WO2015180681A1 - 一种环肽类化合物的组合物及其制备方法和用途 - Google Patents

一种环肽类化合物的组合物及其制备方法和用途 Download PDF

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WO2015180681A1
WO2015180681A1 PCT/CN2015/080229 CN2015080229W WO2015180681A1 WO 2015180681 A1 WO2015180681 A1 WO 2015180681A1 CN 2015080229 W CN2015080229 W CN 2015080229W WO 2015180681 A1 WO2015180681 A1 WO 2015180681A1
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composition
formula
compound
water
preparation
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PCT/CN2015/080229
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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 US15/314,452 priority Critical patent/US20170190742A1/en
Priority to JP2017514772A priority patent/JP7109189B2/ja
Priority to EP15799598.6A priority patent/EP3150621A4/en
Publication of WO2015180681A1 publication Critical patent/WO2015180681A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a composition of a compound, and more particularly to a composition of a cyclic peptide compound and water, 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.
  • 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 formula I in an aqueous single alcohol solution or 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 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. Exposure to the environment, easy to absorb moisture, poor stability.
  • 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 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 invention is to provide a process for the preparation of a combination of a compound of formula I and water.
  • a further object of the invention is to provide the use of a combination of a compound of formula I and water.
  • the present invention provides a combination of a compound of formula I and water.
  • the invention provides a composition of a compound of formula I and water.
  • the mass percentage of water in the composition is from 3% to 20%.
  • the mass percentage of water in the composition is from 4% to 16%.
  • the compound of formula I in the composition has an HPLC purity of 98% or more.
  • the composition has a maximum peak at 120-130 ° C on a differential scanning calorimetry (DSC).
  • the inventors have found through extensive experimental studies that the moisture content of the compound of formula I and water has an important influence on the stability of the compound of formula I. Even more surprisingly, the high moisture content not only does not accelerate the decomposition of the compound of formula I, but the stability of the compound of formula I is degraded, which in turn effectively increases the stability of the compound of formula I. Its stability is significantly better than that of other moisture contents, and is superior to the B82 type crystal and amorphous solid disclosed in WO03/018615.
  • the DSC chart indicates that the composition loses amorphous water at around 105 ° C, and the composition does not contain crystal water, and the stability is poor.
  • the water content is higher than 20%, the composition of the compound of formula I and water cannot exist in a solid form.
  • the inventors found in the stability experiment that after 30 days of standing at 25 ° C, the composition of the compound of formula I with water having a water content of less than 3% was significantly degraded, and the purity was reduced from 99.52% to 92.18%. Under the same conditions, the purity of the composition of the compound of formula I and water having a water content of more than 3% is substantially unchanged.
  • only a compound of formula I in the composition can be stably present in a composition having a moisture content in the composition of the compound of formula I and water in the range of from 3% to 20%.
  • the inventors further studied the properties of the compound of formula I and water after various combinations and instruments.
  • DSC Differential calorimetric scanning analysis
  • the composition of the compound of formula I obtained with the process of the invention and water has a maximum peak at 120-130 °C as determined by DSC.
  • the composition of the compound of formula I obtained with the process of the invention and water having a maximum peak at about 129 ° C, preferably having a DSC substantially consistent with that of Figure 1 is determined by DSC.
  • the composition of the compound of formula I obtained with the process of the invention and water having a maximum peak at about 123 °C, preferably having a DSC substantially consistent with that of Figure 2 is determined by DSC.
  • the composition of the compound of formula I obtained with the process of the invention and water having a maximum peak at about 127 °C, preferably having a DSC substantially consistent with that of Figure 3 is determined by DSC.
  • the inventors performed the preparation of the B82-type needle crystal according to the method of Example 1 of the patent WO03/018615, and detected it by DSC, and there was no obvious endothermic peak at 120-130 ° C in the DSC chart.
  • 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).
  • HPLC High Performance Liquid Chromatography
  • Diluent phosphate buffer of water
  • Detection wavelength 210 nm
  • Injection volume 10 ⁇ l.
  • 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 spectrum using an X-ray powder diffractometer of the RIGAKU D/max 2550 VB/PC model at a scanning speed of 2° per minute.
  • the compounds of formula I in the compositions of the compounds of formula I according to the invention and water have a specific crystal form with specific characteristic peaks in the X-ray powder diffraction pattern.
  • the X-ray powder diffraction pattern of the compound of formula I in the composition of the 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 X-ray powder diffraction pattern of the compound of formula I in the composition of the invention has characteristic peaks at the following 2 theta angles: 4.4 ⁇ 0.1 °, 5.2 ⁇ 0.1 °, 8.5 ⁇ 0.1 °, 9.6 ⁇ 0.2°; in another preferred embodiment, the map also has characteristic peaks at the following 2 ⁇ angles: 7.5 ⁇ 0.2°, 8.8 ⁇ 0.1°, 16.6 ⁇ 0.1°, 13.7 ⁇ 0.1°, 22.5 ⁇ 0.1°; In a preferred embodiment, the map also has characteristic peaks at the following 2 theta angles: 12.6 ⁇ 0.1 °, 14.9 ⁇ 0.1 °, 15.6 ⁇ 0.2 °, 25.1 ⁇ 0.1 °. More preferably, the compound of formula I in the composition has an X-ray powder diffraction (XRPD) pattern substantially identical to that shown in FIG.
  • XRPD X-ray powder diffraction
  • the material state of the X-ray powder diffraction method is identified by comparing the relative intensity of the diffraction peaks and the mirror spacing d (or 2 ⁇ ) of the different crystalline drug samples.
  • the deviation of the 2 ⁇ angle of the crystal form is specified: “For different crystalline substances of the same chemical substance, the allowable deviation value of 2 ⁇ should be less than ⁇ 0.2°.
  • the US Pharmacopoeia (USP27, pages 2401-2402) also has relevant regulations. "The diffraction angle of the sample and reference should be consistent within the calibration accuracy of the diffractometer (2 ⁇ value should be reproducible, ⁇ 0.10 degrees)". It can be seen that for two crystals of the same compound, when X-ray powder diffraction pattern The upper characteristic peak deviation is greater than ⁇ 0.2° and is considered to be a different characteristic peak, and the two crystals are different crystal forms.
  • the peak at the 2 ⁇ reflection angle on the X-ray powder diffraction pattern of the compound of the formula I in the composition of the compound of the formula I according to the invention and water is a special feature, which corresponds to the X-ray powder diffraction pattern of the B82 crystal disclosed in WO 03/018615. There is a significant difference in the characteristic peaks at the upper 2 ⁇ reflection angle.
  • the absorption intensity and 2 ⁇ angle of the compound of formula I and B82 in the composition are compared as follows: (1) The compound of the formula I in the composition prepared according to the invention has a characteristic absorption peak of medium strength at 5.1-5.2 °, while the X-ray powder diffraction pattern of the crystal of type B82 disclosed in WO 03/018615 has an absorption peak only at 5.5 °, The two characteristic peaks differ by 0.3-0.4°, and the error range measured by the Japanese Pharmacopoeia and the US Pharmacopoeia, as well as the existing X-ray powder diffractometer, is generally within 0.1° and the maximum is not more than 0.2°, so the two The difference in characteristic peaks is not due to instrumental errors, but is indeed a different characteristic peak; (2) the compound of formula I in the composition has the strongest characteristic absorption peak at 4.4°, while the strongest characteristic absorption peak of the B82 type crystal is 9.8°. .
  • the present invention provides a process for the preparation of a combination of a compound of formula I and water.
  • a solvate of a compound of formula I can be obtained by means of lowering the temperature or by adding a poorly soluble solvent or the like to reduce the solubility of the compound of formula I in solution.
  • the obtained solvate is dried together with the aqueous system to remove the organic solvent, and a composition of the compound of the formula I and water having good stability can be obtained.
  • the inventors have finalized the preparation of a combination of a compound of formula I and water after extensive solvent screening tests.
  • a process for the preparation of a composition of a compound of formula I and water comprising the steps of:
  • step (c) The solid obtained in the step (b) is vacuum dried together with the aqueous system to control the moisture content to obtain the composition.
  • 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.
  • 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, 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 water system described in the step (c) is selected from the group consisting of tap water, pure water, ice water mixture or other substances capable of releasing water vapor.
  • the vacuum drying of the obtained solid together with the water system as described in the step (c) means placing the obtained solid in a place where the sample is normally placed under vacuum drying, and is placed around the obtained solid to release water vapor.
  • the open container of the substance means placing the obtained solid in a place where the sample is normally placed under vacuum drying, and is placed around the obtained solid to release water vapor.
  • the controlled moisture content in the step (c) is from 3% to 20%, preferably from 4% to 16%.
  • compositions of the compounds of formula I and water provided herein are in the form of drug substances useful in the preparation of pharmaceutical compositions, particularly for the preparation of a medicament for the treatment of fungal infections.
  • composition of a compound of formula I and water and “a combination of a compound of formula I and water” are used interchangeably and refer to a mixture of a compound of formula I and water, water as water of crystallization and non- The form of crystal water exists.
  • 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 by methods conventional in the art, such as, but not limited to, the preparation of the compound as reported in patent WO9611210; it is also commercially available, such as, but not limited to, such as Fujisawa Corporation of Japan.
  • the term "API" is used in accordance with the provisions of ICH Q7A. Any substance or mixture of substances in the manufacture of a drug, and when used in pharmaceuticals, becomes an active ingredient of a drug. Such substances may have pharmacological activity or other direct effects in the diagnosis, treatment, symptom relief, treatment or prevention of diseases, or may affect the function or structure of the body.
  • the main ingredient has a dry content of more than 90%, preferably more than 95%, more preferably more than 98%.
  • the dry content of the raw material drug refers to the mass percentage of the active ingredient in the raw material medicine after the volatile impurities such as moisture and residual solvent are removed.
  • 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 process for the preparation of a composition of a compound of formula I and water is provided, and the process is very suitable for scale production.
  • Figure 1 shows a DSC spectrum of a composition of a compound of formula I and water.
  • Figure 2 shows a DSC spectrum of a combination of a compound of formula I and water.
  • Figure 3 shows a DSC spectrum of a combination of a compound of formula I and water.
  • Figure 4 is a DSC chart showing the composition of the compound of formula I and water.
  • Figure 5 is an X-ray powder diffraction (XRPD) pattern of a compound of formula I in a composition of a compound of formula I and water;
  • XRPD X-ray powder diffraction
  • Figure 6 shows an amorphous X-ray powder diffraction (XRPD) pattern of a compound of formula I.
  • Figure 7 is a HPLC chromatogram of the composition of the compound of formula I obtained in Example 2 and water at 25 ° C, after 30 days.
  • Fig. 8 is a HPLC chart of the B82 type crystal obtained in Comparative Example 1 at 25 ° C for 30 days.
  • 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 B82-type needle crystal was prepared according to the method of Example 1 of Patent WO 03/018615. It was found by DSC that the crystal had no significant endothermic peak at 120-130 °C.
  • a solid amorphous powder of the compound of formula I is prepared according to the method of U.S. Patent 7,199,248, the XRPD of which is shown in Figure 6.
  • the obtained solid was placed in a vacuum drying oven, and a tray of tap water was placed in the bottom of the drying oven to control the water content of 9.1%, and vacuum-dried to obtain a composition of the compound of the formula I and water, and the purity of the compound of the formula I was 99.53%.
  • the DSC and XRPD patterns are shown in Figures 1 and 5.
  • the obtained solid was placed in a vacuum drying oven, and a tray of crushed ice was placed in the bottom of the drying oven to control the water content of 3%, and vacuum-dried to obtain a composition of the compound of the formula I and water, and the purity of the compound of the formula I was determined by HPLC to be 99.61%. See Figure 2 for the DSC diagram.
  • the obtained solid was placed in a vacuum drying oven, and a disk of ice-water mixture was placed in the bottom of the drying oven to control the water content of 12.3%, and vacuum-dried to obtain a composition of the compound of the formula I and water, and the purity of the compound of the formula I was determined by HPLC to be 99.65%.
  • the obtained solid was placed in a vacuum drying oven, and a disk of ice water mixture was placed in the bottom of the drying oven to control the water content of 4%, and dried under vacuum to obtain a composition of the compound of the formula I and water, and the purity of the compound of the formula I was determined by HPLC to be 99.58%.
  • the obtained solid was placed in a vacuum drying oven, and a disk of pure water was placed in the bottom of the drying oven to control the water content of 8.9%, and dried under vacuum to obtain a composition of the compound of the formula I and water, and the purity of the compound of the formula I was determined by HPLC to be 99.63%.
  • Examples 1-11 and Comparative Examples 1-6 were respectively placed in a sealed state at 25 ° C for 30 days, and then the impurity content of the sample was analyzed.
  • the stability of the composition of the compound of formula I and water having a water content of 3% to 20% is significantly better than that of the B82 type crystal, and is superior to the amorphous solid.
  • the moisture content of the composition of the compound of formula I and water has a significant effect on the stability of the composition, the composition having a water content of from 3% to 20% compared to a composition having a water content of more than 20% or less than 3%. In the case of long-term placement, it has more excellent stability.
  • Example 2 0.2 g of the composition of the compound of the formula I obtained in the same manner as in Example 2 and water was taken, and an eye drop was prepared according to the method of Example 2 of US2007249546A1.

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Abstract

本发明公开了一种含水量在3％-20％的环肽类化合物的组合物，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组合物及其制备方法和用途 技术领域
本发明涉及化合物组合物，更具体地涉及一种环肽类化合物与水的组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 PCTCN2015080229-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。
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°、5.5°、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，为细小针状晶体。暴露在环境中，容易吸潮，稳定性差。
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化合物组合物，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式I化合物与水的组合物。
本发明的另一个目的是提供式I化合物与水的组合物的制备方法。
本发明的又一个目的是提供式I化合物与水的组合物的用途。
式I化合物与水的组合物
本发明提供了式I化合物与水的组合物。
在本发明的一个优选例中，本发明提供本发明提供了式I化合物与水的组合物。
在本发明的一个优选例中，所述组合物中水的质量百分含量为3％-20％。
在本发明的一个优选例中，所述组合物中水的质量百分含量为4％-16％。
在本发明的另一优选例中，所述组合物中式I所示化合物HPLC纯度在98％以上。
在本发明的另一个优选例中，所述组合物在差示扫描量热法图(DSC)上120-130℃有最大峰值。
本领域众所周知，药物的稳定性与水分含量有着密切的关系。在药物相关文献和书籍(例如《药剂学》)中均有报道，水是化学反应的媒介，固体药物吸附了水分以后，在表面形成一层液膜，水解或氧化分解反应在膜中进行，微量的水能加速不稳定药物的分解。原料药物如氨苄青霉素的水分含量要控制比较低的水平，一般在1％左右，水分含量越高分解速度越快。发明人对无定型式I化合物稳定性进行研究后发现，水分含量越低，尤其是水分含量控制在1％以下时，式I化合物稳定性越好。然而即使是水分含量1％以下的无定型式I化合物，在常温下长期保存也会发生明显降解，并不能满足本领域对式I化合物稳定性的要求。
发明人经过大量实验研究发现，式I化合物与水的组合物中水分含量对式Ⅰ化合物的稳定性有重要影响。更令人意外的是，高水分含量不仅没有加速式Ⅰ化合物的分解，使式Ⅰ化合物的稳定性变差，反而有效提高了式Ⅰ化合物的稳定性。其稳定性明显优于其他水分含量时的稳定性，更优于WO03/018615公开的B82型晶体和无定型固体。
发明人通过对不同含水量的式I化合物与水的组合物进行DSC检测及研究后发现，所获得的式I化合物与水的组合物的含水量在3％-20％时，其DSC图在120-130℃附近具有明显的吸热峰，表明组合物中含有结晶水，从DSC图还可以看出组合物还含有非结晶水。组合物中水分含量在3％-20％范围内变化时，非结晶水发生了变化，结晶水并未发生明显变化，因此含水量在3％-20％的组合物始终保持优异的稳定性。而当式I化合物与水的组合物含水量低于3％时，DSC图表明组合物在105℃左右失去了非结晶水，组合物中不含结晶水，稳定性较差。当含水量高于20％时，式I化合物与水的组合物不能以固体形式存在。发明人在稳定性实验中发现，在25℃下放置30天后，含水量在3％以下的式I化合物与水的组合物明显降解，纯度从99.52％降低至92.18％。而相同条件下，含水量在3％以上的式I化合物与水的组合物纯度基本不变。因此，只有控制式I化合物与水的组合物中水分含量在3％-20％范围内，组合物中式I化合物才能稳定存在。
式I化合物与水的组合物的鉴定和性质
本发明人在获得式I化合物与水的组合物后进一步采用多种方式和仪器对其性质进行了研究。
“示差扫描量热分析”，又称“差示量热扫描分析”(DSC)是在加热过程中，测量被测物质与参比物之间的能量差与温度之间关系的一种技术。DSC图谱上的峰位置、形状和峰数目与物质的性质有关，故可以定性地用来鉴定物质。本领域常用该方法来检测物质的相变温度、玻璃化转变温度、反应热等多种参数。DSC测定方法在本领域中是已知的。例如可使用DSC Q20示差扫描量热分析仪，以10℃每分钟的升温速率，从25℃升温至300℃，获得晶体的DSC扫描图谱。在DSC检测过程中，一般情况下被检测物质会在105℃前失去非结晶水，在120℃以上失去的则是结晶水，结晶水在测定中会有明显吸热峰。
在本发明的一个实施方式中，采用DSC测得用本发明方法获得的式I化合物与水的组合物在120-130℃有最大峰值。在本发明的另一个实施方式中，采用DSC测得用本发明方法获得的式I化合物与水的组合物在129℃左右有最大峰值,优选具有与图1基本一致的DSC。在本发明的另一个实施方式中，采用DSC测得用本发明方法获得的式I化合物与水的组合物在123℃左右有最大峰值,优选具有与图2基本一致的DSC。在本发明的又一个实施方式中，采用DSC测得用本发明方法获得的式I化合物与水的组合物在127℃左右具有最大峰值,优选具有与图3基本一致的DSC。
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，并使用DSC对其进行检测，其DSC图中120-130℃没有明显的吸热峰。
本发明人制备的得到了式I化合物的无定型固体，并使用DSC对其进行检测，其DSC图中120-130℃没有明显的吸热峰。
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。
“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。
“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/max2550VB/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化合物与水的组合物中的式I化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，本发明的组合物中的式I化合物的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，本发明的组合物中的式I化合物的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±0.2°；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：7.5±0.2°，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±0.2°，25.1±0.1°。更佳地，所述组合物中的式I化合物具有与图5基本一致所示的X-射线粉末衍射(XRPD)图。
X射线粉末衍射法的物质状态鉴别是通过比较不同晶型药物样品的衍射峰相对强度与镜面间距d(或2θ)值。日本药典中对晶型2θ角偏差的规定：“对于同种化学药物的不同晶型物质，其2θ的允许偏差值应小于±0.2°。美国药典(USP27，2401-2402页)中也有相关规定：“样品和参考物的衍射角应当在衍射仪校准精度范围内一致(2θ值应可重现，±0.10度)”。可见对于同种化合物的两个晶体而言，当X射线粉末衍射图上特征峰偏差大于±0.2°则被认为是不同的特征峰，两个晶体即是不同的晶型。
本发明的式I化合物与水的组合物中的式I化合物的X射线粉末衍射图上2θ反射角处的峰是特别的特征，这与WO03/018615公开的B82型晶体的X射线粉末衍射图上2θ反射角处的特征峰存在明显的差别。组合物中的式I化合物和B82型晶体图谱吸收强度和2θ角比较如下： (1)本发明制备的组合物中的式I化合物在5.1-5.2°存在中等强度的特征吸收峰，而WO03/018615公开的B82型晶体的X射线粉末衍射图仅在5.5°有吸收峰，这两个特征峰相差0.3-0.4°，而根据日本药典和美国药典要求，以及现有X射线粉末衍射仪测定的误差范围一般在0.1°以内，最大也不会超过0.2°，所以这两个特征峰的差别不是仪器误差造成的，确实是不同的特征峰；(2)组合物中的式I化合物在4.4°有最强特征吸收峰，而B82型晶体的最强特征吸收峰为9.8°。因此，本发明制备的组合物中的式I化合物和B82型晶体的X射线粉末衍射图不相同，是两种不同的晶型。
式I化合物与水的组合物的制备
本发明提供式I化合物与水的组合物的制备方法。
发明人在式I化合物的研究过程中发现：单纯的利用两相体系，得到的固体均为无定型且稳定性很差。为了能够获得稳定性好的式I化合物，发明人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，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，能够获得式I化合物的溶剂合物。所获得的溶剂合物与水体系一起干燥去除有机溶剂，能够获得稳定性好的式I化合物与水的组合物。发明人在进行了大量的溶剂筛选试验后，最终确定了式I化合物与水的组合物的制备工艺。
式I化合物与水的组合物的制备方法，所述方法包含以下步骤：
(a)将式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，控制水分含量得到所述的组合物。
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(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。
其中，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。
其中，步骤(c)中所述所述的将所得固体与水体系一起进行真空干燥，是指将所得固体放置在真空干燥通常放置样品的地方，并在所得固体周围放置盛着能释放水蒸汽的物质的敞开的容器。
其中，步骤(c)中所述控制水分含量为3％-20％，优选4％-16％。
式I化合物与水的组合物的用途及其组合物
本发明提供的式I化合物与水的组合物是原料药形式，可用于制备药物组合物，特别是用于制备治疗真菌感染的药物。
相关术语
如本文所用，术语“式I化合物与水的组合物”和“式I所示化合物与水的组合物”可以互换使用，都是指式I化合物与水的混合物，水以结晶水和非结晶水形式存在。
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 PCTCN2015080229-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WO9611210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“原料药”，根据ICH Q7A中的规定是指用于 药品制造中的任何一种物质或物质的混合物，而且在用于制药时，成为药品的一种活性成分。此种物质在疾病的诊断，治疗，症状缓解，处理或疾病的预防中有药理活性或其他直接作用，或者能影响机体的功能或结构。指用于生产各类制剂的原料药物，是制剂中的有效成份，但病人无法直接服用的物质。所述原料药中主成分折干含量大于90％，优选大于95％，更优选大于98％。所述原料药折干含量，是指原料药中折除水分、残留溶剂等挥发性杂质后，有效成份占原料药的质量百分比。
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.提供一种稳定性优越的式I化合物与水的组合物，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化合物与水的组合物的制备方法，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化合物与水的组合物的DSC谱图。
图2所示为式I化合物与水的组合物的DSC谱图。
图3所示为式I化合物与水的组合物的DSC谱图。
图4所示为式I化合物与水的组合物的DSC谱图。
图5所示为式I化合物与水的组合物中的式I化合物的X射线粉末衍射(XRPD)图谱；其中
峰号 2-θ d(A) I％(相对强度)
1 4.4 19.8888 100.0
2 5.2 17.0426 46.0
3 7.5 11.8100 20.3
4 8.5 10.3938 55.2
5 8.8 10.0411 46.5
6 9.6 9.2244 69.7
7 12.6 7.0200 19.3
8 13.7 6.4581 25.4
9 14.9 5.9329 20.4
10 15.7 5.6400 25.4
11 16.7 5.3169 41.9
12 22.5 3.9443 43.0
13 25.1 3.5395 38.0
图6所示为式I化合物无定型的X射线粉末衍射(XRPD)图谱。
图7所示为实施例2获得的式I化合物与水的组合物在25℃,30天后的HPLC图谱。
图8所示为对比例1获得的B82型晶体在25℃,30天后的HPLC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。
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B82型针状晶体。使用DSC检测发现该晶体在120-130℃没有明显的吸热峰。
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XRPD见附图6。
实施例2
制备式I化合物与水的组合物
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℃，溶液中有固体析出，并保持此温度继续搅拌3.5h大量固体析出，慢慢加入90ml乙酸乙酯，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘自来水，控制含水量9.1％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.53％。其DSC、XRPD图见附图1和5。
实施例3
制备式I化合物与水的组合物
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。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量16％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.5％。
实施例4
制备式I化合物与水的组合物
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℃，溶液中有固体析出，继续搅拌2h大量固体析出，过滤得到式I化合物固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘碎冰，控制含水量3％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.61％。其DSC图见附图2。
实施例5
制备式I化合物与水的组合物
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＝1:4:1)中，降温至30℃，溶液中有固体析出，继续搅拌30min大量固体析出，慢慢加入200ml异丙醇，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量20％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.64％。其DSC图见附图3。
实施例6
制备式I化合物与水的组合物
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乙酸甲酯，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘自来水，控制含水量18.3％，真空干燥得到式I化合 物与水的组合物，HPLC测得式I化合物纯度99.63％。
实施例7
制备式I化合物与水的组合物
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℃，溶液中有固体析出，继续搅拌4h大量固体析出，过滤得到固体。将所得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，控制含水量12.3％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.65％。
实施例8
制备式I化合物与水的组合物
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大量固体析出，慢慢加入100ml乙酸异丙酯，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量6.3％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.64％。
实施例9
制备式I化合物与水的组合物
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，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量3.7％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.42％。
实施例10
制备式I化合物与水的组合物
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℃，溶液中有固体析出，继续搅拌1h大量固体析出，过滤得到固体。将所得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，控制含水量4％，真空干燥得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.58％。
实施例11
制备式I化合物与水的组合物
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大量固体析出，慢慢加入100ml乙酸乙酯，过滤得到固体。所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量8.9％，真空干燥，得到式I化合物与水的组合物，HPLC测得式I化合物纯度99.63％。
比较例2
制备不同含水量的式I化合物与水的组合物
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℃，溶液中有固体析出，继续搅拌30min大量固体析出，慢慢加入200ml异丙醇，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量23.5％，真空干燥得到式I化合物与水的组合物，组合物为半液态。
比较例3
制备不同含水量的式I化合物与水的组合物
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＝1:3:2)中，降温至15℃，溶液中有晶体析出，继续搅拌2h大量固体析出，慢慢加入100ml乙酸异丙酯，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘纯水，控制含水量2.3％，真空干燥得到式I化合物与水的组合物。其DSC图见附图4。
比较例4
制备不同含水量的式I化合物与水的组合物
将由实施例1制备得到的无定型的式I化合物2.7g，45℃下溶解于80ml甲醇/正丙醇水溶液(正丙醇：水：甲醇＝8:3:1)中，降温至10℃，溶液中有固体析出，继续搅拌1h大量固体析出，过滤得到固体。将所得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，控制含水量27.3％，得到式I化合物与水的组合物，组合物为半液态。
比较例5
制备不同含水量的式I化合物与水的组合物
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℃，溶液中有固体析出，并保持此温度继续搅拌3.5h大量固体析出，慢慢加入90ml乙酸乙酯，过滤得到固体。将所得固体放入真空干燥箱中，在干燥箱内底部放一盘自来水，控制含水量1.1％，真空干燥得到式I化合物与水的组合物。
比较例6
按照实施例2的制备方法：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/水溶液(甲醇：水＝3:2)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大量固体析出，慢慢加入90ml乙酸乙酯，过滤得到固体，将所得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，测得其含水量为0.8％。所得固体经XRPD检测发现为无定型，DSC检测发现在120-130℃没有明显的吸热峰。
使用不同溶剂按上述方法制备并使用XRPD检测所得固体结构，结果如下：
序号 溶剂 所得固体结构
1 甲醇：水＝3:2 无定型
2 乙醇：水＝5:1 无定型
3 异丙醇：水＝2:3 无定型
4 异丁醇：水＝4:1 无定型
5 正丁醇：水＝9:1 无定型
6 丙酮：水＝4:1 无定型
7 乙腈：水＝3:1 无定型
8 甲醇：乙醇：水＝8:2:1 无定型
9 丙醇：丁醇：水＝6:5:3 无定型
10 甲醇：丁醇：水＝1:7:2 无定型
11 乙醇：丁醇：水＝2:2:5 无定型
12 甲醇：乙腈：水＝4:1:2 无定型
13 甲醇：乙醇：水＝9:2:2 无定型
实施例12
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1-11，比较例1-6的样品，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化合物与水的组合物与B82型晶体、无定型固体稳定性比较结果见下表：
样品 形态 起始样品纯度 25℃，30天样品纯度
实施例2 式I化合物与水的组合物 99.53％ 99.5％
比较例1 B82型晶体 99.50％ 96.98％
比较例6 无定型 99.38％ 89.27％
本发明中不同含水量的式I化合物与水的组合物稳定性比较结果见下表：
样品 含水量 起始样品纯度 25℃，30天样品纯度
实施例2 9.1％ 99.53％ 99.50％
实施例3 16％ 99.5％ 99.37％
实施例4 3％ 99.61％ 99.03％
实施例5 20％ 99.64％ 99.31％
实施例6 18.3％ 99.63％ 99.37％
实施例7 12.3％ 99.65％ 99.60％
实施例8 6.3％ 99.64％ 99.59％
实施例9 3.7％ 99.42％ 99.2％
实施例10 4％ 99.58％ 99.45％
实施例11 8.9％ 99.63％ 99.61％
比较例2 23.5％ 99.66％ 95.42％
比较例3 2.3％ 99.61％ 94.33％
比较例4 27.3％ 99.53％ 93.48％
比较例5 1.1％ 99.52％ 92.18％
由上述数据可知，含水量在3％-20％的式I化合物与水的组合物的稳定性明显优于B82型晶体，更优于无定型固体。且式I化合物与水的组合物中水分含量对组合物稳定性有显著影响，含水量在3％-20％的组合物与含水量高于20％或者低于3％的组合物相比，在长时间放置的情况下，具有更加优异的稳定性。
实施例12
药物组合物的制备
式I化合物与水的组合物 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化合物与水的组合物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化合物与水的组合物的药物组合物。
实施例13
药物组合物的制备
取按实施例2的方法获得的式I化合物与水的组合物0.2g，按照US2007249546A1实施例2的方法制备成滴眼液。
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 (26)

  1. 一种式I所示化合物与水的组合物，其特征在于，所述组合物中水的质量百分含量为3％-20％；
    Figure PCTCN2015080229-appb-100001
  2. 如权利要求1所述的组合物，其特征在于，所述组合物中水的质量百分含量为4％-16％。
  3. 如权利要求1所述的组合物，其特征在于，所述组合物中式I所示化合物HPLC纯度在98％以上。
  4. 一种制备如权利要求1-3任一所述的组合物的方法，其特征在于，所述方法包含以下步骤：
    (a)将式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，控制水分含量得到如权利要求1-3任一所述的组合物。
  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 醇类混合溶液选自：甲醇/异丁醇、甲醇/异丙醇、甲醇/正丙醇。
  6. 如权利要求5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。
  7. 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，醇的总体积与水体积比为0.1-100，优选0.5-10，更优选1-7。
  8. 如权利要求4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。
  9. 如权利要求4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℃。
  10. 如权利要求4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。
  11. 如权利要求4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。
  12. 如权利要求4所述的制备方法，其特征在于，步骤(c)中所述控制水分含量为3％-20％。
  13. 如权利要求12所述的制备方法，其特征在于，步骤(c)中所述控制水分含量为4％-16％。
  14. 一种如权利要求1-3任一所述的组合物的用途，其特征在于，用于制备治疗真菌感染的药物。
  15. 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1-3任一所述的组合物和药学上可接受的载体。
  16. 一种如权利要求15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1-3任一所述的组合物和药学上可接受的载体混合，得到如权利要求15所述的药物组合物。
  17. 如权利要求1所述的组合物，其特征在于，所述组合物在差示扫描量热法图(DSC)上120-130℃有最大峰值。
  18. 如权利要求1所述的组合物，其特征在于，所述组合物中式I所示化合物以晶体形式存在。
  19. 如权利要求18所述的组合物，其特征在于，所述的以晶体形式存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角有峰：4.4±0.2°，5.2±0.2°，8.5±0.2°，9.6±0.2°。
  20. 如权利要求19所述的组合物，其特征在于,所述的以晶体形式存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：7.5±0.2°，8.8±0.2°，16.6±0.2°，13.7±0.2°，22.5±0.2°。
  21. 如权利要求20所述的组合物，其特征在于,所述的以晶体形式存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：12.6±0.2°，14.9±0.2°，15.6±0.2°，25.1±0.2°。
  22. 如权利要求19所述的组合物，其特征在于，所述的以晶体形式 存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角有峰：4.4±0.1°，5.2±0.1°，8.5±0.1°，9.6±0.1°。
  23. 如权利要求22所述的组合物，其特征在于,所述的以晶体形式存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：7.5±0.1°，8.8±0.1°，16.6±0.1°，13.7±0.1°，22.5±0.1°。
  24. 如权利要求23所述的组合物，其特征在于,所述的以晶体形式存在的式I所示化合物的X-射线粉末衍射(XRPD)图上在下述2θ角还有峰：12.6±0.1°，14.9±0.1°，15.6±0.1°，25.1±0.1°。
  25. 如权利要求1所述的组合物，其特征在于，所述组合物中式I所示化合物折干含量在98％以上。
  26. 如权利要求2所述的组合物，其特征在于，所述组合物为原料药。
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