WO2015192606A1 - 洛铂晶体、制备方法及药物应用 - Google Patents

洛铂晶体、制备方法及药物应用 Download PDF

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WO2015192606A1
WO2015192606A1 PCT/CN2014/092571 CN2014092571W WO2015192606A1 WO 2015192606 A1 WO2015192606 A1 WO 2015192606A1 CN 2014092571 W CN2014092571 W CN 2014092571W WO 2015192606 A1 WO2015192606 A1 WO 2015192606A1
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Prior art keywords
lobaplatin
crystal
platinum
dihydrate
trihydrate
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PCT/CN2014/092571
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English (en)
French (fr)
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窦啟玲
隋东虎
张圣贵
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贵州益佰制药股份有限公司
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Priority claimed from CN201410279331.3A external-priority patent/CN105440082B/zh
Priority claimed from CN201410279369.0A external-priority patent/CN105198932B/zh
Priority claimed from CN201410279879.8A external-priority patent/CN105440083B/zh
Application filed by 贵州益佰制药股份有限公司 filed Critical 贵州益佰制药股份有限公司
Priority to EP14894886.2A priority Critical patent/EP3159349B1/en
Priority to KR1020167033218A priority patent/KR20170018822A/ko
Priority to JP2017514760A priority patent/JP6404461B2/ja
Priority to SG11201609948YA priority patent/SG11201609948YA/en
Priority to US15/314,159 priority patent/US9889112B2/en
Priority to RU2016146456A priority patent/RU2648990C1/ru
Publication of WO2015192606A1 publication Critical patent/WO2015192606A1/zh
Priority to PH12016502359A priority patent/PH12016502359B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0013—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group without a metal-carbon linkage
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the invention relates to the field of medicines, in particular to a new crystal form of lobaplatin, a preparation method thereof and application in medicine, and belongs to the technical field of medicine.
  • Lobaplatin (D19466), also known as lobaplatin, is the third generation of platinum antitumor drugs after cisplatin and carboplatin. Its chemical name is: cis-[trans-1,2-cyclobutene Alkyl bis(methylamine)-N,N']-[(2S)-lactic acid-O1,O2]-platinum (II), the molecular formula is C 9 H 18 N 2 O 3 Pt, the molecular weight is 397.34, the chemical structural formula is as follows Equation (1):
  • Lolatine has alkylation and is an alkylating agent (generalized). It has a good anti-tumor effect, such as in vitro AH135-tumor, B16-melanoma, colon cancer 115, in vivo mouse P338 leukemia and the like have a good inhibitory effect.
  • Lobaplatin is characterized by strong anticancer activity, low toxicity, no accumulation toxicity and nephrotoxicity, and less toxicity to bone marrow, no thrombocytopenia.
  • the marketed injection of lobaplatin is mainly used for breast cancer and small cell lung cancer. Treatment of chronic myeloid leukemia.
  • the original drug was developed by ASTA Medica AG, and its original patent EP0324154 first described the preparation method of lobaplatin.
  • a process for the preparation of lobaplatin trihydrate is disclosed, which is obtained by recrystallizing an anatone of lobaplatin to form a crystal water product containing three water molecules, in which the patent indicates
  • the lobaplatin obtained by the production method (Example 1a) described in EP0324154 is deliquescent and easily becomes sticky, making it difficult to prepare a preparation.
  • the technical problem to be solved by the present invention is that the conventional lobaplatin anhydrate has a problem of deliquescence, difficulty in preparation, and poor stability.
  • the invention provides a high bioavailability, good stability, high solubility and flow A new crystal form of lobaplatin which is good in properties, is not easy to absorb moisture and becomes sticky, and has excellent yield and purity.
  • the polymorphic form of the drug has become an indispensable part of the drug research process and the quality control and detection process of the drug.
  • the research on the polymorph of the drug helps the selection of the biological activity of the new drug compound and helps provide the organism.
  • the degree of utilization increases the clinical efficacy, contributes to the selection and design of the drug administration route, and determines the process parameters of the pharmaceutical preparation, thereby improving the production quality of the product.
  • the present invention provides the following technical solutions of several new platinum platinum crystals:
  • the present invention provides a platinum platinum dihydrate (also referred to as lobaplatin crystal A), a preparation method thereof, and a pharmaceutical application, which are described in detail below.
  • the present invention provides a crystal of a lobaplatin compound characterized by containing 2 molecules of water of crystallization in a crystal structure.
  • the crystalline form of the platinum compound of the present invention is A
  • the PXRD pattern has a 2 ⁇ value of about 11.04, 12.32, 12.61, 13.85, 15.14, 15.55, 16.68, 17.67, 17.86, 19.03, 20.06, 21.00, 22.68. , 22.92, 23.76, 25.39, 25.58, 26.37, 26.77, 27.00, 27.71, 28.13, 29.71, 31.42, 31.94, 32.89, 34.29, 34.60, 36.10, 36.93, 37.66, 40.78, 43.41, there are diffraction peaks, wherein the 2 ⁇ value error range Is 0.2.
  • the present invention provides a method of preparing the above-described platinum compound, which comprises the steps of:
  • the drying is vacuum drying.
  • the crystallization solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-dioxane or n-heptane.
  • the suspension is carried out at room temperature, preferably for 45-50 hours.
  • the present invention provides a pharmaceutical composition characterized by using the above-mentioned platinum crystalline compound as an active ingredient.
  • the minimum unit of the pharmaceutical composition contains lobaplatin crystals in an amount of 5 mg, 10 mg or 50 mg.
  • the pharmaceutical composition is any clinically acceptable pharmaceutical dosage form.
  • the dosage form is a lyophilized formulation for injection.
  • the present invention provides the use of the above-described lobaplatin compound crystal or the above pharmaceutical composition for the preparation of an anticancer drug.
  • the present invention provides the use of the above-described lobaplatin compound crystal or pharmaceutical composition for treating cancer, for treating one of breast cancer, small cell lung cancer or chronic myelogenous leukemia.
  • the present invention still further provides the use of the above-described platinum crystalline form in the preparation of a pharmaceutical composition and a pharmaceutical preparation.
  • the present invention provides a platinum platinum crystal B, a preparation method thereof, and a pharmaceutical application, which are described in detail below.
  • a crystal of a lobaplatin compound characterized by having a crystal form B and a PXRD pattern having an angle of 2 ⁇ of about 8.25, 9.77, 11.70, 13.13, 15.28, 16.48, 17.22, 17.74, 19.01, 19.56, 22.28, 23.72, 24.04.
  • the melting point is determined by DSC and evaluated as the maximum peak, and the heating rate is 10 ° C / min.
  • the present invention provides a method for preparing a platinum crystal of Form B, comprising the following steps Step:
  • the present invention also provides a method for preparing a platinum crystal of Form B, which comprises the following step b):
  • the present invention also provides a method for preparing a platinum crystal of Form B, comprising the following step b):
  • the preparation method of the lobaplatin dihydrate comprises the following steps a):
  • a suspension crystallization solvent is added to the platinum sulphate trihydrate, and the suspension is stirred to precipitate crystals. After removing the solvent, the mixture is washed with diethyl ether and dried under vacuum to obtain crystals of the ruthenium dihydrate.
  • the crystallization solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-dioxane or n-heptane.
  • the step b) after the crystallization is separated, it is washed with diethyl ether before drying, and the drying is vacuum drying.
  • the suspension is carried out at room temperature, preferably for 45-50 hours.
  • the organic solvent in the step b) is selected from the group consisting of n-hexane, acetone, ethyl acetate, nitromethane, acetonitrile, tetrahydrofuran, 2-butanone or dichloromethane, and the mass to volume ratio is lobaplatin.
  • Dihydrate: organic solvent 1: 15-30.
  • the present invention provides a pharmaceutical composition characterized by using the aforementioned platinum platinum crystal B as an active ingredient.
  • the amount of the platinum form of the smallest unit of the pharmaceutical composition is 5 mg, 10 mg or 50 mg.
  • the pharmaceutical composition is any clinically acceptable pharmaceutical dosage form.
  • the dosage form is a lyophilized formulation for injection.
  • the present invention also provides the use of the above-described platinum platinum crystal or the pharmaceutical composition for the preparation of an anticancer drug.
  • the present invention provides the use of the above-described lobaplatin compound crystal or pharmaceutical composition for treating cancer, preferably for treating one of breast cancer, small cell lung cancer or chronic myelogenous leukemia.
  • the present invention provides a platinum platinum crystal F, a preparation method thereof, and a pharmaceutical application, which are described in detail below.
  • a crystalline form of a lobaplatin compound characterized by having a crystal form F and a PXRD pattern having an angle of 2 ⁇ of about 8.21, 11.60, 12.99, 15.24, 16.44, 17.11, 17.55, 18.42, 19.01, 19.20, 19.42, 21.81, There are diffraction peaks at 22.17, 22.42, 23.33, 23.85, 24.18, 24.40, 24.77, 25.46, 25.98, 26.13, 27.89, 28.42, 29.03, 30.32, 31.17, 31.94, 33.30, 36.20, 37.62, 39.66, where the 2 ⁇ value error range is 0.2.
  • the melting point was measured by DSC, and the maximum peak value was evaluated, and the heating rate was 10 ° C / min.
  • the present invention provides a method of the platinum crystal, characterized in that it comprises the following step b):
  • the method for preparing the lobaplatin dihydrate comprises the following step a):
  • a suspension crystallization solvent is added to the platinum sulphate trihydrate, and the suspension is stirred to precipitate crystals. After removing the solvent, the mixture is washed with diethyl ether and dried under vacuum to obtain crystals of the ruthenium dihydrate.
  • the crystallization solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-dioxane or n-heptane.
  • the step b) after the crystallization is separated, it is washed with diethyl ether before drying, and the drying is vacuum drying.
  • the organic solvent in the step b) is selected from the group consisting of ethylene glycol dimethyl ether, n-hexane, ethyl acetate, acetone, nitromethane, acetonitrile, tetrahydrofuran or dichloromethane.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the platinum platinum crystal according to claim 1 or 2 as an active ingredient.
  • the amount of the platinum crystals contained in the smallest unit of the pharmaceutical composition is 5 mg, 10 mg or 50 mg.
  • the pharmaceutical composition is any clinically acceptable pharmaceutical dosage form.
  • the dosage form is a lyophilized preparation for injection.
  • the invention also provides the platinum crystals described, or the use of the pharmaceutical composition in the preparation of an anticancer drug.
  • the present invention provides the use of the lobaplatin crystal or the pharmaceutical composition for treating cancer, preferably for treating one of breast cancer, small cell lung cancer or chronic myelogenous leukemia.
  • the raw material lobaplatin trihydrate used in the present invention is prepared by the method of the patent EP0611303 embodiment.
  • the pharmaceutical composition comprises the aforementioned platinum crystalline form as an active ingredient, and the smallest unit contains lobaplatin
  • the amount of the crystal form is 5 mg, 10 mg or 50 mg.
  • the new crystalline form of lobaplatin can be formulated into a pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition can be formulated into any clinically pharmaceutically acceptable dosage form suitable for the raw material, including an injection dosage form, a transdermal dosage form, a respiratory administration dosage form, a mucosal administration form, and other mucosal administration forms of the body. Parenteral dosage forms. A lyophilized powder for injection is preferred.
  • the pharmaceutically acceptable carrier or excipient may be selected from one or more of the following: water for injection, mannitol, lactose, polyethylene glycol, Tween-80, propylene glycol, tartaric acid, citric acid, ascorbic acid. , disodium edetate, sodium calcium edetate, sodium hydrogen sulfite, glucose, sodium chloride, soybean oil, soy lecithin, egg yolk phospholipid, distearoylphosphatidylethanolamine, dextran, glycine, glycerol.
  • the preparation of the above compositions and formulations is generally well known to those skilled in the art.
  • the active form of the lobaplatin compound of the present invention and the marketed lobaplatin preparation is lobaplatin, i.e., anhydrous lobaplatin, and is therefore suitable for all diseases treated by the currently marketed lobaplatin product.
  • Lobaplatin is cis-[trans-1,2-cyclobutane bis(methylamine)-N,N']-[(2S)-lactic acid-O1,O2]-platinum (II), an alkylating agent Cytotoxic drugs, also known as bioalkylating Agengts, can form carbocations or other compounds with active electrophilic groups in the body, and then with biological macromolecules (DNA, RNA, enzymes) in cells.
  • Cytotoxic drugs also known as bioalkylating Agengts
  • a group containing electrons rich in electrons (such as an amino group, a thiol group, a hydroxyl group, a carboxyl group, a phosphate group, etc.) is covalently bonded to cause loss of activity or cleavage of the DNA molecule, resulting in death of the tumor cell, so that the antitumor activity is strong.
  • Pharmacokinetic studies showed that after intravenous injection of lobaplatin, the anti-tumor effect was exerted in the form of total platinum and free platinum in serum, which was an effective effect of anhydrous lobaplatin, regardless of the state of the raw material.
  • the above three new platinum-platinum crystal forms of the invention are new crystal forms developed based on the defect of the amorphous form of lobaplatin, which is easy to deliquesce and become sticky, have poor stability, and are difficult to store, and have high bioavailability, good stability and not easy to deliquesce.
  • lobaplatin trihydrate it is also surprisingly found to have higher solubility, higher yield and purity, and better stability than trihydrate. Therefore, the development of the new crystal form contributes to the selection and design of the drug administration route, as well as the determination of the process parameters of the pharmaceutical preparation, thereby improving the quality of the drug production.
  • the novel lobaplatin compound of the invention is very stable at normal temperature, is not easy to absorb moisture and becomes sticky, has good fluidity, and is more operability in storage, transportation, preparation and treatment than amorphous platinum.
  • Figure 1 X-ray diffraction pattern of lobaplatin dihydrate
  • Figure 2 Molecular stereostructure projection of lobaplatin dihydrate
  • Figure 5 X-ray diffraction pattern of a platinum crystal of Form B
  • Figure 8 X-ray diffraction pattern of a new crystalline form F of lobaplatin
  • Figure 10 Differential thermal analysis TGA plot of the new Form F of Lobaplatin.
  • the present invention provides a crystalline form of lobaplatin dihydrate having good solubility, high yield, and excellent stability.
  • the specific instructions are as follows:
  • the present invention provides a platinum platinum dihydrate of the form A, the X-ray diffraction (PXRD) identification data is as follows:
  • the platinum-type Lobaplatin dihydrate was determined by an X-ray diffractometer of the Bruker model, Bruker D8advance XRD, and the measurement conditions were: CuKa (40 kV, 40 mA), scanning rate 2 ° / min (2 ⁇ Value), scanning range 3°-45° (2 ⁇ value), absorption peak having the characteristics shown in the following Table 1-a, the diffraction spectrum of which is shown in FIG.
  • Peak sequence Diffraction angle 2 ⁇ value (about) Crystal face distance d (about) Relative strength (about) 1 11.04 8.01 66.9 2 12.32 7.18 86.3 3 12.61 7.01 51.3 4 13.85 6.39 22.2 5 15.14 5.85 100 6 15.55 5.69 17.4 7 16.68 5.31 35 8 17.67 5.02 54.5
  • the crystal form is a platinum platinum compound.
  • the X-ray single crystal diffraction experiment is carried out.
  • the crystal is a colorless transparent column and belongs to the orthorhombic system.
  • the platinum-dihydrate of the crystal form A is subjected to differential thermal analysis (DSC-TGA) by a differential thermal analyzer of the model NETZSCH, model NETZSCH DSC 204F1, NETZSCH TG 209F1, and the DSC chart is shown in Fig. 3, TGA
  • the figure is shown in Figure 4.
  • the DSC spectrum has a broad endothermic peak around 117 °C.
  • the peak may be lost by losing 2 crystal waters; there is an exothermic peak at 220 ⁇ 5 °C, combined with TGA and European patent EP0611303 It is judged from the melting point data that the peak is a melting decomposition peak.
  • the TGA profile had a 9.49% weight loss before 150 °C, indicating a loss of 2 crystal water production.
  • the present invention provides a preparation method of a new crystalline form A of Lobaplatin which is simple to prepare, easy to handle, and suitable for scale-up production, and includes the following steps:
  • the invention provides a new crystalline form of lobaplatin with high solubility and excellent stability, and is named as crystal form B.
  • the invention provides a platinum platinum crystal B having a crystalline form B.
  • the following preparation of the isolated platinum platinum form B according to the present invention is specifically described as follows:
  • the platinum platinum form B was measured by a manufacturer's Bruker and Bruker D8advance XRD X-ray diffractometer. The measurement conditions were: CuKa (40 kv, 40 mA), scanning rate 2 ° / min (2 ⁇ value), scanning The range is 3°-45° (2 ⁇ value), and the absorption peak with the following characteristics is shown in Table 1-b below.
  • the diffraction pattern is shown in Figure 5:
  • the new crystal form B of Lobaplatin is subjected to differential thermal analysis (DSC-TGA) by a differential thermal analyzer of the model NETZSCH, model NETZSCH DSC 204F1, NETZSCH TG 209F1, the DSC chart is shown in Fig. 6, and the TGA chart is shown in Fig. 6. 7 is shown.
  • DSC-TGA differential thermal analysis
  • the DSC spectrum has an exothermic peak at 230 ⁇ 5° C., which is judged by the melting point data of TGA and European Patent EP0611303.
  • the peak is a melting decomposition peak
  • the TGA spectrum has no weight loss before 150° C., indicating that it is an unsolvate.
  • the present invention provides a new platinum-platinum which is simple to prepare, easy to handle, and suitable for scale-up production. Method for preparing Form B.
  • the preparation method of the new platinum form B of the present invention comprises the following steps:
  • the preparation of lobaplatin dihydrate weigh the lobaplatin trihydrate in a container, relative to 1g of lobaplatin trihydrate, add 15-30ml of organic solvent, suspension and stirring at room temperature for 45-50h, filtered, washed with ether , after vacuum drying, a white powder is obtained, that is, lobaplatin dihydrate;
  • organic solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-dioxane or n-heptane.
  • step b Preparation of target crystal form: Weigh the platinum platinum dihydrate obtained in step a, place it in a container, add anhydrous methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly volatilize in a fume hood to be crystallized. After the precipitation, the crystals were separated by filtration, washed with diethyl ether 2-3 times, and dried in vacuo to give a white powder, which is a new crystalline form B of lobaplatin.
  • the preferred method for preparing the novel platinum form B of the present invention may further be:
  • the preparation of lobaplatin dihydrate weigh the lobaplatin trihydrate in a container, relative to 1g of lobaplatin trihydrate, add 15-30ml of organic solvent, suspension and stirring at room temperature for 45-50h, filtered, washed with ether , after vacuum drying, a white powder is obtained, that is, lobaplatin dihydrate;
  • organic solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-dioxane or n-heptane.
  • b Preparation of the target crystal form: Weigh the platinum platinum dihydrate obtained in the step a, place it in a container, add an organic solvent, stir and stir at room temperature for 45-50 h, precipitate crystals, and separate the crystal by filtration, and wash with diethyl ether 2 -3 times, after vacuum drying, a white powder is obtained, which is a new crystal form B of lobaplatin.
  • the invention provides a new crystalline form of lobaplatin with high solubility and excellent stability, and is named as crystalline form F.
  • the invention provides a new crystalline form F of lobaplatin in crystalline form.
  • the following detailed description of the isolated platinum platinum form F prepared by the present invention is as follows:
  • the platinum plate form F was measured by an X-ray diffractometer of Bruker and Bruker D8advance XRD.
  • the measurement conditions were: CuKa (40 kv, 40 mA), scanning rate 2 ° / min (2 ⁇ value), scanning The range of 3°-45° (2 ⁇ value), the absorption peak with the following characteristics, see Table 1-c below, the diffraction pattern is shown in Figure 8:
  • Peak sequence Diffraction angle 2 ⁇ value (about) Crystal face distance d (about) Relative strength (about height %) 1 8.21 10.76 100 2 11.60 7.62 0.8 3 12.99 6.81 3.3 4 15.24 5.81 5.2 5 16.44 5.39 8.9 6 17.11 5.18 2 7 17.55 5.05 2.2 8 18.42 4.81 0.9 9 19.01 4.67 6.3 10 19.20 4.62 2.2 11 19.42 4.57 2.1 12 21.81 4.07 0.7 13 22.17 4.01 1.7 14 22.42 3.96 1.8 15 23.33 3.81 0.8 16 23.85 3.73 3.2 17 24.18 3.68 1.2 18 24.40 3.65 0.8
  • the new crystal form F of Lobaplatin is subjected to differential thermal analysis (DSC-TGA) by a differential thermal analyzer manufactured by the manufacturer NETZSCH, model NETZSCH DSC 204 F1, NETZSCH TG 209F1, and the DSC chart is shown in Fig. 9, and the TGA pattern is as shown in Fig. 9.
  • Figure 10 shows.
  • the DSC spectrum has an exothermic peak at 229 ⁇ 5°C.
  • the peak is a melting decomposition peak
  • the TGA spectrum has a weight loss of 1.97% before 150°C, which is judged by DSC data. solvent remains.
  • the present invention provides a process for preparing a new crystalline Form F of Lobaplatin which is simple to prepare, easy to handle, and suitable for scale-up production.
  • the method for preparing the new crystalline form F of the present invention comprises the following steps:
  • the preparation of lobaplatin dihydrate weigh the lobaplatin trihydrate in a container, add 15-30ml of organic solvent, suspension and stirring at room temperature for 45-50h, filtered, washed with ether, vacuum dried to obtain a white powder, ie Lobaplatin dihydrate;
  • organic solvent is selected from the group consisting of methyl tert-butyl ether, toluene, diethyl ether, butyl acetate, 1,4-two Oxyhexane or n-heptane.
  • step b Preparation of target crystal form: Weigh the platinum platinum dihydrate obtained in step a, place it in a container, add methanol or ethanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add organic solvent to be crystallized. After the precipitation, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give a white powder, which is a new crystalline form
  • the organic solvent in the step b is selected from the group consisting of ethylene glycol dimethyl ether, n-hexane, ethyl acetate, acetone, nitrotoluene, acetonitrile, tetrahydrofuran, and dichloromethane.
  • Table 5 shows the model and manufacturer of the crystal form
  • Form A characterized in that the PXRD pattern has a 2 ⁇ value of about 11.04, 12.32, 12.61, 13.85, 15.14, 15.55, 16.68, 17.67, 17.86, 19.03, 20.06, 21.00, 22.68, 22.92, 23.76, 25.39, 25.58, 26.37, 26.77, 27.00, 27.71, 28.13, 29.71, 31.42, 31.94, 32.89, 34.29, 34.60, 36.10, 36.93, 37.66, 40.78, 43.41 have diffraction peaks, wherein the 2 ⁇ value error range is 0.2;
  • Form A characterized in that the DSC pattern has an exothermic peak near 220 ⁇ 5 °C.
  • Form B characterized in that the PXRD pattern has values of about 8.25, 9.77, 11.70, 13.13, 15.28, 16.48, 17.22, 17.74, 19.01, 19.56, 22.28, 23.72, 24.04, 24.30, 25.62, 26.20, 28.57, 30.22, There is a diffraction peak at 30.61, wherein the 2 ⁇ value error range is 0.2;
  • Form B characterized in that the DSC pattern has an exothermic peak near 230 ⁇ 5 °C.
  • Form C characterized in that the PXRD pattern has a 2 ⁇ value of about 6.79, 8.07, 12.24, 12.61, 13.50, 16.50, 17.83, 18.32, 18.79, 20.09, 21.64, 22.27, 23.19, 24.73, 27.34, 28.35, 29.12, 31.92. There are diffraction peaks, wherein the 2 ⁇ value error range is 0.2;
  • Form C characterized in that the DSC pattern has an exothermic peak near 228 ⁇ 5 °C.
  • Form D characterized in that the PXRD pattern has a 2 ⁇ value of about 6.76, 11.07, 12.35, 12.65, 13.88, 15.18, 15.56, 16.68, 17.70, 17.90, 20.08, 21.02, 22.70, 22.92, 25.41, 25.64, 26.41, 26.79, There are diffraction peaks at 27.02, 28.15, 31.44, 31.96, 32.96, 34.34, 34.62, 36.93, 40.82, and 43.46, wherein the 2 ⁇ value error range is 0.2;
  • Form D characterized in that the DSC pattern has an exothermic peak near 218 ⁇ 5 °C.
  • Form E characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 6.61, 8.09, 12.38, 13.03, 15.40, 16.66, 17.47, 19.07, wherein the 2 ⁇ value error range is 0.2;
  • Form E characterized in that the DSC pattern has an exothermic peak near 214 ⁇ 5 °C.
  • Form F characterized in that the PXRD pattern is about 8.21, 11.60, 12.99, 15.24, 16.44, 17.11, 17.55, 18.42, 19.01, 19.20, 19.42, 21.81, 22.17, 22.42, 23.33, 23.85, 24.18, 24.40, 24.77, 25.46, 25.98, 26.13, 27.89, 28.42, 29.03, 30.32, 31.17, 31.94, 33.30, 36.20, 37.62, 39.66 have diffraction peaks, wherein the 2 ⁇ value error range is 0.2;
  • Form F characterized in that the DSC pattern has an exothermic peak near 229 ⁇ 5 °C.
  • Form G characterized in that the PXRD pattern has a 2 ⁇ value of about 8.62, 10.82, 11.03, 12.26, 12.59, 13.82, 15.12, 15.57, 16.59, 17.43, 17.65, 18.48, 19.46, 20.11, 20.37, 21.01, 22.66, 22.86, 24.60, 25.40, 26.33, 26.77, 27.00, 28.11, 29.79, 31.42, 31.94, 32.87, 34.25, 34.58, There are diffraction peaks at 36.06, 40.76, 42.75, and 43.39, where the 2 ⁇ value error range is 0.2.
  • Form H characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 8.35, 8.53, 8.68, 12.97, 15.24, 17.41, 18.40, 19.13, 19.48, 20.37, 24.68, 25.41, 30.33, 31.66, 36.34, wherein 2 ⁇
  • the value error range is 0.2.
  • Form I characterized in that the PXRD pattern has a 2 ⁇ value of about 6.75, 8.39, 11.07, 11.59, 12.32, 12.63, 12.99, 15.20, 16.80, 17.07, 17.57, 19.14, 19.46, 21.00, 22.13, 22.84, 23.29, 23.77, There are diffraction peaks at 24.22, 25.82, 26.76, 28.38, 30.34, 30.83, 31.90, 33.63, 36.32, 38.47, where the 2 ⁇ value error range is 0.2.
  • Form J characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 5.94, 8.35, 9.87, 13.05, 15.28, 16.66, 19.15, 22.22, 22.68, 25.09, 30.71, 33.56, wherein the 2 ⁇ value error range is 0.2.
  • Form K characterized in that the PXRD pattern has a 2 ⁇ value of about 8.29, 11.02, 12.31, 12.61, 13.84, 15.14, 15.53, 16.70, 17.66, 19.05, 20.06, 20.98, 22.68, 22.90, 25.60, 26.37, 26.77, 26.98, There are diffraction peaks at 27.68, 28.23, 29.75, 31.40, 31.88, 32.90, 33.81, 34.29, 34.60, 36.10, 36.84, 37.64, 39.93, 40.76, 41.51, 42.36, 42.70, 43.39, where the 2 ⁇ value error range is 0.2.
  • Form L characterized in that the PXRD pattern has a 2 ⁇ value of about 6.71, 7.91, 10.75, 11.84, 14.06, 14.29, 15.85, 16.78, 17.29, 19.76, 20.20, 20.63, 21.08, 21.58, 21.89, 22.17, 23.87, 25.09, There are diffraction peaks at 26.83, 27.02, 28.73, 29.18, 29.92, 30.56, 31.61, 33.95, 40.33, and 41.33, where the 2 ⁇ value error range is 0.2.
  • Form M characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 8.05, 13.03, 15.20, 16.19, 17.47, 18.77, 19.32, 24.06, wherein the 2 ⁇ value error range is 0.2.
  • Form N characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 7.94, 12.67, 14.83, 16.32, 17.16, 18.71, 21.83, 22.44, 24.10, 24.89, 27.97, 30.02, 30.48, wherein the 2 ⁇ value error range is 0.2
  • Form O characterized in that the PXRD pattern has a 2 ⁇ value of about 6.75, 8.15, 16.29, 18.95, 22.23, There are diffraction peaks at 24.52 and 29.93, where the 2 ⁇ value error range is 0.2.
  • Form P characterized in that the PXRD pattern has diffraction peaks at 2 ⁇ values of about 6.61, 8.17, 13.34, 16.52, 20.10, 24.97, 27.02, 33.99, 41.06, wherein the 2 ⁇ value error range is 0.2.
  • the raw materials are subjected to crystallization screening by means of normal temperature volatilization, suspension crystallization, dissolution crystallization, etc., and after PXRD characterization, the spectra are analyzed and compared, and it is preliminarily determined that there may be 16 crystal forms of AP in the loba; Verification, it is finally determined that the crystal form AF can be repeated well and is relatively stable. Crystal form; other crystal forms have lower yields, and it is difficult to carry out amplification production; some have crystal transformation phenomenon, which is inferred to be unstable crystal form. Therefore, the crystal form A-F was selected for further investigation.
  • Example 2 Preparation, product properties and comparative analysis of a new crystalline form of Lobaplatine named as Form A
  • lobaplatin trihydrate 1 g was weighed into a container, 15 ml of toluene was added, and the mixture was suspended and stirred at room temperature for 48 hours to precipitate crystals. The crystals were separated by filtration, washed with diethyl ether 2-3 times, and dried under vacuum to give white powder (0.85 g). It is lobaplatin dihydrate.
  • the samples prepared in the above examples were subjected to XRD diffraction measurement according to the method of 1.4 in the above Example 1, and the crystal forms of the six samples were identified to be the same, and the characteristic peaks thereof were as follows: the PXRD pattern was about 11.04, 12.32, and 12.61 in the 2 ⁇ value.
  • This crystal form is named as type A.
  • the lobaplatinic dihydrates 1-6 of the present invention are respectively the lobaplatin dihydrates of the crystal form A obtained by the preparation method of the examples 1-6 of the present invention;
  • Comparative sample 1 Lobaplatin prepared by the method of Example 1a of the patent EP0324154, the specific preparation method is as follows:
  • reaction mixture was concentrated, and then dissolved in methanol and added to activated carbon to dissolve and discolor.
  • the activated carbon was filtered off, diethyl ether was added to the filtrate, and the solid was quickly concentrated to obtain an amorphous platinum.
  • Comparative sample 2 Lobaplatin trihydrate prepared by the method of the patent EP0611303, the specific preparation method is as follows:
  • Comparative sample 1 the obtained lobaplatin is in an amorphous state
  • Comparative Sample 2 By X-ray diffraction, the PXRD pattern was approximately 6.71, 8.35, 12.89, 15.14, 16.74, 17.45, 19.01, 19.40, 22.07, 22.76, 23.16, 24.30, 25.21, 25.74, 27.08, 30.26, 30. There is a diffraction peak with a 2 ⁇ value error range of less than 0.2, and its melting point is 210 ° C (decomposition) as described in patent EP0611303;
  • Samples 1-6 of Form A of the present invention By X-ray diffraction, the PXRD pattern has a 2 ⁇ value of about 11.04, 12.32, 12.61, 13.85, 15.14, 15.55, 16.68, 17.67, 17.86, 19.03, 20.06, 21.00, 22.68.
  • the platinum platinum trihydrate reference solution was prepared at a concentration of 60 ⁇ g/ml, 80 ⁇ g/ml, 200 ⁇ g/ml, 400 ⁇ g/ml, and 800 ⁇ g/ml, respectively, and a standard curve was prepared by HPLC.
  • Sample 6 and Comparative Sample 2 of Lobaplatin Dihydrate were made into a saturated aqueous solution (suspension), shaken at 25 ° C for 6 h, then filtered, diluted by appropriate multiples, and subjected to HPLC analysis. The solubility results are shown in Table 7 below:
  • the new platinum form A obtained by the invention has the characteristics of high content, low impurity and good yield compared with the platinum anhydrate and the lobaplatin trihydrate.
  • the sample 6 and the comparative sample 2 prepared in the examples of the present invention were respectively placed in a 60 ° C oven, and the relative humidity was about 95%, and the light stability test chamber with an illumination of about 4500 lux (a conventional incubator with a light function) Within 5 days and 10 days, the samples were taken out for PXRD test and HPLC analysis to investigate the stability of the samples under high temperature, high humidity and light conditions. The results are shown in Table 9.
  • Example 3 Preparation, product properties and comparative analysis of a new crystalline form of Lobaplatine named as Form B
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 30 ml of toluene, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain 1.73 g of white powder. Platinum dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 40 ml of anhydrous methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly volatilize the fume hood. After the crystals were precipitated, the crystals were separated by filtration, washed with diethyl ether 2-3 times, and dried in vacuo to give a white powder, 0.74 g, which is a new crystalline form B of lobaplatin.
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of methyl tert-butyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.84. g, that is, lobaplatin dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 50 ml of anhydrous methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly evaporate in a fume hood. After crystallizing, the crystals were separated by filtration, washed with diethyl ether 2-3 times, and dried in vacuo to give a white powder, 0.76 g, which is a new crystalline form B of lobaplatin.
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 20 ml of butyl acetate, stir and stir at room temperature for 50 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.68 g, ie Lobaplatin dihydrate;
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 25 ml of 1,4-dioxane, stir and stir at room temperature for 45 h, filter, wash with diethyl ether, and dry under vacuum to obtain white Powder 1.76g, It is lobaplatin dihydrate;
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 30 ml of n-heptane, stir and stir at room temperature for 50 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.75 g, ie Lobaplatin dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place it in a container, add 18 ml of ethyl acetate, stir and stir at room temperature for 50 h, precipitate crystals, and separate the crystal by filtration and wash with diethyl ether. After 2-3 times, vacuum drying gave 0.75 g of a white powder, which is a new crystalline form B of lobaplatin.
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of diethyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain 1.78 g of white powder. Platinum dihydrate;
  • step b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place it in a container, add 25 ml of nitromethane, stir and stir at room temperature for 48 h, precipitate crystals, and separate the crystal by filtration and wash with diethyl ether. After 2-3 times, vacuum drying gave 0.77 g of a white powder, which is a new crystalline form B of lobaplatin.
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 18 ml of methyl tert-butyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.82. g, that is, lobaplatin dihydrate;
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 25 ml of methyl tert-butyl ether, stir and stir at room temperature for 46 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.83. g, that is, lobaplatin dihydrate;
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 30 ml of methyl tert-butyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.85. g, that is, lobaplatin dihydrate;
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of methyl tert-butyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.84. g, that is, lobaplatin dihydrate;
  • the samples prepared in the above steps ) in the above steps 1-10 were subjected to XRD diffraction measurement according to the method in Section 1.4 of the above-mentioned Example 1, and the crystal forms of the 10 samples were identified as the same, and the crystal form was A.
  • the identification data is the same as the data shown in the above section (1) "First Embodiment of the Invention" and the data shown in the above embodiment 2.
  • the samples prepared in the above step 1-5 and the samples prepared in the examples 11-12 were subjected to XRD diffraction according to the method of 1.4 in the above-mentioned Example 1, and the crystal forms of the 12 samples were identified to be the same.
  • the characteristic peaks are as follows: the 2 ⁇ angle values in the PXRD pattern are 8.25, 9.77, 11.70, 13.13, 15.28, 16.48, 17.22, 17.74, 19.01, 19.56, 22.28, 23.72, 24.04, 24.30, 25.62, 26.20, 28.57, 30.22, There is a diffraction peak at 30.61, where the 2 ⁇ value error range is ⁇ 0.2.
  • This crystal form is named B type.
  • Samples 1-12 are lobaplatin compounds of the form B obtained by the preparation method of the present invention 1-12;
  • Comparative Sample 1 The same as Comparative Sample 1 of Section 2.2 of the previous Example 2, the platinum platinum obtained by the method of Example 1a of the patent EP0324154 is also used, and the preparation method of the specific preparation method and the comparison of the sample of the second part of the second embodiment is the preparation method of the sample 1 the same:
  • Comparative sample 2 same as the comparative sample 2 of the 2.2 part of the previous embodiment 2, the platinum platinum trihydrate prepared by the method of the patent EP0611303 was also used, and the specific preparation method was compared with the second part of the second part of the second embodiment. The preparation method is the same.
  • Comparative sample 1 the obtained lobaplatin is in an amorphous state
  • Comparative Sample 2 By X-ray diffraction, the PXRD pattern was approximately 6.71, 8.35, 12.89, 15.14, 16.74, 17.45, 19.01, 19.40, 22.07, 22.76, 23.16, 24.30, 25.21, 25.74, 27.08, 30.26, 30. There is a diffraction peak with a 2 ⁇ value error range of less than 0.2, and its melting point is 210 ° C (decomposition) as described in patent EP0611303;
  • Samples 1-12 of the present invention by X-ray diffraction, the PXRD patterns are about 8.25, 9.77, 11.70, 13.13, 15.28, 16.48, 17.22, 17.74, 19.01, 19.56, 22.28, 23.72, 24.04, 24.30, 25.62, There are diffraction peaks at 26.20, 28.57, 30.22, and 30.61, and the 2 ⁇ value error range is less than 0.2; the DSC spectrum shows an exothermic peak at 230 ⁇ 5°C, which is judged by the melting point data of TGA and EP0611303, and the peak is a melting decomposition peak. It is indicated that the samples 1-12 are of the same crystal form, that is, the new crystal form B of lobaplatin.
  • the platinum platinum trihydrate reference solution was prepared at a concentration of 60 ⁇ g/ml, 80 ⁇ g/ml, 200 ⁇ g/ml, 400 ⁇ g/ml, and 800 ⁇ g/ml, respectively, and a standard curve was prepared by HPLC.
  • Sample 1 and comparative sample 2 of the new form of Lobaplatin B were made into a saturated aqueous solution (suspension), shaken at 25 ° C for 6 h, then filtered, diluted by appropriate multiples, and subjected to HPLC analysis.
  • Table 10 The solubility results are shown in Table 10 below:
  • the new platinum form B obtained by the present invention has the characteristics of high content, low impurity and good yield compared with the platinum anhydrate and the lobaplatin trihydrate.
  • the sample 1 and the comparative sample 2 of the platinum platinum crystal B prepared in the third embodiment of the present invention were respectively placed in a 60 ° C oven, and the relative humidity was about 95%, and the light stability test chamber with an illumination of about 4500 lux (with light)
  • the sample was taken out for PXRD test and HPLC analysis after 5 days and 10 days in a conventional conventional incubator to examine the stability of the sample under high temperature conditions.
  • Table 12 The results are shown in Table 12 below:
  • Example 4 Preparation, product properties determination and comparative analysis of a new crystalline form of Lobaplatine named as Form F
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 30 ml of toluene, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain 1.73 g of white powder. Platinum dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 40 ml of methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 120 ml of ethylene glycol. Methyl ether, after crystallizing, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give a white powder, 0.71 g, as a new crystalline form
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of methyl tert-butyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.84. g, that is, lobaplatin dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 50 ml of methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 150 ml of n-hexane, wait until After crystallizing, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give white crystals (yield: 0.6 g).
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 20 ml of butyl acetate, stir and stir at room temperature for 50 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.68 g, ie Lobaplatin dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 80 ml of ethanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 200 ml of ethyl acetate. After crystallizing, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give a white powder, 0.70 g, as a new crystalline form
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 25 ml of 1,4-dioxane, stir and stir at room temperature for 45 h, filter, wash with diethyl ether, and dry in vacuo to obtain a white powder. 1.76g, which is lobaplatin dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 90 ml of ethanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 180 ml of acetone to be crystallized. After the precipitation, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give a white powder (yield: 0.72 g).
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 30 ml of n-heptane, stir and stir at room temperature for 50 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.75 g, ie Lobaplatin dihydrate;
  • step b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place it in a container, add 45 ml of methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 160 ml of nitromethane. After crystallizing, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give a white powder, 0.69 g, as a new crystalline form
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of diethyl ether, stir and stir at room temperature for 48 h, filter, wash with diethyl ether, and dry in vacuo to obtain 1.78 g of white powder. Platinum dihydrate;
  • b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place in a container, add 40 ml of methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 150 ml of acetonitrile to be crystallized. After the precipitation, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to yield white crystals (yield: 0.73 g).
  • lobaplatin dihydrate weigh 2 g of lobaplatin trihydrate in a container, add 15 ml of methyl uncle The butyl ether was stirred and stirred at room temperature for 48 h, filtered, washed with diethyl ether and dried in vacuo to give a white powder: 1.
  • lobaplatin dihydrate Preparation of lobaplatin dihydrate: Weigh 2 g of lobaplatin trihydrate in a container, add 20 ml of methyl tert-butyl ether, stir and stir at room temperature for 46 h, filter, wash with diethyl ether, and dry in vacuo to obtain white powder 1.80. g, that is, lobaplatin dihydrate;
  • step b Preparation of target crystal form: Weigh 1 g of lobaplatin dihydrate obtained in step a, place it in a container, add 40 ml of methanol, stir at room temperature until the solid dissolves, filter out insoluble matter, and slowly add 150 ml of dichloromethane, wait until After crystallizing, the crystals were separated by filtration, washed with diethyl ether and dried in vacuo to give white crystals, 0.66 g, as a new crystalline form
  • the samples prepared by the steps a) in the above Examples 1-8 were subjected to XRD diffraction measurement according to the method of 1.4 in the above Example 1, and the crystal forms of the eight samples were identified as the same, and the crystal form was A, and the detailed identification thereof was carried out.
  • the data is the same as the data shown in the above section (1) "First Embodiment of the Invention" and the data shown in the above embodiment 2.
  • Sample 1-8 obtained by the preparation method of the present invention 1-8;
  • Comparative Sample 1 The same as Comparative Sample 1 of Section 2.2 of the previous Example 2, the platinum platinum obtained by the method of Example 1a of the patent EP0324154 is also used, and the preparation method of the specific preparation method and the comparison of the sample of the second part of the second embodiment is the preparation method of the sample 1 the same:
  • Comparative sample 2 same as the comparative sample 2 of the 2.2 part of the previous embodiment 2, the platinum platinum trihydrate prepared by the method of the patent EP0611303 was also used, and the specific preparation method was compared with the second part of the second part of the second embodiment. The preparation method is the same.
  • Comparative sample 1 the obtained lobaplatin is in an amorphous state
  • Comparative Sample 2 By X-ray diffraction, the PXRD pattern was approximately 6.71, 8.35, 12.89, 15.14, 16.74, 17.45, 19.01, 19.40, 22.07, 22.76, 23.16, 24.30, 25.21, 25.74, 27.08, 30.26, 30. There is a diffraction peak with a 2 ⁇ value error range of less than 0.2, and its melting point is 210 ° C (decomposition) as described in patent EP0611303;
  • Inventive Samples 1-8 As described above, by X-ray diffraction, the PXRD pattern was approximately 8.21, 11.60, 12.99, 15.24, 16.44, 17.11, 17.55, 18.42, 19.01, 19.20, 19.42, 21.81, 22.17 at 2 ⁇ values. , 22.42, 23.33, 23.85, 24.18, 24.40, 24.77, 25.46, 25.98, 26.13, 27.89, 28.42, 29.03, 30.32, 31.17, 31.94, 33.30, 36.20, 37.62, 39.66 have diffraction peaks, the 2 ⁇ value error range is less than 0.2
  • the DSC spectrum showed an exothermic peak at 229 °C. Combined with TGA and literature melting point data, the peak is a melting decomposition peak, indicating that samples 1-8 are the same crystalline form, which is also the new crystalline form F of lobaplatin.
  • the platinum platinum trihydrate reference solution was prepared at a concentration of 60 ⁇ g/ml, 80 ⁇ g/ml, 200 ⁇ g/ml, 400 ⁇ g/ml, and 800 ⁇ g/ml, respectively, and a standard curve was prepared by HPLC.
  • Sample 6 and Comparative Sample 2 of the new crystal form of Lobaplatin were made into a saturated aqueous solution (suspension), shaken at 25 ° C for 6 h, then filtered, diluted by appropriate multiples, and subjected to HPLC analysis.
  • the solubility results are shown in Table 13 below:
  • Samples 1-8 and Comparative Samples 1-2 were each taken as 20 mg, and the product quality and yield were examined by taking the product moisture, impurity content, active ingredient content, yield and the like as indicators. The results are shown in Table 14 below:
  • the new crystalline form F of the present invention has the characteristics of high content, low impurity and good yield compared with the platinum anhydrate and the lobaplatin trihydrate.
  • the sample 6 and the comparative sample 2 prepared in the examples of the present invention were respectively placed in a 60 ° C oven, and the relative humidity was about 95%, and the light stability test chamber with an illumination of about 4500 lux (a conventional incubator with illumination function) The samples were taken out after 5 days and 10 days, respectively, for PXRD test and HPLC analysis to investigate the stability of the sample under high temperature conditions.
  • the results are shown in Table 15 below:
  • the lolatine of the present invention is a new crystalline form F, and the solubility is higher than that of the platinum platinum trihydrate, and the yield and purity are very satisfactory. From the results of high temperature, high humidity and light investigation, the new crystalline form of lobaplatin is stable. Good properties, no crystal transformation occurred, HPLC results showed that the content of active ingredients was better than that of lobaplatin trihydrate, and there was no significant change, indicating that the new crystalline form of lobaplatin of the present invention has good stability.

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Abstract

本发明涉及洛铂的新晶体A、B和F以及其制备方法及药物应用。其中，洛铂晶体A其熔点Tm.p..＝220±5℃，通过将洛铂三水合物加入悬浮结晶溶剂得到；洛铂晶体B熔点Tm.p..＝230±5℃，通过将洛铂三水合物进行溶剂挥发，或在洛铂二水合物中加入溶剂后常温挥发或者溶析结晶后干燥得到；洛铂晶型为F熔点Tm.p..＝229±5℃，通过在洛铂二水合物中加入甲醇或乙醇，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入有机溶剂，待结晶析出后，分离出该结晶，干燥后得到。与现有洛铂及洛铂三水合物相比，这些洛铂晶体A、B和F具有更好的稳定性、溶解性，更适于制备各种形式的药物制剂及贮存、使用，能够更好的用于治疗癌症如治疗乳腺癌、小细胞肺癌或慢性粒细胞性白血病。

Description

洛铂晶体、制备方法及药物应用 技术领域
本发明涉及药物领域，特别涉及洛铂的新晶型及其制备方法和在药物中的应用，属于医药技术领域。
背景技术
洛铂(Lobaplatin，D19466)，又名洛巴铂，是继顺铂、卡铂之后的第三代铂类抗肿瘤药物，其化学名称为：顺式-[反式-1,2-环丁烷双(甲胺)-N,N']-[(2S)-乳酸-O1,O2]-铂(II)，分子式为C9H18N2O3Pt，分子量为397.34，化学结构式如下下式(1)所示：
Figure PCTCN2014092571-appb-000001
洛铂具烷化作用,属烷化剂(广义)。具有良好的抗肿瘤作用，如对离体AH135-瘤、B16-黑色素瘤、结肠癌115，在体小鼠P338白血病等具有很好的抑制作用。洛铂的特点是抗癌活性强，毒性低，无蓄积毒性和肾毒性，并且对骨髓毒性较小，无血小板减少症，目前已上市的注射用洛铂主要用于乳腺癌、小细胞肺癌及慢性粒细胞性白血病的治疗。
该药物原研方为德国爱斯达制药股份有限公司(ASTA Medica AG)，其原始专利EP0324154首次描述了洛铂的制备方法。在随后的专利EP0611303中，又公开了洛铂三水合物的制备方法，该产品是通过将洛铂无水物进行重结晶，形成含三个水分子的结晶水产物，在该专利中，指出EP0324154中所述的制备方法(实施例1a)得到的洛铂有潮解性，容易变粘，难以制成制剂。
发明内容
本发明要解决的技术问题是，以往洛铂无水物存在潮解性、难以制成制剂、稳定性差的问题。本发明提供一种生物利用度高、稳定性好、溶解度高、流动 性好、不易吸潮变粘、收率及纯度均非常理想的洛铂的新晶型。
本领域技术人员知道，同一种药物，晶型不同，其生物利用度也可能会存在差别，其稳定性、流动性、可压缩性等也可能会不同，这些理化性质对药物的应用产生一定的影响。药物的多晶型已经成为药物研究过程和药品成产质量控制及检测过程中必不可少的重要组成部分，对药物多晶型的研究有助于新药化合物生物活性的选择，有助于提供生物利用度，增加临床疗效，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高产品生产质量。
我们通过不断的研究改进，发明了洛铂的新晶型及其制备方法和在药物中的应用。
具体来说，为了解决上述技术问题，本发明提供了如下几种洛铂新晶体的技术方案：
(1)洛铂二水合物
第一，本发明提供一种洛铂二水合物(也称洛铂晶体A)、其制备方法及药物应用，详述如下。
本发明提供一种洛铂化合物晶体，其特征在于，晶体结构中含有2分子结晶水。
优选地，其中，本发明的所述洛铂化合物晶型为A，PXRD图谱在2θ值约为11.04、12.32、12.61、13.85、15.14、15.55、16.68、17.67、17.86、19.03、20.06、21.00、22.68、22.92、23.76、25.39、25.58、26.37、26.77、27.00、27.71、28.13、29.71、31.42、31.94、32.89、34.29、34.60、36.10、36.93、37.66、40.78、43.41处有衍射峰，其中2θ值误差范围为0.2。
优选地，上述洛铂化合物晶体熔点Tm.p..＝220±5℃。
优选地，上述洛铂化合物晶体其晶型为A，其晶体属于正交晶系，空间群为P212121，晶胞参数为
Figure PCTCN2014092571-appb-000002
α＝β＝γ＝90.0°，晶胞体积
Figure PCTCN2014092571-appb-000003
晶胞内不对称单位数Z＝4。
另一方面，本发明还提供一种制备上述洛铂化合物的方法，其特征在于，包括如下步骤：
将洛铂三水合物加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后干 燥得到该结晶。
优选地，该方法中，去除溶剂后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
优选地，该方法中，所述洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
优选地，该方法中，所述的结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
优选地，该方法中，所述悬浮于室温下进行，优选悬浮45-50h。
另一方面，本发明还提供一种药物组合物，其特征在于，以上述洛铂晶体化合物作为活性成分。
优选地，所述药物组合物最小单元中含有洛铂晶体的量为5mg、10mg或50mg。
优选地，所述药物组合物是任何临床上可接受的药物剂型。
优选地，所述剂型为注射用冻干制剂。
另一方面，本发明还提供上述洛铂化合物晶体、或者上述药物组合物在制备抗癌药中的应用。
另一方面，本发明还提供上述洛铂化合物晶体或者药物组合物的治疗癌症的应用，用于治疗乳腺癌、小细胞肺癌或慢性粒细胞性白血病中的一种。
本发明还进一步提供了上述洛铂晶型在制备药物组合物及药物制剂中的应用。
(2)洛铂晶体B
第二，本发明提供一种洛铂晶体B、其制备方法及药物应用，详述如下。
一种洛铂化合物晶体，其特征在于，其晶型为B，PXRD图谱在2θ角值约为8.25、9.77、11.70、13.13、15.28、16.48、17.22、17.74、19.01、19.56、22.28、23.72、24.04、24.30、25.62、26.20、28.57、30.22、30.61处有衍射峰，其中2θ值误差范围为0.2。
优选地，本发明的洛铂化合物晶体，其熔点Tm.p..＝230±5℃。
其中该熔点是以DSC测定，以最大峰值评估，加热速率：10℃/分。
另一方面，本发明提供一种晶型为B的洛铂晶体的制备方法，包括如下步 骤：
在洛铂三水合物中加入无水甲醇或无水乙醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
优选地，上述制备方法中，所述无水甲醇与洛铂三水合物的质量体积比为洛铂三水合物：无水甲醇＝1:40-50；无水乙醇与洛铂三水合物的质量体积比为洛铂二水合物：无水乙醇＝1:80-90。
另一方面，本发明还提供一种晶型为B的洛铂晶体的制备方法，其中，包括如下步骤b)：
在洛铂二水合物中加入无水甲醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
另一方面，本发明还提供一种晶型为B的洛铂晶体的制备方法，包括如下步骤b)：
在洛铂二水合物中加入有机溶剂，于室温下悬浮搅拌，析出结晶，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
优选地，上述制备方法中，所述的洛铂二水合物的制备方法包括如下步骤a)：
在洛铂三水合物中加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后，用乙醚洗涤，真空干燥得到该洛铂二水合物结晶。
优选地，上述制备方法中，步骤a)中，所述洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
优选地，上述制备方法中，步骤a)中，所述的结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
优选地，上述制备方法中，步骤b)中，分离出结晶后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
优选地，上述制备方法中，步骤b)中，所述悬浮于室温下进行，优选悬浮45-50h。
优选地，上述制备方法中，所述步骤b)中无水甲醇与洛铂二水合物的质 量体积比为洛铂二水合物：无水甲醇＝1:40-50。
优选地，上述制备方法中，所述步骤b)中有机溶剂选自正己烷、丙酮、乙酸乙酯、硝基甲烷、乙腈、四氢呋喃、2-丁酮或二氯甲烷，质量体积比为洛铂二水合物：有机溶剂＝1:15-30。
另一方面，本发明还提供一种药物组合物，其特征在于，以前述的洛铂晶体B作为活性成分。
优选地，所述药物组合物最小单元中含有洛铂晶型的量为5mg、10mg或50mg。
优选地，所述药物组合物是任何临床上可接受的药物剂型。
优选地，所述剂型为注射用冻干制剂。
另一方面，本发明还提供上述洛铂晶体或者所述的药物组合物在制备抗癌药中的应用。
另一方面，本发明还提供上述洛铂化合物晶体或者药物组合物的治疗癌症的应用，优选地用于治疗乳腺癌、小细胞肺癌或慢性粒细胞性白血病中的一种。
(3)洛铂晶体F
第三，本发明提供一种洛铂晶体F、其制备方法及药物应用，详述如下。
一种洛铂化合物晶型，其特征在于，其晶型为F，PXRD图谱在2θ角值约为8.21、11.60、12.99、15.24、16.44、17.11、17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、24.18、24.40、24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、31.94、33.30、36.20、37.62、39.66处有衍射峰，其中2θ值误差范围为0.2。
其中，所述洛铂化合物晶体其熔点Tm.p..＝229±5℃。
另外，其中该熔点是以DSC测定，以最大峰值评估，加热速率：10℃/分。
另一方面，本发明提供所述洛铂晶体的方法，其特征在于，包括如下步骤b)：
在洛铂二水合物中，加入甲醇或乙醇，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入有机溶剂，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型F。
优选地，其中，所述的洛铂二水合物的制备方法包括如下步骤a)：
在洛铂三水合物中加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后，用乙醚洗涤，真空干燥得到该洛铂二水合物结晶。
优选地，其中，步骤a)中，所述洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
优选地，其中，步骤a)中，所述的结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
优选地，其中，步骤b)中，分离出结晶后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
优选地，其中，所述步骤b)中有机溶剂选自乙二醇二甲醚、正己烷、乙酸乙酯、丙酮、硝基甲烷、乙腈、四氢呋喃或二氯甲烷。
优选地，其中，所述步骤b)中洛铂二水合物和有机溶剂的质量体积比为洛铂二水合物：有机溶剂＝1:120-200。
优选地，其中，所述步骤b)中洛铂二水合物与甲醇质量体积比为洛铂二水合物：甲醇＝1:40-50，洛铂二水合物与乙醇质量体积比为洛铂二水合物：乙醇＝1:80-90。
另一方面，本发明提供一种药物组合物，其特征在于，以权利要求1或2所述的洛铂晶体作为活性成分。
优选地，其中，所述药物组合物最小单元中含有洛铂晶体的量为5mg、10mg或50mg。
优选地，其中，所述药物组合物是任何临床上可接受的药物剂型。
优选地，其中，所述剂型为注射用冻干制剂。
另一方面，本发明还提供所述的洛铂晶体，或者所述的药物组合物在制备抗癌药中的应用。
另一方面，本发明还提供所述的洛铂晶体或者所述的药物组合物治疗癌症的应用，优选地其用于治疗乳腺癌、小细胞肺癌或慢性粒细胞性白血病中的一种。
在本发明中所用的原料洛铂三水合物采用专利EP0611303实施例的方法来制备。
所述药物组合物，以前述的洛铂晶型作为活性成分，最小单元中含有洛铂 晶型的量为5mg、10mg或50mg。洛铂新晶型可与一种或多种药学上可接受的载体或赋形剂制成药物组合物。进一步的，所述药物组合物可制成适于原料的临床上任何可药用的剂型，包括注射剂型、经皮肤给药剂型、呼吸道给药剂型、腔道及身体其它部位黏膜给药剂型等非胃肠道给药剂型。优选为注射用冻干粉针。
所述的药用载体或赋形剂可选自以下中的一种或多种：注射用水、甘露醇、乳糖、聚乙二醇类、吐温-80、丙二醇、酒石酸、枸橼酸、抗坏血酸、依地酸二钠、依地酸钙钠、亚硫酸氢钠、葡萄糖、氯化钠、大豆油、大豆卵磷脂、蛋黄磷脂、二硬脂酰磷脂酰乙醇胺、右旋糖酐、甘氨酸、甘油。
上述组合物及制剂的制备方法通常是本领域技术人员熟知常规的方法。本发明的洛铂化合物与上市的洛铂制剂活性形式都是洛铂，即无水洛铂，故适用于现已上市的洛铂产品治疗的所有疾病。
洛铂即顺式-[反式-1,2-环丁烷双(甲胺)-N,N']-[(2S)-乳酸-O1,O2]-铂(II)，属烷化剂，细胞毒类药物，又称生物烷化剂(BioalkylatingAgengts)，在体内能形成碳正离子或其他具有活泼的亲电性基团的化合物，进而与细胞中的生物大分子(DNA，RNA，酶)中含有丰富电子的基团(如氨基，巯基，羟基，羧基、磷酸基等)发生共价结合，使其丧失活性或使DNA分子发生断裂，导致肿瘤细胞死亡，故抗肿瘤活性强。药代动力学研究表明，静脉注射洛铂后，在血清中以总铂和游离铂的形式发挥抗肿瘤作用，即为无水洛铂发挥有效作用，与原料状态无关。
本发明的上述三种洛铂新晶型，是基于无定形态洛铂容易潮解变粘、稳定性差，不易贮存等缺陷而开发的新晶型，具有生物利用度高，稳定性好，不易潮解等特点，与洛铂三水合物相比较，还意外发现其相比三水合物具有溶解度高，收率和纯度高、稳定性更优的优势。因此该新晶型的开发，有助于药物给药途径的选择与设计，以及药物制剂工艺参数的确定，从而提高药品生产质量。本发明新的洛铂化合物在常温下非常稳定，其不易吸潮变粘、流动性好，在贮存、运输以及制剂和处理时的可操作性明显优于无定型态洛铂。
附图说明
图1：洛铂二水合物的X-射线衍射图；
图2：洛铂二水合物的分子立体结构投影图；
图3：洛铂二水合物的差热分析DSC图；
图4：洛铂二水合物的差热分析TGA图。
图5：晶型为B的洛铂晶体的X-射线衍射图；
图6：晶型为B的洛铂晶体的差热分析DSC图；
图7：晶型为B的洛铂晶体的差热分析TGA图；
图8：洛铂新晶型F的X-射线衍射图；
图9：洛铂新晶型F的差热分析DSC图；
图10：洛铂新晶型F的差热分析TGA图。
具体实施方式
(1)本发明的第一实施方案
本发明提供一种溶解度好、收率高、且稳定性优异的晶体形态的洛铂二水合物。具体说明如下：
本发明提供一种晶型为A的洛铂二水合物，其X-射线衍射(PXRD)鉴定数据如下：
采用生产厂家为Bruker、型号为Bruker D8advance XRD的X射线衍射仪，对晶型为A的洛铂二水合物进行测定，测定条件为：CuKa(40kv，40mA)，扫描速率2°/min(2θ值)，扫描范围3°-45°(2θ值)，具有以下表1-a所示特征的吸收峰，其衍射谱图如图1所示。
表1-a晶型为A的洛铂二水合物X-射线衍射(PXRD)测定结果
峰序 衍射角2θ值(约) 晶面距d(约) 相对强度(约)
1 11.04 8.01 66.9
2 12.32 7.18 86.3
3 12.61 7.01 51.3
4 13.85 6.39 22.2
5 15.14 5.85 100
6 15.55 5.69 17.4
7 16.68 5.31 35
8 17.67 5.02 54.5
9 19.03 4.66 4.8
10 20.06 4.42 16.8
11 21.00 4.23 75.9
12 22.68 3.92 25.4
13 22.92 3.88 28.2
14 23.76 3.74 2
15 25.58 3.48 7.8
16 26.77 3.33 37.4
17 27.00 3.30 22.9
18 27.71 3.22 8.3
19 28.13 3.17 19.2
20 29.71 3.00 8.4
21 31.42 2.84 33.5
22 31.94 2.80 25.1
23 32.89 2.72 8.9
23 34.60 2.59 17.3
25 36.93 2.43 10.3
26 37.66 2.39 7.3
27 40.78 2.21 12.3
28 43.41 2.08 9.8
该晶型为A的洛铂化合物，通过进行X-射线单晶衍射实验，晶体呈无色透明柱状，属于正交晶系，空间群为P212121，晶胞参数：a＝10.601(2)，b＝14.020(3)，
Figure PCTCN2014092571-appb-000004
α＝β＝γ＝90.0°,晶胞体积
Figure PCTCN2014092571-appb-000005
晶胞内不对称单位数Z＝4；
用Bruker SMART APEX-II衍射仪收集衍射强度数据，CuKα辐射，石墨单色器，单导管直径ф＝0.50mm，晶体与CCD探测器距离d＝60.3mm，管压40kV，管流30mA，扫描方式：φ/ω扫描，收集总衍射点数为5844个，独立衍射点数为2376个，可观察点数(|F|2≥2σ|F|2)为2376个。
采用直接法(Shelxs97)解析晶体结构，可获得全部17个非氢原子位置，使用最小二乘法修正结构参数和判别原子种类，使用几何计算法和差值Fourier法获得全部氢原子位置，最终可靠因子R1＝0.0569，wR2＝0.1491(w＝1/σ|F|2)，S＝1.077。最终确定化学计量式为C9H18N2O3Pt·2H2O，计算分子量为433.36，计算晶体密度1.975g/cm3。经结构解析可确定制得的洛铂新晶型为洛铂二水合物，其分子结构如下式(2)所示：
Figure PCTCN2014092571-appb-000006
该晶型为A的洛铂二水合物的分子立体结构投影图如图2所示。
该晶型为A的洛铂二水合物通过生产厂家为NETZSCH、型号为NETZSCH DSC 204F1、NETZSCH TG 209F1的差热分析仪进行差热分析(DSC-TGA)，DSC图如图3所示，TGA图如图4所示。结果显示，以DSC测定，以最大峰值评估，熔点Tm.p..＝220±5℃，加热速率：10℃/分。具体为：DSC图谱在117℃左右有一宽吸热峰，结合单晶及TGA数据判断，该峰可能为失去2个结晶水产生；在220±5℃有一放热峰，结合TGA及欧洲专利EP0611303熔点数据判断，该峰为熔融分解峰。TGA图谱在150℃之前有9.49％的失重，表明为失去2个结晶水产生。
另一方面，本发明提供一种制备简单、易于操作、适合放大生产的洛铂新晶型A的制备方法，包括如下步骤：
称取洛铂三水合物于容器中，加入有机溶剂，于室温下悬浮搅拌45-50h，过滤、用乙醚洗涤，真空干燥后得白色粉末，即为洛铂二水合物；所述有机溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷，质量体积比为洛铂三水合物：有机溶剂＝1:15-30。
(2)本发明的第二实施方案
本发明提供一种溶解度高、稳定性优异的洛铂新晶型，命名为晶型B。
一方面，本发明提供一种晶体形态为B的洛铂晶体B。下面就本发明制备分离出的洛铂晶型B具体说明如下：
采用生产厂家为Bruker、型号为Bruker D8advance XRD的X射线衍射仪，对洛铂晶型B进行测定，其测定条件为：CuKa(40kv，40mA)，扫描速率2°/min(2θ值)，扫描范围3°-45°(2θ值)，具有以下特征的吸收峰，见下表1-b，其衍射图谱如图5所示：
表1-b洛铂晶型B的X-射线衍射(PXRD)测定结果
Figure PCTCN2014092571-appb-000007
该洛铂的新晶型B通过生产厂家为NETZSCH、型号为NETZSCH DSC 204F1、NETZSCH TG 209F1的差热分析仪进行差热分析(DSC-TGA)，DSC图如图6所示，TGA图如图7所示。结果显示，以DSC测定，以最大峰值评估，熔点Tm.p..＝230±5℃，加热速率：10℃/分。具体为：DSC图谱在230±5℃有一放热峰，结合TGA及欧洲专利EP0611303熔点数据判断，该峰为熔融分解峰，TGA图谱在150℃之前无失重，说明其为非溶剂化物。
另一方面，本发明提供一种制备简单、易于操作、适合放大生产的洛铂新 晶型B的制备方法。
在一种优选的实施方式中，本发明所述洛铂新晶型B的制备方法，包括如下步骤：
a、制备洛铂二水合物：称取洛铂三水合物于容器中，相对于1g洛铂三水合物，加入15-30ml有机溶剂，于室温下悬浮搅拌45-50h，过滤、用乙醚洗涤，真空干燥后得白色粉末，即为洛铂二水合物；
其中，所述有机溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
b、制备目标晶型：称取步骤a所得的洛铂二水合物，置于容器中，加入无水甲醇，于室温下搅拌至固体溶解，滤去不溶物，置通风橱缓慢挥发，待结晶析出后，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末，即为洛铂的新晶型B。
所述步骤b中质量体积比为洛铂二水合物：无水甲醇＝1:40-50。
在另一种优选的实施方式中，本发明的优选的所述洛铂新晶型B的制备方法，还可以为：
a、制备洛铂二水合物：称取洛铂三水合物于容器中，相对于1g洛铂三水合物，加入15-30ml有机溶剂，于室温下悬浮搅拌45-50h，过滤、用乙醚洗涤，真空干燥后得白色粉末，即为洛铂二水合物；
其中，所述有机溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
b、制备目标晶型：称取步骤a所得的洛铂二水合物，置于容器中，加入有机溶剂，于室温下悬浮搅拌45-50h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末，即为洛铂的新晶型B。
所述步骤b中有机溶剂选自正己烷、丙酮、乙酸乙酯、硝基甲烷、乙腈、四氢呋喃、2-丁酮或二氯甲烷，质量体积比为洛铂二水合物：有机溶剂＝1:15-30。
在又一种优选的实施方式中，本发明的优选的所述洛铂新晶型B的制备方法，还可以为：在洛铂三水合物中加入无水甲醇或无水乙醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。质量体积比为洛铂三水合物：无水甲醇 ＝1:40-50，洛铂三水合物：无水乙醇＝1:80-90。
(3)本发明的第三实施方案
本发明提供一种溶解度高、稳定性优异的洛铂新晶型，命名为晶型F。
一方面，本发明提供一种晶体形态的洛铂新晶型F。下面就本发明制备分离出的洛铂晶型F具体说明如下：
采用生产厂家为Bruker、型号为Bruker D8advance XRD的X射线衍射仪，对洛铂晶型F进行测定，其测定条件为：CuKa(40kv，40mA)，扫描速率2°/min(2θ值)，扫描范围3°-45°(2θ值)，具有以下特征的吸收峰，见下表1-c，其衍射图谱如图8所示：
表1-c洛铂新晶型F的X-射线衍射(PXRD)测定结果
峰序 衍射角2θ值(约) 晶面距d(约) 相对强度(高度约％)
1 8.21 10.76 100
2 11.60 7.62 0.8
3 12.99 6.81 3.3
4 15.24 5.81 5.2
5 16.44 5.39 8.9
6 17.11 5.18 2
7 17.55 5.05 2.2
8 18.42 4.81 0.9
9 19.01 4.67 6.3
10 19.20 4.62 2.2
11 19.42 4.57 2.1
12 21.81 4.07 0.7
13 22.17 4.01 1.7
14 22.42 3.96 1.8
15 23.33 3.81 0.8
16 23.85 3.73 3.2
17 24.18 3.68 1.2
18 24.40 3.65 0.8
19 24.77 3.59 1.7
20 25.46 3.50 1.6
21 25.98 3.43 1.3
22 26.13 3.41 1.1
23 27.89 3.20 0.6
24 28.42 3.14 0.6
25 29.03 3.07 0.5
26 30.32 2.95 4.8
27 31.17 2.87 0.5
28 31.94 2.80 0.5
29 33.30 2.69 1.1
30 36.20 2.48 1.8
31 37.62 2.39 1.2
32 39.66 2.27 0.8
该洛铂的新晶型F通过生产厂家为NETZSCH、型号为NETZSCH DSC 204 F1、NETZSCH TG 209F1的差热分析仪进行差热分析(DSC-TGA)，DSC图如图9所示，TGA图如图10所示。结果显示，以DSC测定，以最大峰值评估，熔点Tm.p..＝229±5℃，加热速率：10℃/分。具体为：DSC图谱在229±5℃有一放热峰，结合TGA及欧洲专利EP0611303熔点数据判断，该峰为熔融分解峰，TGA图谱在150℃之前有1.97％的失重，结合DSC数据判断其为溶剂残留。
另一方面，本发明提供一种制备简单、易于操作、适合放大生产的洛铂新晶型F的制备方法。
在一种优选的实施方式中，本发明所述洛铂新晶型F的制备方法，包括如下步骤：
a、制备洛铂二水合物：称取洛铂三水合物于容器中，加入15-30ml有机溶剂，于室温下悬浮搅拌45-50h，过滤、用乙醚洗涤，真空干燥后得白色粉末，即为洛铂二水合物；
其中，所述有机溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二 氧六环或正庚烷。
b、制备目标晶型：称取步骤a所得的洛铂二水合物，置于容器中，加入甲醇或乙醇，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入有机溶剂，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末，即为洛铂的新晶型F。
所述步骤b中有机溶剂选自乙二醇二甲醚、正己烷、乙酸乙酯、丙酮、硝基甲苯、乙腈、四氢呋喃、二氯甲烷。洛铂二水合物与有机溶剂质量体积比为洛铂二水合物：有机溶剂＝1:120-200。
所述步骤b中洛铂二水合物与甲醇质量体积比为洛铂二水合物：甲醇＝1:40-50，洛铂二水合物与乙醇质量体积比为洛铂二水合物：乙醇＝1:80-90。
实施例
以下通过实施例来具体说明本发明的洛铂晶型A、B和F的制备方法以及各新晶型的筛选分离过程及其鉴定和性能测定。
实施例一：各晶型的筛选分析
1.1常温挥发结晶法筛选
取20mg洛铂三水合物样品放入10ml样品瓶中，加入3ml无水乙醇或无水甲醇，充分溶解后，置于25℃环境下缓慢挥发，得到固体干燥物，进行PXRD测定。结果见下表2：
表2常温挥发结晶试验结果
编号 溶剂 PXRD(可能晶型编号)
1-1 无水乙醇 B
1-2 无水甲醇 B
结果表明：在无水甲醇和无水乙醇中获得的晶型，经比较得知其为同一晶型，暂命名为晶型B。
1.2悬浮结晶法筛选
取20mg洛铂三水合物样品放入10ml样品瓶中，加入4ml下述有机溶剂，制 备成悬浮液，置于25℃环境下震荡1.5h后去除溶剂，固体干燥后进行PXRD测定。结果见下表3：
表3悬浮结晶试验结果
Figure PCTCN2014092571-appb-000008
结果表明：悬浮结晶可获得的晶型有9种，暂命名为晶型A、B、C、D、E、G、H、I、L。
1.3溶析结晶法筛选
取20mg洛铂三水合物样品，溶解在3ml无水甲醇或无水乙醇中配制成溶液，向其中逐步加入下述有机溶剂，直到析出固体，除去上清液，固体干燥后进行PXRD测定。结果见下表4：
表4溶析结晶试验结果
Figure PCTCN2014092571-appb-000009
结果表明：悬浮结晶可获得的晶型有7种，暂命名为晶型F、J、K、M、N、O、P。
1.4各晶型的表征
除了对晶型A-P样品进行PXRD测定外，还进行DCS、TGA表征，其中，所采用的各仪器名称、型号和厂家如下表5所示。
表5对晶型进行表征时的各仪器型号和厂商
Figure PCTCN2014092571-appb-000010
测定结果如下：
晶型A，其特征在于PXRD图谱在2θ值约为11.04、12.32、12.61、13.85、15.14、15.55、16.68、17.67、17.86、19.03、20.06、21.00、22.68、22.92、23.76、25.39、25.58、26.37、26.77、27.00、27.71、28.13、29.71、31.42、31.94、32.89、34.29、34.60、36.10、36.93、37.66、40.78、43.41处有衍射峰，其中2θ值误差范围为0.2；
晶型A，其特征在于DSC图谱在220±5℃附近有放热峰。
晶型B，其特征在于PXRD图谱在2θ值约为8.25、9.77、11.70、13.13、15.28、16.48、17.22、17.74、19.01、19.56、22.28、23.72、24.04、24.30、25.62、26.20、28.57、30.22、30.61处有衍射峰，其中2θ值误差范围为0.2；
晶型B，其特征在于DSC图谱在230±5℃附近有放热峰。
晶型C，其特征在于PXRD图谱在2θ值约为6.79、8.07、12.24、12.61、13.50、16.50、17.83、18.32、18.79、20.09、21.64、22.27、23.19、24.73、27.34、28.35、29.12、31.92处有衍射峰，其中2θ值误差范围为0.2；
晶型C，其特征在于DSC图谱在228±5℃附近有放热峰。
晶型D，其特征在于PXRD图谱在2θ值约为6.76、11.07、12.35、12.65、13.88、15.18、15.56、16.68、17.70、17.90、20.08、21.02、22.70、22.92、25.41、25.64、26.41、26.79、27.02、28.15、31.44、31.96、32.96、34.34、34.62、36.93、40.82、43.46处有衍射峰，其中2θ值误差范围为0.2；
晶型D，其特征在于DSC图谱在218±5℃附近有放热峰。
晶型E，其特征在于PXRD图谱在2θ值约为6.61、8.09、12.38、13.03、15.40、16.66、17.47、19.07处有衍射峰，其中2θ值误差范围为0.2；
晶型E，其特征在于DSC图谱在214±5℃附近有放热峰。
晶型F，其特征在于PXRD图谱在2θ值约为8.21、11.60、12.99、15.24、16.44、17.11、17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、24.18、24.40、24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、31.94、33.30、36.20、37.62、39.66处有衍射峰，其中2θ值误差范围为0.2；
晶型F，其特征在于DSC图谱在229±5℃附近有放热峰。
晶型G，其特征在于PXRD图谱在2θ值约为8.62、10.82、11.03、12.26、12.59、 13.82、15.12、15.57、16.59、17.43、17.65、18.48、19.46、20.11、20.37、21.01、22.66、22.86、24.60、25.40、26.33、26.77、27.00、28.11、29.79、31.42、31.94、32.87、34.25、34.58、36.06、40.76、42.75、43.39处有衍射峰，其中2θ值误差范围为0.2。
晶型H，其特征在于PXRD图谱在2θ值约为8.35、8.53、8.68、12.97、15.24、17.41、18.40、19.13、19.48、20.37、24.68、25.41、30.33、31.66、36.34处有衍射峰，其中2θ值误差范围为0.2。
晶型I，其特征在于PXRD图谱在2θ值约为6.75、8.39、11.07、11.59、12.32、12.63、12.99、15.20、16.80、17.07、17.57、19.14、19.46、21.00、22.13、22.84、23.29、23.77、24.22、25.82、26.76、28.38、30.34、30.83、31.90、33.63、36.32、38.47处有衍射峰，其中2θ值误差范围为0.2。
晶型J，其特征在于PXRD图谱在2θ值约为5.94、8.35、9.87、13.05、15.28、16.66、19.15、22.22、22.68、25.09、30.71、33.56处有衍射峰，其中2θ值误差范围为0.2。
晶型K，其特征在于PXRD图谱在2θ值约为8.29、11.02、12.31、12.61、13.84、15.14、15.53、16.70、17.66、19.05、20.06、20.98、22.68、22.90、25.60、26.37、26.77、26.98、27.68、28.23、29.75、31.40、31.88、32.90、33.81、34.29、34.60、36.10、36.84、37.64、39.93、40.76、41.51、42.36、42.70、43.39处有衍射峰，其中2θ值误差范围为0.2。
晶型L，其特征在于PXRD图谱在2θ值约为6.71、7.91、10.75、11.84、14.06、14.29、15.85、16.78、17.29、19.76、20.20、20.63、21.08、21.58、21.89、22.17、23.87、25.09、26.83、27.02、28.73、29.18、29.92、30.56、31.61、33.95、40.33、41.33处有衍射峰，其中2θ值误差范围为0.2。
晶型M，其特征在于PXRD图谱在2θ值约为8.05、13.03、15.20、16.19、17.47、18.77、19.32、24.06处有衍射峰，其中2θ值误差范围为0.2。
晶型N，其特征在于PXRD图谱在2θ值约为7.94、12.67、14.83、16.32、17.16、18.71、21.83、22.44、24.10、24.89、27.97、30.02、30.48处有衍射峰，其中2θ值误差范围为0.2
晶型O，其特征在于PXRD图谱在2θ值约为6.75、8.15、16.29、18.95、22.23、 24.52、29.93处有衍射峰，其中2θ值误差范围为0.2。
晶型P，其特征在于PXRD图谱在2θ值约为6.61、8.17、13.34、16.52、20.10、24.97、27.02、33.99、41.06处有衍射峰，其中2θ值误差范围为0.2。
1.5重复、放大实验
进一步选择晶型A-P，按照上述“1.2悬浮结晶法筛选”分别进行100mg放大重复试验，验证晶型的可重复性。结果见下表6：
表6重复试验结果
Figure PCTCN2014092571-appb-000011
结果表明：晶型A-F稳定，晶型G-P有的放大困难，有的出现转晶现象，不适于进一步考察。
也就是说，综合常温挥发、悬浮结晶、溶析结晶等方法对原料进行结晶筛选，采用PXRD表征后通过对图谱进行分析比对，初步判定洛铂可能存在16种晶型A-P；通过重复、放大验证，最终确定晶型A-F可重复较好，为相对稳定 晶型；其他晶型有的收率较低，难以进行放大生产；有的出现转晶现象，推断其为不稳定晶型。因此，选择晶型A-F，进一步进行全面考察。
实施例二：命名为晶型A的洛铂新晶型的制备、产品性质及对比分析
2.1命名为晶型A的洛铂二水合物的制备
制备例1
称取1g洛铂三水合物于容器中，加入15ml甲苯，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.85g，即为洛铂二水合物。
制备例2
称取1g洛铂三水合物于容器中，加入15ml乙醚，于室温下悬浮搅拌45h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.88g，即为洛铂二水合物晶型。
制备例3
称取1g洛铂三水合物于容器中，加入20ml乙酸丁酯，于室温下悬浮搅拌50h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.83g，即为洛铂二水合物。
制备例4
称取1g洛铂三水合物于容器中，加入25ml 1,4-二氧六环，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.90g，即为洛铂二水合物。
制备例5
称取1g洛铂三水合物于容器中，加入30ml正庚烷，于室温下悬浮搅拌46h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.87g，即为洛铂二水合物。
制备例6
称取1g洛铂三水合物于容器中，加入15ml甲基叔丁基醚，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.92g，即为洛铂二水合物。
上面各实施例制备得到的样品按照上述实施例1中1.4的方法进行XRD衍射测定后，鉴定为6种样品的晶型相同，其特征峰如下：PXRD图谱在2θ值约为11.04、12.32、12.61、13.85、15.14、15.55、16.68、17.67、17.86、19.03、20.06、21.00、22.68、22.92、23.76、25.39、25.58、26.37、26.77、27.00、27.71、28.13、29.71、31.42、31.94、32.89、34.29、34.60、36.10、36.93、37.66、40.78、43.41处有衍射峰，其中2θ值误差范围为0.2。
元素分析结果为：C9H18N2O3Pt*2H2O M＝433.36
计算值(％)：C 24.95 H 5.11 N 6.46 Pt 45.01
实测值(％)：C 24.94 H 5.08 N 6.41 Pt 45.07
将这种晶型命名为A型。
2.2晶型为A的洛铂晶体产品性质测定及对比分析
1.试验样品
本发明的洛铂二水合物1-6：分别为本发明实施例1-6制备方法得到的晶型为A的洛铂二水合物；
对比样品1：采用专利EP0324154实施例1a方法制得的洛铂，具体制备方法如下：
3.8g(0.01mol)顺式-[反式-1,2-环丁基双(甲胺)-N,N']-二氯铂(I I)悬浮于20ml水中，加热至40℃，向其中加入3.39g(0.02mol)硝酸银。搅拌1.5小时后，于冰箱冷却，滤除析出的氯化银沉淀，并用10ml水洗涤，滤液通过含100ml碱性离子交换柱，用150ml水洗涤。然后滴加到4.5g(0.01mol，20％水溶液)的L-乳酸中。室温下搅拌3天后，将反应混合物浓缩，后溶解于甲醇中并加入活性炭搅拌脱色。再将活性炭滤去，滤液中加入乙醚，快速浓缩得固体，即为无定型态洛铂。
对比样品2：采用专利EP0611303实施例方法制得的洛铂三水合物，具体制备方法如下：
3.8g(0.01mol)顺式-[反式-1,2-环丁基双(甲胺)-N,N']-二氯铂(I I)悬 浮于20ml水中，加热至40℃，向其中加入3.39g(0.02mol)硝酸银。搅拌1.5小时后，于冰箱冷却，滤除析出的氯化银沉淀，并用10ml水洗涤，滤液通过含100ml碱性离子交换柱，用150ml水洗涤。然后滴加到4.5g(0.01mol，20％水溶液)的L-乳酸中。室温下搅拌3天后，将反应混合物浓缩至大约20ml，冰箱中放置过夜。吸滤析出的结晶，滤液浓缩，冰箱放置过夜，又析出结晶，再滤集，合并结晶后，用20ml水/丙酮(1/1，V/V)重结晶，所得晶体即为洛铂三水合物。
2.形态鉴定
对比样品1：得到的洛铂为无定形态；
对比样品2：通过X-射线衍射，PXRD图谱在2θ值约为6.71、8.35、12.89、15.14、16.74、17.45、19.01、19.40、22.07、22.76、23.16、24.30、25.21、25.74、27.08、30.26、30.79处有衍射峰，其2θ值误差范围小于0.2，专利EP0611303中描述其熔点为210℃(分解)；
本发明的晶型A的样品1-6：通过X-射线衍射，PXRD图谱在2θ值约为11.04、12.32、12.61、13.85、15.14、15.55、16.68、17.67、17.86、19.03、20.06、21.00、22.68、22.92、23.76、25.39、25.58、26.37、26.77、27.00、27.71、28.13、29.71、31.42、31.94、32.89、34.29、34.60、36.10、36.93、37.66、40.78、43.41处有衍射峰，其2θ值误差范围小于0.2；DSC图谱显示在117℃左右有一宽吸热峰，结合单晶及TGA数据判断，该峰可能为失去2个结晶水产生；在220±5℃有一放热峰，结合TGA及文献欧洲专利EP0611303中熔点数据判断，该峰为熔融分解峰。TGA图谱在150℃之前有9.49％的失重，为失去2个结晶水产生。表明样品1-6为同一晶型，也即为洛铂二水合物。
3.溶解度考察
分别配制浓度为60μg/ml、80μg/ml、200μg/ml、400μg/ml、800μg/ml的洛铂三水合物对照品溶液，通过HPLC法制造标准曲线，所得标准曲线方程为Y＝4.8641X+20.5794，R＝0.9998。将洛铂二水合物的样品6及对比样品2制成饱和水溶液(悬浮液)，置25℃摇床震荡6h，然后过滤，稀释适当倍数，进行HPLC分析。溶解度结果如下表7：
表7溶解度考察结果
晶型 样品6 对比样品2
溶解度(mg/ml) 16.7307 10.3271
结果表明：本发明制得的洛铂二水合物溶解性优于洛铂三水合物。
4.洛铂新晶型质量对比研究
取洛铂二水合物的6个样品、对比样品1-2各20mg，以产品水分、杂质含量、活性成分含量、收率等为指标，考察产品质量和收率。结果见下表8：
表8晶型为A的洛铂二水合物的质量对比研究
Figure PCTCN2014092571-appb-000012
上述结果表明，与洛铂无水物及洛铂三水合物相比，本发明获得的洛铂新晶型A具有含量高、杂质低、收率好的特点。
注1：含量测定方法：照高效液相色谱法测定：色谱条件：用十八烷基硅烷键合硅胶为填充剂，以磷酸二氢钾溶液：乙腈＝92:8为流动相，检测波长为210nm，柱温40℃，理论板数按洛铂峰计算应补低于1000，洛铂峰与杂质峰分离度符合要求；对照品溶液的制备：取洛铂三水合物对照品10mg，精密称定置50ml量瓶中，加水稀释至刻度，摇匀即得；供试品溶液的制备：取样品各20mg，精密称定，分别置100ml量瓶中，加水稀释至刻度，摇匀即得；测定及结果：精密量取对照品及样品溶液各10μl，分别注入液相色谱仪，记录色谱图，按外标法以峰面积计算，按无水物计算即得，标准范围为97.0％-102％。
注2：杂质检查方法：用薄层层析测定洛铂、1，2-二氨甲基环丁烷(CBMA)、乳酸等已知的和未知的杂质含量。展开剂：乙醇：氯仿：25％氨水：水＝53： 39：15：1.5(体积比),薄层层析板：硅胶60F25410×10薄层板。展开后至碘蒸气中用0.3％茚三酮试剂和对亚硝基二甲苯胺试剂显色，检查杂质CBMA以及未知杂质。
注3：水分测定方法：采用KarlFischer方法测定。二水合物含水分理论量为8.77％，三水合物含水分理论量为11.96％。
5.稳定性考察
将本发明实施例制得的样品6和对比样品2分别置于60℃烘箱内、相对湿度约为95％的环境下、照度约为4500lux的光稳定试验箱(带光照功能的常规的恒温箱)内，分别于5天、10天后将样品取出进行PXRD测试及HPLC分析，以考察样品在高温、高湿、光照条件下的稳定性，结果见表9。
表9稳定性评价结果
Figure PCTCN2014092571-appb-000013
上述试验结果表明，本发明的洛铂为新晶型，溶解度高于洛铂三水合物，收率和纯度非常理想，从高温、高湿、光照考察结果来看，洛铂新晶型稳定性好，无转晶现象发生，HPLC结果表明有效成分含量优于洛铂三水合物，且未发生明显变化，说明本发明洛铂新晶型稳定性优于洛铂三水合物，不易潮解变粘、流动性好。
实施例三：命名为晶型B的洛铂新晶型的制备、产品性质及对比分析
3.1命名为晶型B的洛铂新晶型的制备
制备例1
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入30ml甲苯，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.73g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入无水甲醇40ml，于室温下搅拌至固体溶解，滤去不溶物，置通风橱缓慢挥发，待结晶析出后，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.74g，即为洛铂的新晶型B。
制备例2
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml甲基叔丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.84g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入无水甲醇50ml，于室温下搅拌至固体溶解，滤去不溶物，置通风橱缓慢挥发，待结晶析出后，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.76g，即为洛铂的新晶型B。
制备例3
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入20ml乙酸丁酯，于室温下悬浮搅拌50h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.68g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入20ml正己烷，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.75g，即为洛铂的新晶型B。
制备例4
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入25ml 1,4-二氧六环，于室温下悬浮搅拌45h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.76g， 即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入15ml丙酮，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.78g，即为洛铂的新晶型B。
制备例5
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入30ml正庚烷，于室温下悬浮搅拌50h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.75g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入18ml乙酸乙酯，于室温下悬浮搅拌50h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.75g，即为洛铂的新晶型B。
制备例6
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml乙醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.78g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入25ml硝基甲烷，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.77g，即为洛铂的新晶型B。
制备例7
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入18ml甲基叔丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.82g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入30ml四氢呋喃，于室温下悬浮搅拌46h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.79g，即为洛铂的新晶型B。
制备例8
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入25ml甲基叔丁基醚，于室温下悬浮搅拌46h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.83g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入15ml二氯甲烷，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.76g，即为洛铂的新晶型B。
制备例9
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入30ml甲基叔丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.85g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入25ml乙腈，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.78g，即为洛铂的新晶型B。
制备例10
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml甲基叔丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.84g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入20ml 2-丁酮，于室温下悬浮搅拌48h，析出结晶，过滤分离出该结晶，用乙醚洗涤2-3次，真空干燥后得白色粉末0.73g，即为洛铂的新晶型B。
制备例11
称取洛铂三水合物1g于容器中，加入40ml无水甲醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，过滤分离出该结晶，干燥后得白色粉末0.68g，即为洛铂的晶型B。
制备例12
称取洛铂三水合物1g于容器中，加入无水乙醇85ml，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，过滤分离出该结晶，干燥后得白色粉末0.70g，即为洛铂的晶型B。
上面各实施例1-10中步骤a)制备得到的样品按照上述实施例一中1.4节的方法进行XRD衍射测定后，鉴定为10种样品的晶型相同，该晶型为A，其详细的鉴定数据与前面具体实施方式中第(1)部分“本发明的第一实施方案”的鉴定数据和上面的实施例二中所示数据相同。
另一方面，对上面实施例1-10中步骤b)及实施例11-12中制备得到的样品按照上述实施例一中1.4的方法进行XRD衍射测定后，鉴定为12种样品的晶型相同，其特征峰如下：PXRD图谱中在2θ角值为8.25、9.77、11.70、13.13、15.28、16.48、17.22、17.74、19.01、19.56、22.28、23.72、24.04、24.30、25.62、26.20、28.57、30.22、30.61处有衍射峰，其中2θ值误差范围为±0.2。
将这种晶型命名为B型。
3.2晶型为B的产品性质测定及对比分析
1、试验样品
样品1-12：分别为通过本发明实施例1-12制备方法得到的晶型为B的洛铂化合物；
对比样品1：与前面实施例二的2.2部分的对比样品1相同，也采用专利EP0324154实施例1a方法制得的洛铂，具体制备方法与前面实施例二的2.2部分的对比样品1的制备方法相同：
对比样品2：与前面实施例二的2.2部分的对比样品2相同，也采用专利EP0611303实施例方法制得的洛铂三水合物，具体制备方法与前面实施例二的2.2部分的对比样品2的制备方法相同。
2、形态鉴定
鉴定结果与实施例二的2.2部分的对比样品1和对比样品2相同，具体如下：
对比样品1：得到的洛铂为无定形态；
对比样品2：通过X-射线衍射，PXRD图谱在2θ值约为6.71、8.35、12.89、15.14、16.74、17.45、19.01、19.40、22.07、22.76、23.16、24.30、25.21、25.74、27.08、30.26、30.79处有衍射峰，其2θ值误差范围小于0.2，专利EP0611303中描述其熔点为210℃(分解)；
本发明样品1-12：通过X-射线衍射，PXRD图谱在2θ值约为8.25、9.77、11.70、13.13、15.28、16.48、17.22、17.74、19.01、19.56、22.28、23.72、24.04、24.30、25.62、26.20、28.57、30.22、30.61处有衍射峰，其2θ值误差范围小于0.2；DSC图谱显示在230±5℃处有放热峰，结合TGA及EP0611303熔点数据判断，该峰为熔融分解峰。表明样品1-12为同一晶型，也即为洛铂的新晶型B。
3、溶解度考察
分别配制浓度为60μg/ml、80μg/ml、200μg/ml、400μg/ml、800μg/ml的洛铂三水合物对照品溶液，通过HPLC法制造标准曲线，所得标准曲线方程为Y＝4.8641X+20.5794，R＝0.9998。将洛铂新晶型B的样品1及对比样品2制成饱和水溶液(悬浮液)，置25℃摇床震荡6h，然后过滤，稀释适当倍数，进行HPLC分析。溶解度结果如下表10：
表10溶解度考察结果
晶型 样品1 对比样品1
溶解度(mg/ml) 17.7341 10.3271
结果表明：本发明制得的洛铂化合物溶解性优于洛铂三水合物。
4、洛铂新晶型质量对比研究
取样品1-12、对比样品1-2各50mg，以产品水分、杂质含量、活性成分含量、收率等为指标，考察产品质量和收率。三水合物含水分理论量为11.96％。结果见下表11：
表11洛铂新晶型B质量对比研究
Figure PCTCN2014092571-appb-000014
上述结果表明，与洛铂无水物及洛铂三水合物相比，本发明获得的洛铂新晶型B具有含量高、杂质低、收率好的特点。
注1：含量测定方法：与前面实施例二的2.2部分相同；
注2:杂质检查方法：与前面实施例二的2.2部分相同；
注3：水分测定方法：与前面实施例二的2.2部分相同。
5、稳定性考察
将本发明实施例三制得的洛铂晶体B的样品1、对比样品2分别置于60℃烘箱内、相对湿度约为95％的环境下、照度约为4500lux的光稳定试验箱(带光照功能的常规的恒温箱)内，分别于5天、10天后将样品取出进行PXRD测试及HPLC分析，以考察样品在高温条件下的稳定性。结果见下表12：
表12稳定性评价结果
Figure PCTCN2014092571-appb-000015
上述试验结果表明，本发明的洛铂新晶型B，溶解度高于洛铂三水合物，收率和纯度非常理想，从高温、高湿、光照考察结果来看，洛铂新晶型B稳定性好，无转晶现象发生，HPLC结果表明有效成分含量优于洛铂三水合物，且未发生明显变化，说明本发明洛铂新晶型稳定性优于现有洛铂，不易潮解变粘、流动性好。
实施例四：命名为晶型F的洛铂新晶型的制备、产品性质测定及对比分析
4.1命名为晶型F的洛铂新晶型的制备
制备例1
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入30ml甲苯，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.73g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入甲醇40ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入120ml乙二醇二甲醚，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.71g，即为洛铂的新晶型F。
制备例2
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml甲基叔丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.84g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入甲醇50ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入150ml正己烷,待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.68g，即为洛铂的新晶型F。
制备例3
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入20ml乙酸丁酯，于室温下悬浮搅拌50h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.68g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入乙醇80ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入200ml乙酸乙酯，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.70g，即为洛铂的新晶型F。
制备例4
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入25ml1,4-二氧六环，于室温下悬浮搅拌45h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.76g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入乙醇90ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入180ml丙酮，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.72g，即为洛铂的新晶型F。
制备例5
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入30ml正庚烷，于室温下悬浮搅拌50h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.75g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入甲醇45ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入160ml硝基甲烷，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.69g，即为洛铂的新晶型F。
制备例6
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml乙醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.78g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入甲醇40ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入150ml乙腈，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.73g，即为洛铂的新晶型F。
制备例7
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入15ml甲基叔 丁基醚，于室温下悬浮搅拌48h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.84g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g，置于容器中，加入乙醇85ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入180ml四氢呋喃，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.67g，即为洛铂的新晶型F。
制备例8
a、制备洛铂二水合物：称取洛铂三水合物2g于容器中，加入20ml甲基叔丁基醚，于室温下悬浮搅拌46h，过滤、用乙醚洗涤，真空干燥后得白色粉末1.80g，即为洛铂二水合物；
b、制备目标晶型：称取步骤a所得的洛铂二水合物1g置于容器中，加入甲醇40ml，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入150ml二氯甲烷，待结晶析出后，过滤分离出该结晶，用乙醚洗涤，真空干燥后得白色粉末0.66g，即为洛铂的新晶型F。
上面各实施例1-8中步骤a)制备得到的样品按照上述实施例一中1.4的方法进行XRD衍射测定后，鉴定为8种样品的晶型相同，该晶型为A，其详细的鉴定数据与前面具体实施方式中第(1)部分“本发明的第一实施方案”的鉴定数据和上面的实施例二中所示数据相同。
另一方面，对上面各实施例1-8制备得到的样品按照上述实施例一中1.4的方法进行XRD衍射测定后，鉴定为8种样品的晶型相同，其特征峰如下：PXRD图谱中在2θ角值为8.21、11.60、12.99、15.24、16.44、17.11、17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、24.18、24.40、24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、31.94、33.30、36.20、37.62、39.66处有衍射峰，其中2θ值误差范围为±0.2。将这种晶型命名为F型。
4.2产品性质测定及对比分析
1、试验样品
样品1-8：本发明实施例1-8制备方法得到；
对比样品1：与前面实施例二的2.2部分的对比样品1相同，也采用专利EP0324154实施例1a方法制得的洛铂，具体制备方法与前面实施例二的2.2部分的对比样品1的制备方法相同：
对比样品2：与前面实施例二的2.2部分的对比样品2相同，也采用专利EP0611303实施例方法制得的洛铂三水合物，具体制备方法与前面实施例二的2.2部分的对比样品2的制备方法相同。
2、形态鉴定
鉴定结果与实施例二的2.2部分的对比样品1和对比样品2相同，具体如下：
对比样品1：得到的洛铂为无定形态；
对比样品2：通过X-射线衍射，PXRD图谱在2θ值约为6.71、8.35、12.89、15.14、16.74、17.45、19.01、19.40、22.07、22.76、23.16、24.30、25.21、25.74、27.08、30.26、30.79处有衍射峰，其2θ值误差范围小于0.2，专利EP0611303中描述其熔点为210℃(分解)；
本发明样品1-8：如前所述，通过X-射线衍射，PXRD图谱在2θ值约为8.21、11.60、12.99、15.24、16.44、17.11、17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、24.18、24.40、24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、31.94、33.30、36.20、37.62、39.66处有衍射峰，其2θ值误差范围小于0.2；DSC图谱显示在229℃附件有放热峰，结合TGA及文献熔点数据判断，该峰为熔融分解峰，表明样品1-8为同一晶型，也即为洛铂的新晶型F。
3、溶解度考察
分别配制浓度为60μg/ml、80μg/ml、200μg/ml、400μg/ml、800μg/ml的洛铂三水合物对照品溶液，通过HPLC法制造标准曲线，所得标准曲线方程为Y＝4.8641X+20.5794，R＝0.9998。将洛铂新晶型的样品6及对比样品2制成饱和水溶液(悬浮液)，置25℃摇床震荡6h，然后过滤，稀释适当倍数，进行HPLC分析。溶解度结果如下表13：
表13溶解度考察结果
晶型 样品6 对比样品1
溶解度(mg/ml) 21.4957 10.3271
结果表明：本发明制得的洛铂化合物溶解性优于洛铂三水合物。
4、洛铂新晶型质量对比研究
取样品1-8、对比样品1-2各20mg，以产品水分、杂质含量、活性成分含量、收率等为指标，考察产品质量和收率。结果见下表14：
表14洛铂新晶型质量对比研究
Figure PCTCN2014092571-appb-000016
上述结果表明，与洛铂无水物及洛铂三水合物相比，本发明获得的洛铂新晶型F具有含量高、杂质低、收率好的特点。
注1：含量测定方法：与前面实施例二的2.2部分相同；
注2：杂质检查方法：与前面实施例二的2.2部分相同；
注3：水分测定方法：与前面实施例二的2.2部分相同。
5、稳定性考察
将本发明实施例制得的样品6、对比样品2分别置于60℃烘箱内、相对湿度约为95％的环境下、照度约为4500lux的光稳定试验箱(带光照功能的常规的恒温箱)内，分别于5天、10天后将样品取出进行PXRD测试及HPLC分析，以考察样品在高温条件下的稳定性。结果见下表15：
表15稳定性评价结果
Figure PCTCN2014092571-appb-000017
上述试验结果表明，本发明的洛铂为新晶型F，溶解度高于洛铂三水合物，收率和纯度非常理想，从高温、高湿、光照考察结果来看，洛铂新晶型稳定性好，无转晶现象发生，HPLC结果表明有效成分含量优于洛铂三水合物，且未发生明显变化，说明本发明洛铂新晶型稳定性好。

Claims (36)

  1. 一种洛铂化合物晶体，其特征在于，晶体结构中含有2分子结晶水。
  2. 根据权利要求1所述的洛铂化合物晶体，其中，其晶型为A，PXRD图谱在2θ值约为11.04、12.32、12.61、13.85、15.14、15.55、16.68、17.67、17.86、19.03、20.06、21.00、22.68、22.92、23.76、25.39、25.58、26.37、26.77、27.00、27.71、28.13、29.71、31.42、31.94、32.89、34.29、34.60、36.10、36.93、37.66、40.78、43.41处有衍射峰，其中2θ值误差范围为0.2。
  3. 根据权利要求2所述的洛铂化合物晶体，其中，熔点Tm.p..＝220±5℃。
  4. 根据权利要求1所述的洛铂化合物晶体，其中，其晶型为A，其晶体属于正交晶系，空间群为P212121，晶胞参数为
    Figure PCTCN2014092571-appb-100001
    Figure PCTCN2014092571-appb-100002
    α＝β＝γ＝90.0°，晶胞体积
    Figure PCTCN2014092571-appb-100003
    晶胞内不对称单位数Z＝4。
  5. 一种制备权利要求1-4任一项所述的洛铂化合物的方法，其特征在于，包括如下步骤：
    将洛铂三水合物加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后干燥得到该结晶。
  6. 如权利要求5所述的方法，其中，去除溶剂后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
  7. 如权利要求5或6所述的方法，其中，所述洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
  8. 如权利要求书5-7任一项所述的方法，其中，所述的结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷。
  9. 如权利要求5-8任一项所述的方法，其中，所述悬浮于室温下进 行，优选悬浮45-50h。
  10. 一种洛铂化合物晶体，其特征在于，其晶型为B，PXRD图谱在2θ角值约为8.25、9.77、11.70、13.13、15.28、16.48、17.22、17.74、19.01、19.56、22.28、23.72、24.04、24.30、25.62、26.20、28.57、30.22、30.61处有衍射峰，其中2θ值误差范围为0.2。
  11. 如权利要求10所述的洛铂晶体，其特征在于，熔点Tm.p..＝230±5℃。
  12. 制备权利要求10或11所述洛铂晶体的方法，其中，包括如下步骤：
    在洛铂三水合物中加入无水甲醇或无水乙醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
  13. 制备权利要求10或11所述洛铂晶体的方法，其中，包括如下步骤b)：
    在洛铂二水合物中加入无水甲醇，于室温下搅拌至固体溶解，除去不溶物，缓慢挥发，待结晶析出后，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
  14. 制备权利要求10或11所述洛铂晶体的方法，其中，包括如下步骤b)：
    在洛铂二水合物中加入有机溶剂，于室温下悬浮搅拌，析出结晶，分离出该结晶，干燥后得白色粉末，即为洛铂的晶型B。
  15. 如权利要求13或14所述的方法，其中，所述的洛铂二水合物的制备方法包括如下步骤a)：
    在洛铂三水合物中加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后，用乙醚洗涤，真空干燥得到该洛铂二水合物结晶。
  16. 如权利要求15所述的方法，其中，步骤a)中，所述结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷， 洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
  17. 如权利要求13-14任一项、或15-16任一项所述的方法，其中，步骤b)中，分离出结晶后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
  18. 如权利要求14或15-17任一项所述的方法，其中，步骤b)中，所述悬浮于室温下进行，优选悬浮45-50h。
  19. 如权利要求13或15-18任一项所述的方法，其中，所述步骤b)中无水甲醇与洛铂二水合物的质量体积比为洛铂二水合物：无水甲醇＝1:40-50。
  20. 如权利要求14或15-19任一项所述的方法，其中，所述步骤b)中有机溶剂选自正己烷、丙酮、乙酸乙酯、硝基甲烷、乙腈、四氢呋喃、2-丁酮或二氯甲烷，质量体积比为洛铂二水合物：有机溶剂＝1:15-30。
  21. 如权利要求12所述的方法，其中，所述无水甲醇与洛铂三水合物的质量体积比为洛铂三水合物：无水甲醇＝1:40-50；无水乙醇与洛铂三水合物的质量体积比为洛铂三水合物：无水乙醇＝1:80-90。
  22. 一种洛铂化合物晶体，其特征在于，其晶型为F，PXRD图谱在2θ角值约为8.21、11.60、12.99、15.24、16.44、17.11、17.55、18.42、19.01、19.20、19.42、21.81、22.17、22.42、23.33、23.85、24.18、24.40、24.77、25.46、25.98、26.13、27.89、28.42、29.03、30.32、31.17、31.94、33.30、36.20、37.62、39.66处有衍射峰，其中2θ值误差范围为0.2。
  23. 如权利要求22所述的洛铂晶体，其特征在于，熔点Tm.p..＝229±5℃。
  24. 制备权利要求22或23所述洛铂晶体的方法，其特征在于，包括如下步骤b)：
    在洛铂二水合物中，加入甲醇或乙醇，于室温下搅拌至固体溶解，滤去不溶物，再缓慢加入有机溶剂，待结晶析出后，分离出该结晶，干 燥后得白色粉末，即为洛铂的晶型F。
  25. 如权利要求24所述的方法，其中，所述的洛铂二水合物的制备方法包括如下步骤a)：
    在洛铂三水合物中加入悬浮结晶溶剂，悬浮搅拌，析出结晶，去除溶剂后，用乙醚洗涤，真空干燥得到该洛铂二水合物结晶。
  26. 如权利要求25所述的方法，其中，步骤a)中，所述的结晶溶剂选自甲基叔丁基醚、甲苯、乙醚、乙酸丁酯、1,4-二氧六环或正庚烷，所述洛铂三水合物与结晶溶剂的质量体积比为洛铂三水合物：结晶溶剂＝1:15-30。
  27. 如权利要求24-26任一项所述的方法，其中，步骤b)中，分离出结晶后，在干燥之前用乙醚洗涤，所述干燥为真空干燥。
  28. 如权利要求24-26任一项所述的方法，其中，所述步骤b)中有机溶剂选自乙二醇二甲醚、正己烷、乙酸乙酯、丙酮、硝基甲烷、乙腈、四氢呋喃或二氯甲烷。
  29. 如权利要求24-28任一项所述的方法，其中，所述步骤b)中洛铂二水合物和有机溶剂的质量体积比为洛铂二水合物：有机溶剂＝1:120-200。
  30. 如权利要求24-29任一项所述的方法，其中，所述步骤b)中洛铂二水合物与甲醇质量体积比为洛铂二水合物：甲醇＝1:40-50，洛铂二水合物与乙醇质量体积比为洛铂二水合物：乙醇＝1:80-90。
  31. 一种药物组合物，其特征在于，以权利要求1-4任一项、10、11、22或23所述的洛铂晶体作为活性成分。
  32. 如权利要求31所述的药物组合物，其特征在于，所述药物组合物最小单元中含有洛铂晶体的量为5mg、10mg或50mg。
  33. 如权利要求31或32所述的药物组合物，其特征在于，所述药物组合物是任何临床上可接受的药物剂型。
  34. 如权利要求31-33任一项所述的药物组合物，其特征在于，所述 剂型为注射用冻干制剂。
  35. 权利要求1-4任一项、10、11、22或23所述的洛铂晶体，或者权利要求31-34任一项所述的药物组合物在制备抗癌药中的应用。
  36. 权利要求1-4任一项、10、11、22或23所述的洛铂晶体，或者权利要求31-34任一项所述的药物组合物，其用于治疗乳腺癌、小细胞肺癌或慢性粒细胞性白血病。
PCT/CN2014/092571 2014-06-20 2014-11-28 洛铂晶体、制备方法及药物应用 WO2015192606A1 (zh)

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EP3845544B1 (en) 2018-09-01 2023-11-15 Beijing Showby Pharmaceutical Co., Ltd. Phosphate of platinum compound and preparation method therefor
CN111721840B (zh) * 2019-03-19 2022-07-12 海南长安国际制药有限公司 洛铂中有关物质的检测
CN111721841B (zh) * 2019-03-19 2022-07-12 海南长安国际制药有限公司 与洛铂有关物质的检测
CN115032297B (zh) * 2022-05-27 2023-11-14 四川汇宇制药股份有限公司 反式-1,2-二氨甲基环丁烷与其顺式异构体的分离检测方法

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