WO2017032281A1 - 帕比司他乳酸盐的新晶型 - Google Patents

帕比司他乳酸盐的新晶型 Download PDF

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WO2017032281A1
WO2017032281A1 PCT/CN2016/096075 CN2016096075W WO2017032281A1 WO 2017032281 A1 WO2017032281 A1 WO 2017032281A1 CN 2016096075 W CN2016096075 W CN 2016096075W WO 2017032281 A1 WO2017032281 A1 WO 2017032281A1
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lactate
paclitaxel
crystal form
ray powder
powder diffraction
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PCT/CN2016/096075
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English (en)
French (fr)
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陈敏华
张炎锋
李骄洋
张晓宇
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苏州晶云药物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

  • the present invention relates to a novel crystalline form of pabisstat lactate and a process for its preparation and use.
  • the crystal form is known to be an important factor affecting the quality of the drug. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, the development of new crystal forms that are more suitable for application is of great significance for drug development.
  • Panobinostat an anticancer drug developed by Novartis, is a small molecule histone deacetylase (HDAC) inhibitor that blocks cancer and various pathological pathways associated with cancer and reduces cancer. The survival of the cells induces apoptosis of cancer cells.
  • HDAC histone deacetylase
  • Pabicz Panobinostat; trade name Farydak
  • CN101641328B, CN102584673B, CN101466672B and the like have reported an anhydrate form A of pabastatin lactate, a monohydrate form H A , and an ethanol solvate S A .
  • the prior art teaches that in most cases, Form H A is slowly converted to Form A, which is less stable and unsuitable for development.
  • the solvate introduces impurity molecules and is not suitable for development when selected.
  • the new crystalline form of pabisstat lactate provided by the present invention has an advantage in solubility and particle size compared to the prior art superior crystalline form A, and an unexpected technical effect is obtained.
  • One of the objects of the present invention is to provide a new crystalline form of pabisstat lactate.
  • Another object of the present invention is to provide a method and use for the preparation of the novel crystalline form.
  • the present invention adopts the following technical solutions:
  • a pabbital lactate crystal form H having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having a 2theta value of 11.8 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, 15.0 ° ⁇ 0.2 ° Characteristic peaks.
  • the X-ray powder diffraction pattern of Form H also has a diffraction peak at one or more of the 2theta values of 20.4 ° ⁇ 0.2 °, 22.5 ° ⁇ 0.2 °, and 19.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form H also has a diffraction peak at one or more of the 2theta values of 15.9 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, and 9.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form H is substantially identical to that of Figure 1.
  • the crystal form H has a weight loss of about 2.8% when subjected to thermogravimetric analysis.
  • a significant advantage of the crystalline form H of the present invention over the prior art form of pacitrate lactate is that it has a relatively higher solubility and can increase the bioavailability of the drug.
  • the solubility of Form H in simulated artificial gastric juice at pH 1.8 is greater than 4.5 mg/mL at room temperature, and the solubility in artificial intestinal juice is greater than 0.2 mg/mL under simulated feeding state of pH 5.0, simulated fasting at pH 6.5.
  • the solubility in artificial intestinal juice is greater than 0.4 mg/mL.
  • the present invention also provides a paclitaxel lactate crystal form I having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C in a 2theta value of 10.2 ° ⁇ 0.2 °, 25.0 ° ⁇ 0.2 °, 22.9 ° ⁇ There is a characteristic peak at 0.2°.
  • the X-ray powder diffraction pattern of Form I also has a diffraction peak at one or more of the 2theta values of 19.5 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, and 24.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I also has a diffraction peak at one or more of the 2theta values of 9.8 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, and 20.3 ° ⁇ 0.2 °.
  • Form I is substantially identical to that of FIG.
  • Form I begins to exhibit a first endothermic peak at 54.7 ⁇ 2 ° C and a second endothermic peak begins at 142.0 ⁇ 2 ° C.
  • Form I had a weight loss of about 12.4% when subjected to thermogravimetric analysis.
  • Form I can be converted to Form H by vacuum drying of Form I at room temperature.
  • the present invention also provides a paclitaxel lactate crystal form G having an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C in a 2theta value of 7.7 ° ⁇ 0.2 °, 20.0 ° ⁇ 0.2 °, 10.3 ° ⁇ There is a characteristic peak at 0.2°.
  • the X-ray powder diffraction pattern of Form G also has a diffraction peak at one or more of the 2theta values of 6.5 ° ⁇ 0.2 °, 17.4 ° ⁇ 0.2 °, and 15.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form G is still at a 2theta value of 16.3 ° ⁇ 0.2 °, 22.4 ° ⁇ 0.2 °, 23.5 ° ⁇ 0.2 ° One or more of them have diffraction peaks.
  • the X-ray powder diffraction pattern of Form G is substantially identical to that of Figure 8.
  • Form G began to exhibit a first endothermic peak at 65.2 ⁇ 2 ° C, and a second endothermic peak appeared at 116.0 ⁇ 2 ° C.
  • Form G when subjected to thermogravimetric analysis, Form G has a weight loss of about 5.5%, and this Form G is a hydrate.
  • the invention also relates to the use of the above crystalline form for the preparation of an anticancer drug.
  • the present invention also provides a pharmaceutical preparation comprising one or more of the above-described paclitaxel lactate crystal forms.
  • the pharmaceutical preparation is usually an anticancer drug.
  • the paclitaxel lactate form H can be obtained by subjecting paclitaxel to lactic acid in a mixed solvent of an alcohol solvent and an ester solvent at room temperature to precipitate a solid. Finally, the solid is collected (for example, by centrifuging the supernatant) and dried (usually under vacuum at room temperature).
  • the ester solvent is preferably isopropyl acetate or n-butyl acetate
  • the alcohol solvent is preferably methanol.
  • the molar ratio of pabitatin to lactic acid feed is from 1:0.8 to 1.4, preferably from 1:1 to 1.3.
  • the method is carried out by dissolving lactic acid in an alcohol solvent to obtain an alcohol solution of lactic acid, and then slowly dropping the alcohol solution into a mixed system of pabisstat and an ester solvent at room temperature. Stir under for at least 18 hours.
  • the stirring time at room temperature is 20 hours or more, more preferably 24 hours or more, and most preferably 24 to 48 hours.
  • the paclitaxel lactate crystal form G can be obtained by reacting paclitaxel with lactic acid in a mixed solvent of an alcohol solvent and toluene, and finally volatilizing to remove the solvent to obtain a crystal form G,
  • the molar ratio of paclitaxel to lactic acid feed is 1:0.8 to 1.2, preferably 1:1 to 1.1
  • the alcohol solvent is preferably methanol.
  • the method is carried out as follows: dissolving lactic acid in an alcohol solvent to obtain an alcohol solution of lactic acid, and then adding the solution to paclitaxel, adding toluene, and observing the solution after clarification, placing The solvent is removed by volatilization at a temperature of 10 ° C or less, and finally, the solvent is removed by volatilization at room temperature.
  • the time of 10 ° C or lower is 1 hour or longer, more preferably 2 hours or longer, and most preferably 2 to 4 hours.
  • the paclitaxel lactate crystal form I can be obtained by dissolving pabexatin and lactic acid in a mixed solvent of an alcohol solvent and an ester solvent at room temperature to precipitate a solid. Finally, the supernatant is centrifuged to remove the supernatant.
  • the ester solvent is preferably isopropyl acetate or n-butyl acetate, and the alcohol solvent is preferably methanol.
  • the molar ratio of pabitatin to lactic acid feed is from 1:0.8 to 1.4, preferably from 1:1 to 1.3.
  • the method is carried out by dissolving lactic acid in an alcohol solvent to obtain an alcohol solution of lactic acid, and then slowly dropping the alcohol solution into a mixed system of pabisstat and an ester solvent at room temperature. After stirring for at least 18 hours, centrifugation was carried out.
  • the stirring time at room temperature is 20 hours or more, more preferably 24 hours or more, and most preferably 24 to 48 hours.
  • the lactate in the paclitaxel lactate of the present invention may be L-lactate, D-lactate, or DL-lactate, and experiments have shown that these three structural forms exhibit the same XRPD diffraction peak. .
  • the paclitaxel lactate is paclitaxel lactate L-Lactate.
  • the present invention has the following advantages compared with the prior art:
  • the inventors of the present application have unexpectedly discovered three new crystal forms of pabisstat lactate, and the discovery of these three crystal forms can help researchers understand and control the polymorphism of pabiscital lactate, which is advantageous for preparation. More effective or stable drugs.
  • the crystal form H of the present invention has good stability, and the solubility is significantly improved and the wettability is lower than that of the existing pabestatin lactate form A.
  • the crystal form G of the invention has good stability, and the crystal form G is more suitable for application in the development of the nano-powder preparation than the existing pabestatin lactate form A, and can simplify the preparation process and industrialization of the nano-powder. The value is significant.
  • the crystalline form I of the present invention has a purification effect and can be used as a raw material for preparing a stable crystalline form H.
  • Figure 1 is an XRPD pattern of the crystalline form H of pabisstat lactate:
  • Figure 2 is a DSC chart of Form H of pabastatin lactate
  • Figure 3 is a TGA diagram of Form H of pabisstat lactate
  • Figure 4 is a 1 H NMR chart of Form H of pabastatin lactate
  • Figure 5 is an XRPD pattern of Form I of Pabisstat Lactate:
  • Figure 6 is a DSC chart of Form I of Pabisstat Lactate
  • Figure 7 is a TGA diagram of Form I of pabastatin lactate
  • Figure 8 is an XRPD pattern of the crystalline form G of pabisstat lactate:
  • Figure 9 is a DSC chart of the crystalline form G of pabisstat lactate:
  • Figure 10 is a TGA diagram of Form G of pabisstat lactate:
  • Figure 11 is a 1 H NMR chart of Form G of pabastatin lactate
  • Figure 12 shows the stability of Form H of pabiscital lactate, where the A spectrum is the XRPD pattern of the crystalline H sample at the start, and the B spectrum is the crystalline H sample at 25 ° C, 60% humidity. The obtained XRPD pattern was tested after being placed for 11 months under conditions; C is the XRPD pattern of the crystalline H sample after being placed at 40 ° C, 75% humidity for 11 months;
  • Figure 13 shows the stability of Form G of pabastatin lactate, where the A spectrum is the XRPD pattern of the crystalline Form G sample at the beginning, and the B spectrum is the Form G sample at 25 ° C, 60% humidity. The obtained XRPD pattern was tested after being placed for 11 months under the conditions;
  • Figure C is the XRPD pattern of the Form G sample after being placed at 40 ° C, 75% humidity for 11 months;
  • Figure 14 is a transmission electron micrograph of the crystalline form G of paclitaxel lactate of the present invention.
  • Figure 15 is a transmission electron micrograph of Pabastol lactate Form A reported by CN102584673B;
  • Figure 16 is a DVS diagram of Form H of paclitaxel lactate of the present invention.
  • Figure 17 is a DVS diagram of paclitaxel lactate Form A reported by CN102584673B.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like.
  • Preparation method of paclitaxel lactate form H Weigh 19.7 mg of pabisstat, add it to 0.4 mL of isopropyl acetate, and dissolve 6.8 mg of L-lactic acid in 0.1 mL of methanol. Solution and slowly add the solution to the solution In a mixed system of pabisstat and isopropyl acetate, stirring was carried out for 24 hours at room temperature, and the supernatant was filtered off by centrifugation, and vacuum-dried at room temperature for 3 hours to obtain a solid.
  • the X-ray powder diffraction data of Form H is shown in Table 1.
  • the XRPD pattern is shown in Figure 1.
  • the 2theta value is 11.75°, 21.03°.
  • the diffraction peak at 14.94° is a characteristic peak.
  • the diffraction peaks at 2theta values of 20.38°, 22.53°, and 19.35° are important peaks.
  • the diffraction peaks at 2theta values of 15.87°, 16.78, and 9.69° are the most important peaks.
  • the DSC pattern of Form H is shown in Figure 2, which shows that an endothermic peak begins to appear when heated to around 141.2 °C.
  • Preparation method of paclitaxel lactate form H Weigh 19.7 mg of pabisstat, add it to 0.4 mL of n-butyl acetate, and dissolve 6.8 mg of L-lactic acid in 0.1 mL of methanol. The solution was slowly added dropwise to a mixed system of pabisstat and n-butyl acetate, and stirred at room temperature for 24 hours. The supernatant was filtered off by centrifugation and dried under vacuum at room temperature for 3 hours to obtain a solid. .
  • the X-ray powder diffraction data of the form H obtained in this example is shown in Table 2.
  • Table 2 The X-ray powder diffraction data of the form H obtained in this example is shown in Table 2.
  • the diffraction peaks at 2theta values of 11.75°, 21.06° and 14.98° are characteristic peaks.
  • the diffraction peaks at 2theta values of 20.44°, 22.53°, and 19.34° are important peaks.
  • the diffraction peaks at 2theta values of 15.87°, 16.78, and 9.69° are the most important peaks.
  • Preparation method of paclitaxel lactate form I Weigh 19.7 mg of pabisstat, add it to 0.4 mL of isopropyl acetate, and dissolve 6.8 mg of L-lactic acid in 0.1 mL of methanol. The solution was slowly added dropwise to a mixed system of pabisstat and isopropyl acetate, and stirred at room temperature for 24 hours, and the supernatant was filtered off by centrifugation to obtain a solid crystal form I.
  • the X-ray powder diffraction data of Form I is shown in Table 3.
  • the XRPD pattern is shown in Figure 5.
  • the 2theta value is 10.16°, 25.03°.
  • the diffraction peak at 22.85° is a characteristic peak.
  • the diffraction peaks at 2theta values of 19.46°, 18.98°, and 24.53° are important peaks.
  • the diffraction peak at 2theta values of 9.77°, 13.74, and 20.25° is the second most important peak.
  • the DSC pattern of Form I is shown in Figure 6, which shows that an endothermic peak begins to appear when heated to around 54.7 °C.
  • the TGA plot of Form I is shown in Figure 7, which shows a weight loss gradient of about 12.4% when heated to 140 °C.
  • Preparation method of paclitaxel lactate form G Weigh 19.4 mg of pabestatin, dissolve 5.16 mg of L-lactic acid in 0.3 mL of methanol to form a solution, and slowly add the solution to the paprizita. Further, 0.15 mL of toluene was further added, and after complete clarification was observed, it was allowed to stand at 4 ° C for two hours, and then left to volatilize at room temperature to obtain a solid crystal form G.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 4.
  • the XRPD pattern is shown in Figure 8.
  • the diffraction peaks at 7.73°, 19.97°, and 10.28° are characteristic peaks based on various factors such as d value, low angle, intensity, characteristic line and peak shape.
  • the diffraction peaks at 2theta values of 6.48°, 17.42°, and 15.37° are important peaks.
  • the 2theta values are the most important peaks at 16.27°, 22.38, and 23.49°.
  • the DSC chart of the crystal form G obtained in this example is shown in Fig. 9, which shows that an endothermic peak starts to appear when heated to around 65.2 °C.
  • TGA pattern of Form G obtained in this example is shown in Figure 10, which shows a weight loss gradient of about 5.5% when heated to 110 °C.
  • the NMR spectrum of the product of the form G obtained in the present example is shown in Fig. 11.
  • the crystalline form H of paclitaxel lactate of the present invention and the existing pabestatin lactate form A sample were respectively pH 1.8SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (simulated eating state)
  • the artificial intestinal juice), pH 6.5 FaSSIF (simulated artificial intestinal juice in the fasting state) was prepared into a saturated solution, and after 1 hour, the content of the sample in the saturated solution was determined by high performance liquid chromatography. The results are shown in Table 5.
  • Form H has good stability.
  • the crystal form G has the same crystal form before and after standing, and the stability is also good.
  • the transmission electron microscope sample test method is as follows: place about 0.5 mg of the sample in a vial, add ethanol as a dispersing agent, fully ultrasonically oscillate and disperse uniformly, add a small amount of turbid liquid to the small copper piece, and dry it under infrared light for 10 minutes. Above until it is completely dry. The sample was placed in a transmission electron microscope to start the test.
  • TEM transmission electron microscopy
  • the existing pabitastyl lactate form A particles have a diameter on the order of micrometers and a large particle size.
  • the crystal form G particles of the present invention have a particle size of nanometers, which is very suitable.
  • the crystalline form G of the present invention can improve the permeation efficiency of the drug in human tissues, and the specific surface area of the crystalline form G is larger than that of the form A, which can increase the dissolution rate of the drug in the living body, thereby achieving high Through the effect of high absorption.
  • the crystal form G is more suitable for application in the development of a nano-fine powder preparation, and can simplify the preparation process of the nano-fine powder, and the industrialization value is remarkable.
  • the form H prepared in the examples of the present invention and about 10 mg of the paclitaxel lactate form A reported in the prior CN102584673B were tested for wettability by a dynamic moisture adsorption (DVS) instrument.
  • the experimental results are shown in Table 6.
  • the DVS diagram of the wettability test is shown in Figs. 16 and 17 .
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%

Abstract

提供帕比司他乳酸盐的新晶型，分别命名为晶型G、晶型H及晶型I。晶型G的X射线粉末衍射图在2theta值为7.7°±0.2°, 20.0°±0.2°, 10.3°±0.2°处具有特征峰。晶型H的X射线粉末衍射图在2theta值为11.8°±0.2°, 21.0°±0.2°, 15.0°±0.2°处具有特征峰。晶型I的X射线粉末衍射图在2theta值为10.2°±0.2°, 25.0°±0.2°, 22.9°±0.2°处具有特征峰。提供的帕比司他乳酸盐的三种新晶型能够帮助研究者了解和控制帕比司他乳酸盐多晶现象，有利于制备更有效或更稳定的药物。

Description

帕比司他乳酸盐的新晶型 技术领域
本发明涉及帕比司他乳酸盐的新晶型及其制备方法和用途。
背景技术
已知晶型是影响药品质量的重要因素。同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效产生不同的影响。因此，研发新的更适合应用的晶型对于药物开发具有非常重要的意义。
由诺华公司研制开发的抗癌药帕比司他(Panobinostat)是一种小分子的组蛋白去乙酰酶(HDAC)抑制剂，能阻断癌症和与癌症发生有关的多种病理通路，降低癌细胞的存活，诱导癌细胞的凋亡。帕比司他的CAS号为404950-80-7，化学结构式如下：
Figure PCTCN2016096075-appb-000001
2015年2月23日，美国FDA批准帕比司他(Panobinostat；商品名Farydak)用于多发性骨髓瘤患者治疗。
目前，已有CN101641328B、CN102584673B、CN101466672B等报道了帕比司他乳酸盐的无水物形式A、一水合物形式HA、乙醇溶剂合物SA。现有技术指出，在大多数情况下，形式HA缓慢转化成形式A，该晶型稳定性较差，不适合用于开发。而溶剂合物引入了杂质分子，在有选择的情况下不适合用于开发。
本发明提供的帕比司他乳酸盐的新晶型，相比现有技术的优势晶型形式A，在溶解度、粒径方面具有优势，取得了意想不到的技术效果。
发明内容
本发明的目的之一是提供帕比司他乳酸盐的新晶型。
本发明的目的之二是提供所述新晶型的制备方法和用途。
为实现以上目的，本发明采取如下技术方案：
一种帕比司他乳酸盐晶型H，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为11.8°±0.2°，21.0°±0.2°，15.0°±0.2°处具有特征峰。
进一步地，晶型H的X射线粉末衍射图还在2theta值为20.4°±0.2°，22.5°±0.2°，19.4°±0.2°中的一处或多处具有衍射峰。
进一步地，晶型H的X射线粉末衍射图还在2theta值为15.9°±0.2°，16.8°±0.2°，9.7°±0.2°中的一处或多处具有衍射峰。
根据本发明的一个具体方面，晶型H的X射线粉末衍射图基本上与图1一致。
进一步地，当进行差示扫描量热分析时，所述晶型H在141±2℃开始出现吸热峰。
进一步地，当进行热重分析时，所述晶型H具有约2.8％的失重。
本发明晶型H与现有的帕比司他乳酸盐晶型相比的一个显著优势是其具有相对更高的溶解度，可以提高该药物的生物利用度。根据测试，室温下，晶型H在pH 1.8的模拟人工胃液中的溶解度大于4.5mg/mL，在pH 5.0的模拟进食状态下人工肠液中的溶解度大于0.2mg/mL，在pH 6.5的模拟空腹状态下人工肠液中溶解度大于0.4mg/mL。
本发明还提供一种帕比司他乳酸盐晶型I，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为10.2°±0.2°，25.0°±0.2°，22.9°±0.2°处具有特征峰。
进一步地，晶型I的X射线粉末衍射图还在2theta值为19.5°±0.2°，19.0°±0.2°，24.5°±0.2°中的一处或多处具有衍射峰。
进一步地，晶型I的X射线粉末衍射图还在2theta值为9.8°±0.2°，13.7°±0.2°，20.3°±0.2°中的一处或多处具有衍射峰。
进一步地，晶型I的X射线粉末衍射图基本上与图5一致。
进一步地，当进行差示扫描量热分析时，晶型I在54.7±2℃开始出现第一个吸热峰，在142.0±2℃开始出现第二个吸热峰。
进一步地，当进行热重分析时，晶型I具有约12.4％的失重。通过室温下真空干燥晶型I可以转化为晶型H。
本发明还提供一种帕比司他乳酸盐晶型G，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为7.7°±0.2°，20.0°±0.2°，10.3°±0.2°处具有特征峰。
进一步地，晶型G的X射线粉末衍射图还在2theta值为6.5°±0.2°，17.4°±0.2°，15.4°±0.2°中的一处或多处具有衍射峰。
进一步地，晶型G的X射线粉末衍射图还在2theta值为16.3°±0.2°，22.4°±0.2°，23.5°±0.2° 中的一处或多处具有衍射峰。
优选地，晶型G的X射线粉末衍射图基本上与图8一致。
进一步地，当进行差示扫描量热分析时，晶型G在65.2±2℃开始出现第一个吸热峰，在116.0±2℃开始出现第二个吸热峰。
进一步地，当进行热重分析时，晶型G具有约5.5％的失重，此晶型G为水合物。
本发明还涉及上述晶型在制备抗癌药物中的应用。
本发明同时还提供一种药物制剂，其包含上述的帕比司他乳酸盐晶型中的一种或多种。该药物制剂通常为抗癌药物。
根据本发明，帕比司他乳酸盐晶型H可通过如下方法制得：使帕比司他与乳酸在醇类溶剂和酯类溶剂的混合溶剂中，于室温条件下搅拌，有固体析出，最后收集固体(例如通过离心滤掉上清液)，并进行干燥(通常在室温真空下)即得。所述酯类溶剂优选为乙酸异丙酯或者乙酸正丁酯，所述醇类溶剂优选甲醇。帕比司他与乳酸投料摩尔比为1∶0.8～1.4，优选1∶1～1.3。根据一个具体的方面，所述方法实施如下：将乳酸溶解于醇类溶剂中获得乳酸的醇溶液，然后将该醇溶液缓慢滴加到帕比司他和酯类溶剂的混合体系中，于室温下搅拌至少18小时。优选地，室温下搅拌时间为20小时以上，更优选24小时以上，最优选24～48小时。
根据本发明，帕比司他乳酸盐晶型G可通过如下方法制得：使帕比司他与乳酸在醇类溶剂和甲苯的混合溶剂中反应，最后挥发除去溶剂即得晶型G，其中帕比司他与乳酸投料摩尔比为1∶0.8～1.2，优选1∶1～1.1，醇类溶剂优选甲醇。根据一个具体的方面，所述方法实施如下：将乳酸溶解于醇类溶剂中获得乳酸的醇溶液，然后将该溶液加入到帕比司他中，再加入甲苯，观察到溶液澄清后，置于10℃以下0.5小时以上，最后置于室温下通过挥发除去溶剂，其中优选地，置于10℃以下的时间为1小时以上，更优选为2小时以上，最优选为2～4小时。
根据本发明，帕比司他乳酸盐晶型I可通过如下方法制得：使帕比司他与乳酸在醇类溶剂和酯类溶剂的混合溶剂中，于室温条件下搅拌，有固体析出，最后离心滤掉上清液，即得。所述酯类溶剂优选为乙酸异丙酯或者乙酸正丁酯，所述醇类溶剂优选甲醇。帕比司他与乳酸投料摩尔比为1∶0.8～1.4，优选1∶1～1.3。根据一个具体的方面，所述方法实施如下：将乳酸溶解于醇类溶剂中获得乳酸的醇溶液，然后将该醇溶液缓慢滴加到帕比司他和酯类溶剂的混合体系中，于室温下搅拌至少18小时后，进行离心。优选地，室温下搅拌时间为20小时以上，更优选24小时以上，最优选24～48小时。
本发明的帕比司他乳酸盐中乳酸盐可以是L-乳酸盐，D-乳酸盐，或DL-乳酸盐，实验表明，这三种结构形式表现出相同的XRPD衍射峰。
根据一个具体且优选方面，帕比司他乳酸盐为帕比司他乳酸盐左旋乳酸盐。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本申请发明人意外发现了帕比司他乳酸盐的三种新的晶型，这三种晶型的发现能够帮助研究者了解和控制帕比司他乳酸盐多晶现象，有利于制备更有效或更稳定的药物。
本发明的晶型H稳定性良好，与现有帕比司他乳酸盐形式A相比，溶解度有较明显提高，引湿性较低。
本发明的晶型G稳定性良好，与现有帕比司他乳酸盐形式A相比，晶型G更适于应用在纳米微粉制剂的开发当中，可简化纳米微粉的制备过程，产业化价值显著。
本发明的晶型I具有提纯效果，且可作为制备稳定晶型H的原料。
附图说明
图1为帕比司他乳酸盐的晶型H的XRPD图：
图2为帕比司他乳酸盐的晶型H的DSC图；
图3为帕比司他乳酸盐的晶型H的TGA图；
图4为帕比司他乳酸盐的晶型H的1H NMR图；
图5为帕比司他乳酸盐的晶型I的XRPD图：
图6为帕比司他乳酸盐的晶型I的DSC图；
图7为帕比司他乳酸盐的晶型I的TGA图；
图8为帕比司他乳酸盐的晶型G的XRPD图：
图9为帕比司他乳酸盐的晶型G的DSC图：
图10为帕比司他乳酸盐的晶型G的TGA图：
图11为帕比司他乳酸盐的晶型G的1H NMR图；
图12显示了帕比司他乳酸盐的晶型H的稳定性，其中A谱图为起始时晶型H样品的XRPD图，B谱图为晶型H样品在25℃，60％湿度条件下放置11个月后测试所得XRPD图；C图为晶型H样品在40℃，75％湿度条件下放置11个月后测试所得XRPD图；
图13显示了帕比司他乳酸盐的晶型G的稳定性，其中A谱图为起始时晶型G样品的XRPD图，B谱图为晶型G样品在25℃，60％湿度条件下放置11个月后测试所得XRPD图； C图为晶型G样品在40℃，75％湿度条件下放置11个月后测试所得XRPD图；
图14为本发明帕比司他乳酸盐的晶型G的透射电子显微镜图；
图15为CN102584673B报道的帕比司他乳酸盐形式A的透射电子显微镜图；
图16为本发明帕比司他乳酸盐的晶型H的DVS图；
图17为CN102584673B报道的帕比司他乳酸盐形式A的DVS图。
具体实施方式
以下结合具体的实施例对本发明做进一步详细的说明，但本发明不限于以下实施例。实施例中未注明的条件为常规条件。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
1.540598；
Figure PCTCN2016096075-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40毫安培(mA)
发散狭缝：自动
扫描模式：连续
扫描范围：自3.0至40.0度
取样步长：0.013度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2，200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。
实施例1
帕比司他乳酸盐的晶型H的制备方法：称量19.7mg帕比司他，将其加入到0.4mL乙酸异丙酯中，另将6.8mg左旋乳酸溶解于0.1mL甲醇中配成溶液，并将该溶液缓慢滴加到 帕比司他和乙酸异丙酯的混合体系中，于室温条件下进行搅拌24小时，通过离心滤掉上清液，在室温下真空干燥3小时得到固体。
晶型H的X射线粉末衍射数据参见表1，其XRPD图参见图1，综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为11.75°、21.03°、14.94°处的衍射峰为特征峰。2theta值为20.38°、22.53°、19.35°处的衍射峰为重要的峰。2theta值为15.87°、16.78、9.69°处的衍射峰为次重要的峰。
表1晶型H的X射线粉末衍射数据
2theta d间隔 强度％
9.69 9.13 44.76
10.80 8.19 25.37
11.75 7.53 100.00
12.20 7.25 11.46
13.11 6.75 20.69
14.94 5.93 64.31
15.87 5.58 51.64
16.37 5.42 19.20
16.78 5.28 46.35
17.48 5.07 42.77
18.25 4.86 11.58
19.35 4.59 56.92
19.92 4.46 16.51
20.38 4.36 62.36
21.03 4.23 97.89
21.36 4.16 29.89
21.73 4.09 38.20
22.53 3.95 57.50
23.27 3.82 30.57
24.48 3.64 23.16
25.59 3.48 14.45
26.40 3.38 21.55
27.46 3.25 33.07
28.04 3.18 10.89
29.15 3.06 11.42
30.48 2.93 11.13
31.35 2.85 5.59
32.08 2.79 8.69
33.47 2.68 8.32
35.07 2.56 4.44
晶型H的DSC图如图2，其中显示当加热至141.2℃附近时开始出现吸热峰。
晶型H的TGA图如图3，其中显示加热至120℃时，具有约2.8％的重量损失梯度。
实施例2
帕比司他乳酸盐的晶型H的制备方法：称量19.7mg帕比司他，将其加入到0.4mL乙酸正丁酯中，另将6.8mg左旋乳酸溶解于0.1mL甲醇中配成溶液，并将该溶液缓慢滴加到帕比司他和乙酸正丁酯的混合体系中，于室温条件下进行搅拌24小时，通过离心滤掉上清液，在室温下真空干燥3小时得到固体。
本实施例得到的晶型H的X射线粉末衍射数据如表2所示。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为11.75°、21.06°、14.98°处的衍射峰为特征峰。2theta值为20.44°、22.53°、19.34°处的衍射峰为重要的峰。2theta值为15.87°、16.78、9.69°处的衍射峰为次重要的峰。
表2晶型H的X射线粉末衍射数据
2theta d间隔 强度％
4.53 19.51 8.43
9.69 9.13 53.50
10.78 8.20 20.94
11.75 7.53 100.00
13.15 6.73 22.76
14.98 5.92 57.29
15.87 5.58 42.98
16.78 5.28 31.78
17.52 5.06 29.72
19.34 4.59 36.80
20.44 4.35 51.65
21.06 4.22 80.50
21.72 4.09 24.96
22.53 3.95 36.29
23.30 3.82 18.88
24.53 3.63 19.08
26.43 3.37 13.96
27.45 3.25 20.33
30.29 2.95 5.36
实施例1和2制备得到的帕比司他乳酸盐的晶型H的产品，其NMR谱图参见图4，具体数据如下：1H NMR(400MHz，DMSO)δ10.71(s，1H)，7.57-7.32(m，6H)，7.21(d，J＝7.9Hz，1H)，6.99-6.88(m，2H)，6.44(d，J＝15.8Hz，1H)，4.01-3.77(m，4H)，2.83(d，J＝6.7Hz，2H)，2.76(d，J＝6.7Hz，2H)，2.30(s，3H)，1.20(d，J＝6.8Hz，3H).
实施例3
帕比司他乳酸盐的晶型I的制备方法：称量19.7mg帕比司他，将其加入到0.4mL乙酸异丙酯中，另将6.8mg左旋乳酸溶解于0.1mL甲醇中配成溶液，并将该溶液缓慢滴加到帕比司他和乙酸异丙酯的混合体系中，于室温条件下进行搅拌24小时，通过离心滤掉上清液，得到固体晶型I。
晶型I的X射线粉末衍射数据参见表3，其XRPD图参见图5，综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为10.16°、25.03°、22.85°处的衍射峰为特征峰。2theta值为19.46°、18.98°、24.53°处的衍射峰为重要的峰。2theta值为9.77°、13.74、20.25°处的衍射峰为次重要的峰。
表3晶型H的X射线粉末衍射数据
2theta d间隔 强度％
9.77 9.05 31.60
10.16 8.70 100.00
10.92 8.10 17.39
12.31 7.19 15.80
13.74 6.44 25.82
15.82 5.60 21.24
18.98 4.68 37.43
19.46 4.56 45.89
20.25 4.39 23.67
21.44 4.15 19.22
22.85 3.89 50.61
24.53 3.63 37.13
25.03 3.56 58.18
29.05 3.07 8.60
31.72 2.82 8.32
晶型I的DSC图如图6，其中显示当加热至54.7℃附近时开始出现吸热峰。
晶型I的TGA图如图7，其中显示加热至140℃时，具有约12.4％的重量损失梯度。
实施例4
帕比司他乳酸盐的晶型G的制备方法：称量19.4mg帕比司他，将5.16mg左旋乳酸溶解于0.3mL甲醇中配成溶液，并将该溶液缓慢滴加帕比司他中，再加入0.15mL甲苯，观察到完全澄清后，放置在4℃条件下两个小时，再放置在室温条件下进行挥发得到固体晶型G。
本实施例得到的晶型的X射线粉末衍射数据如表4所示。其XRPD图如图8，综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为7.73°、19.97°、10.28°处的衍射峰为特征峰。2theta值为6.48°、17.42°、15.37°处的衍射峰为重要的峰。2theta值为16.27°、22.38、23.49°处的衍射峰为次重要的峰。
表4晶型G的X射线粉末衍射数据
2theta d间隔 强度％
6.48 13.64 59.09
7.73 11.44 100.00
10.28 8.61 72.79
12.12 7.31 18.55
13.43 6.59 16.31
15.37 5.76 36.30
16.27 5.45 31.22
17.42 5.09 56.64
19.58 4.53 37.22
19.97 4.45 81.25
21.32 4.17 10.92
22.38 3.97 53.96
23.10 3.85 41.54
23.49 3.79 60.80
23.73 3.75 51.61
24.23 3.67 29.41
25.09 3.55 11.47
25.78 3.46 17.39
27.60 3.23 14.79
28.95 3.08 6.85
30.53 2.93 6.61
31.94 2.80 8.04
34.18 2.62 14.99
本实施例得到的晶型G的DSC图如图9，其中显示当加热至65.2℃附近时开始出现吸热峰。
本实施例得到的晶型G的TGA图如图10，其中显示当加热至110℃时，具有约5.5％的重量损失梯度。
上本实施例得到的晶型G的产品，其NMR谱图参见图11，具体数据如下：1H NMR(400MHz，DMSO)δ10.71(s，1H)，7.57-7.32(m，6H)，7.21(d，J＝7.9Hz，1H)，6.99-6.88(m，2H)，6.44(d，J＝15.8Hz，1H)，4.01-3.77(m，4H)，2.83(d，J＝6.7Hz，2H)，2.76(d，J＝6.7Hz，2H)，2.30(s，3H)，1.20(d，J＝6.8Hz，3H).
实施例5
本发明帕比司他乳酸盐的晶型H与现有CN102584673B报道的帕比司他乳酸盐形式A的溶解度对比研究：
室温下，将本发明中的帕比司他乳酸盐的晶型H与现有帕比司他乳酸盐形式A样品分别用pH 1.8SGF(模拟人工胃液)，pH 5.0FeSSIF(模拟进食状态下人工肠液)，pH 6.5FaSSIF(模拟空腹状态下人工肠液)配制成饱和溶液，在1个小时后采用高效液相色谱测定饱和溶液中样品的含量。结果如表5所示。
表5
Figure PCTCN2016096075-appb-000004
结果表明，在SGF、FaSSIF、FeSSIF中放置1个小时后，本发明帕比司他乳酸盐的晶型H与现有帕比司他乳酸盐形式A相比，溶解度有较明显提高。
实施例6
对本发明帕比司他乳酸盐的晶型H和晶型G分别开展稳定性研究：
分别准备二份晶型H样品和二份晶型G样品，各晶型的二份样品分别在25℃，60％湿度条件下和40℃，75％湿度条件下放置11个月，放置前后进行XRPD测试，结果分别参照图12和图13。
结果表明，晶型H具有良好的稳定性。晶型G在放置前后晶型不变，稳定性也较好。
实施例7
帕比司他乳酸盐的晶型G与CN102584673B报道的帕比司他乳酸盐形式A的透射电子显微镜(TEM)对比研究：
透射电子显微镜样品测试方法为：放置约0.5mg的样品于小瓶内，加入乙醇作为分散剂，充分超声震荡分散均匀后，滴加少量浊液于小铜片上，并置于红外灯下干燥10分钟以上直至彻底干燥。放置样品于透射电镜中开始测试。
帕比司他乳酸盐的晶型G与现有帕比司他乳酸盐形式A的透射电子显微镜(TEM)成像结果分别见图14、图15。从中可见，现有帕比司他乳酸盐形式A颗粒直径在微米级别，粒径较大。而本发明的晶型G颗粒粒径为纳米级别，非常合适。与形式A相比，本发明晶型G可提升药物在人体组织内的透过效率，相对于形式A，晶型G的比表面积更大，可提高药物在生物体内的溶出速率，从而达到高透过高吸收的效果。另外，作为纳米级别的药物颗粒，晶型G更适于应用在纳米微粉制剂的开发当中，可简化纳米微粉的制备过程，产业化价值显著。
实施例8
本发明帕比司他乳酸盐的晶型H与现有CN102584673B报道的帕比司他乳酸盐形式A的引湿性对比研究：
取本发明实施例制得的晶型H与现有CN102584673B报道的帕比司他乳酸盐形式A约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表6所示。引湿性实验的DVS图如图16、图17所示。
表6
帕比司他乳酸盐 80％相对湿度的增重
晶型H 1.09％
形式A 3.62％
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的晶型H属于略有引湿性，而专利CN102584673B引湿性较高。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (18)

  1. 一种帕比司他乳酸盐晶型H，其特征在于：其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为11.8°±0.2°,21.0°±0.2°,15.0°±0.2°处具有特征峰。
  2. 根据权利要求1所述的帕比司他乳酸盐晶型H，其特征在于：其X射线粉末衍射图还在2theta值为20.4°±0.2°,22.5°±0.2°,19.4°±0.2°中的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的帕比司他乳酸盐晶型H，其特征在于：其X射线粉末衍射图还在2theta值为15.9°±0.2°,16.8°±0.2°,9.7°±0.2°中的一处或多处具有衍射峰。
  4. 一种如权利要求1至3中任一项权利要求所述的帕比司他乳酸盐晶型H的制备方法，其特征在于：使帕比司他与乳酸在醇类溶剂和酯类溶剂的混合溶剂中，于室温条件下搅拌，有固体析出，收集固体并进行干燥即得帕比司他乳酸盐晶型H。
  5. 根据权利要求4所述的帕比司他乳酸盐晶型H的制备方法，其特征在于：所述酯类溶剂为乙酸异丙酯或乙酸正丁酯或二者的组合。
  6. 根据权利要求4所述的帕比司他乳酸盐晶型H的制备方法，其特征在于：所述醇类溶剂为甲醇。
  7. 根据权利要求4所述的帕比司他乳酸盐晶型H的制备方法，其特征在于：所述方法实施如下：将乳酸溶解于醇类溶剂中获得乳酸的醇溶液，然后将该醇溶液缓慢滴加到帕比司他和酯类溶剂的混合体系中，于室温下搅拌至少18小时。
  8. 根据权利要求7所述的帕比司他乳酸盐晶型H的制备方法，其特征在于：室温下搅拌时间为20小时以上。
  9. 一种帕比司他乳酸盐晶型I，其特征在于：其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为10.2°±0.2°,25.0°±0.2°,22.9°±0.2°处具有特征峰。
  10. 根据权利要求9所述的帕比司他乳酸盐晶型I，其特征在于：其X射线粉末衍射图还在2theta值为19.5°±0.2°,19.0°±0.2°,24.5°±0.2°中的一处或多处具有衍射峰。
  11. 根据权利要求9或10所述的帕比司他乳酸盐晶型I，其特征在于：其X射线粉末衍射图还在2theta值为9.8°±0.2°,13.7°±0.2°,20.3°±0.2°中的一处或多处具有衍射峰。
  12. 一种如权利要求9-11中任一项权利要求所述的帕比司他乳酸盐晶型I的制备方法，其特征在于：使帕比司他与乳酸在醇类溶剂和酯类溶剂的混合溶剂中，于室温条件下搅拌，有固体析出，收集固体即为所述的帕比司他乳酸盐晶型I。
  13. 一种帕比司他乳酸盐晶型G，其特征在于：其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为7.7°±0.2°,20.0°±0.2°,10.3°±0.2°处具有特征峰。
  14. 根据权利要求13所述的帕比司他乳酸盐晶型G，其特征在于：其X射线粉末衍射图还在2theta值为6.5°±0.2°,17.4°±0.2°,15.4°±0.2°中的一处或多处具有衍射峰。
  15. 根据权利要求13或14所述的帕比司他乳酸盐晶型G，其特征在于：其X射线粉末衍射图还在2theta值为16.3°±0.2°,22.4°±0.2°,23.5°±0.2°中的一处或多处具有衍射峰。
  16. 一种如权利要求13-15中任一项权利要求所述的帕比司他乳酸盐晶型G的制备方法，其特征在于：使帕比司他与乳酸在醇类溶剂和甲苯的混合溶剂中反应，最后挥发除去溶剂即得晶型G。
  17. 根据权利要求16所述的帕比司他乳酸盐晶型G的制备方法，其特征在于：所述醇类溶剂为甲醇。
  18. 一种药物制剂，其特征在于：其包含权利要求1-3、9-11以及13-15中任一项权利要求所述的帕比司他乳酸盐晶型。
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CN101466672A (zh) * 2006-06-12 2009-06-24 诺瓦提斯公司 N-羟基-3-[4-[[[2-(2-甲基-1h-吲哚-3-基)乙基]氨基]甲基]苯基]-2e-2-丙烯酰胺的盐
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CN102584673A (zh) * 2006-06-12 2012-07-18 诺瓦提斯公司 N-羟基-3-[4-[[[2-(2-甲基-1h-吲哚-3-基)乙基]氨基]甲基]苯基]-2e-2-丙烯酰胺的多晶型物

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* Cited by examiner, † Cited by third party
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CN1450991A (zh) * 2000-09-01 2003-10-22 诺瓦提斯公司 脱乙酰酶抑制剂
CN101466672A (zh) * 2006-06-12 2009-06-24 诺瓦提斯公司 N-羟基-3-[4-[[[2-(2-甲基-1h-吲哚-3-基)乙基]氨基]甲基]苯基]-2e-2-丙烯酰胺的盐
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