剂合物
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异丁醇/甲醇水溶液(异丁醇：水：甲醇＝8:2:1)中，降温约5℃，温度维持在5℃约60小时，得到式I化合物的溶剂合物。经单晶X射线衍射分析，确认晶胞含1分子式I化合物、1/2分子甲醇和2分子水，溶剂合物的晶体结构图见附图2，晶胞堆积图见附图3。
实施例12
制备不含溶剂的式I化合物晶体
将由实施例1制备得到的无定型的式I化合物1.5g，20℃下溶解于70ml甲醇/异丁醇水溶液(异丁醇：水：甲醇＝8:2:1)中，缓慢降温至0℃，溶液中有晶体析出，并保持此温度继续搅拌4.5h晶体大量析出，慢慢加入100ml乙酸乙酯，过滤得到式I化合物溶剂合物。所得溶剂合物放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量7.9％，真空干燥得到不含溶剂的式I化合物晶体，其XRPD见附图6，使用GC检测，未测出含甲醇或其他有机溶剂。
实施例13
制备不含溶剂的式I化合物晶体
将由实施例1制备得到的无定型的式I化合物2g，27℃下溶解于100ml甲醇/异丁醇水溶液(异丁醇：水：甲醇＝8:2:1)中，缓慢降温至-20℃，溶液中有晶体析出，并保持此温度继续搅拌4h晶体大量析出，慢慢加入150ml乙酸乙酯，过滤得到式I化合物溶剂合物。所得溶剂合物放入真空干燥箱中，在干 燥箱内底部放一盘自来水，干燥16h。撤去自来水，继续真空干燥，控制水分含量3.7％，得到不含溶剂的式I化合物晶体，其XRPD见附图7，使用GC检测，未测出含有甲醇或其他有机溶剂。
比较例2
不同溶剂对式I化合物晶型的影响
将由实施例1制备得到的无定型的式I化合物0.4g，25℃下溶解于10ml甲醇水溶液(甲醇：水＝3:2)，缓慢降温至5℃，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。
比较例3
不同溶剂对式I化合物晶型的影响
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丙酮水溶液(丙酮：水＝1:1)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。
比较例4
不同溶剂对式I化合物晶型的影响
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。
比较例5
不同溶剂对式I化合物晶型的影响
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。
比较例6
不同溶剂对式I化合物晶型的影响
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/乙醇水溶液(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。
实施例14
纯度和稳定性测试
在本实施例中，将比较例与实施例所得样品的纯度与稳定性进行比较。方法如下：
分别取实施例2制备得到的式I化合物的溶剂合物，比较例1得到的B82型晶体，及实施例1得到的无定型固体，密闭置于25℃保温放置30天，然后分析样品的杂质含量。本发明中式I化合物的溶剂合物与B82型晶体、无定型固体稳定性比较结果见下表：
样品 起始样品纯度 25℃，30天样品纯度
式I化合物的溶剂合物 99.55％ 99.50％
B82型晶体 99.50％ 96.98％
无定型固体 99.38％ 89.27％
实施例15
药物组合物的制备
式I化合物的溶剂合物 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化合物的溶剂合物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化合物的溶剂合物的冻干组合物。
实施例16
药物组合物的制备
取按实施例2的方法获得的式I化合物的溶剂合物0.2g，按照 US2007249546 A1实施例2制备成滴眼液。
式I化合物的溶剂合物的测定
采用X射线粉末衍射仪测定实施例2中获得的式I化合物的溶剂合物，其X射线粉末衍射图在下述2θ角有特征峰：3.6±0.2°，6.4±0.2°，6.8±0.2°，7.5±0.2°,9.5±0.2°，11.0±0.2°，12.4±0.2°，13.4±0.2°，20.2±0.2°，X射线粉末衍射图如图1所示。
式I化合物的溶剂合物的单晶结构图如图2所示。
式I化合物的溶剂合物的晶胞堆积图如图3所示。
经检测，实施例3-11的晶体结构与实施例2的晶体结构相同。可见，本发明方法的重复性很好，可获得稳定的式I化合物的溶剂合物。
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 (16)

  1. 一种式I所示化合物的溶剂合物，其特征在于,所述1分子式I化合物的溶剂合物中含有2分子结晶水和0.5分子甲醇；
    Figure PCTCN2015080232-appb-100001
  2. 如权利要求1所述的溶剂合物，其特征在于，所述溶剂合物的X-射线粉末衍射(XRPD)图上在下述2θ角有峰：3.6±0.2°，6.4±0.2°，6.8±0.2°,9.5±0.2°。
  3. 一种制备如权利要求1或2所述的溶剂合物的方法，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)，得到如权利要求1或2所述的溶剂合物。
  4. 如权利要求3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。
  5. 如权利要求4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。
  6. 如权利要求3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，醇的总体积与水体积比为0.1-100，优选0.5-10，更优选1-7。
  7. 如权利要求3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。
  8. 如权利要求3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℃。
  9. 如权利要求3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。
  10. 一种如权利要求1或2所述的溶剂合物的用途，其特征在于，用于制备不含溶剂的式I化合物晶体。
  11. 如权利要求10所述的溶剂合物的用途，其特征在于，所述制备不含溶剂的式I所示化合物的晶体的方法包含以下步骤：
    将如权利要求1或2所述的溶剂合物与水体系一起进行真空干燥，得到不含溶剂的晶体。
  12. 如权利要求11所述的溶剂合物的用途，其特征在于，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。
  13. 一种如权利要求1或2所述的溶剂合物的用途，其特征在于，用于制备治疗真菌感染的药物。
  14. 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或2所述的溶剂合物和药学上可接受的载体。
  15. 一种如权利要求14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或2任一所述的溶剂合物和药学上可接受的载体混合，得到如权利要求14所述的药物组合物。
  16. 如权利要求1或2所述的溶剂合物，其特征在于，所述溶剂合物中还含有制备过程中使用的溶剂或水，所述溶剂或水为游离形式存在。
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