WO2016037530A1 - 一种罗米地辛的新晶型及其药物组合物、制备方法和用途 - Google Patents

一种罗米地辛的新晶型及其药物组合物、制备方法和用途 Download PDF

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WO2016037530A1
WO2016037530A1 PCT/CN2015/088109 CN2015088109W WO2016037530A1 WO 2016037530 A1 WO2016037530 A1 WO 2016037530A1 CN 2015088109 W CN2015088109 W CN 2015088109W WO 2016037530 A1 WO2016037530 A1 WO 2016037530A1
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romidepsin
crystal form
solvent
same
preparation
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French (fr)
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张辉
王继栋
杜敏娜
郑玲辉
骆红英
白骅
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浙江海正药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution

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  • the invention relates to the field of pharmacy. More specifically, the present invention relates to a novel crystalline form of romidepsin and a pharmaceutical composition, a preparation method and use thereof containing the novel crystalline form.
  • HDACs histone deacetylases
  • Romidepsin also known as FK228 or FR901228, is an HDAC inhibitor.
  • HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in regulation of gene expression. HDACs also deacetylate acetyl non-histone proteins, such as transcription factors.
  • romidepsin leads to the accumulation of acetylated histones, and induce cell cycle arrest and apoptosis in some cancer cell lines, the range of IC 50 values in terms of nanograms.
  • CTCL Cutaneous T-Cell Lymphoma
  • Other indications such as breast cancer, non-Hodgkin's lymphoma, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and kidney cancer, are in Phase II clinical studies.
  • Romidepsin is composed of four amino acid groups (D-valine, D-cysteine, dehydrogenated ⁇ -aminobutyric acid and L-valine) and 3-hydroxy-7-sulfo-4 a natural product of a depsipeptide which comprises an amide and an ester bond, and has the following structural formula:
  • U.S. Patent No. 761,172,482 discloses Form A and Form B of romidepsin.
  • International Patent Application No. WO 2012009336 discloses crystal forms C, D, E, F, H, I, J, K, L and N of romidepsin, as well as various amorphous forms thereof and various types of crystal forms obtained therefrom. method.
  • the international patent application WO 2012009336 also discloses that under certain conditions, the crystal forms B, C, D, E and H are easily converted into the crystal form A.
  • Form A is a crystalline form of medicinal use
  • the international patent application WO 2008083288 discloses a complete preparation method thereof, in which a crude romidepsin crystal is dissolved in an 85% aqueous acetone solution (about 13 L/kg of romidepsin crystals). And then under stirring. Precipitation was carried out by slowly adding purified water (about 65 L/kg of romidepsin crystals). The precipitated crystals were obtained by filtration, and washed with a 15% aqueous acetone solution (about 5 L/kg of crude romidepsin crystals). Finally, the wet crystals were dried under vacuum at ⁇ -70 °C. The vacuum drying technique of ⁇ -70 ° C is required in the preparation process, so the industrial production cost is high.
  • the inventors of the present invention have found a large amount of romidepsin crystal form O.
  • the crystal form has good stability and is left at room temperature for several months. No crystal transformation phenomenon is found, the crystal grain size is large and easier to filter, and the drying is carried out by ordinary vacuum drying, and the industrial operation is more convenient and the cost is lower.
  • One of the objects of the present invention is to provide a novel, stable crystalline form of romidepsin, designated as Form O.
  • the romidepsin crystal form O of the present invention uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern represented by the 2 ⁇ angle has characteristic peaks at the following positions: 8.82 ⁇ 0.20°, 9.69 ⁇ 0.20°, 10.86 ⁇ 0.20. °, 11.12 ⁇ 0.20 °, 18.43 ⁇ 0.20 °, 18.65 ⁇ 0.20 °, 21.30 ⁇ 0.20 ° and 23.91 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the romidepsin crystal form O of the present invention expressed by 2 ⁇ angle further has characteristic peaks at the following positions: 14.34 ⁇ 0.20°, 17.55 ⁇ 0.20°, 19.56 ⁇ 0.20 °, 20.23 ⁇ 0.20 °, 21.93 ⁇ 0.20 °, 24.31 ⁇ 0.20 °, 26.46 ⁇ 0.20 ° and 26.99 ⁇ 0.20 °.
  • the X-ray powder diffraction pattern of the romidepsin crystal form O of the present invention expressed by 2 ⁇ angle further has characteristic peaks at the following positions: 9.33 ⁇ 0.20°, 13.49 ⁇ 0.20° , 14.64 ⁇ 0.20°, 20.73 ⁇ 0.20°, 20.99 ⁇ 0.20°, 21.58 ⁇ 0.20°, 27.87 ⁇ 0.20°, 29.28 ⁇ 0.20°, 29.77 ⁇ 0.20°, 30.65 ⁇ 0.20°, 33.92 ⁇ 0.20°, and 35.74 ⁇ 0.20° .
  • the 2 ⁇ angle, d value and relative intensity data of the romidepsin crystal form O of the present invention are shown in Table 1 below:
  • the XRPD pattern of the romidepsin crystal form O of the present invention is shown in FIG.
  • the romidepsin crystal form O of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, according to which the characteristic peaks are at the following positions: 3369 cm -1 , 3316 cm -1 , 3295cm -1, 2962cm -1, 2930cm -1 , 2876cm -1, 1741cm -1, 1692cm -1, 1661cm -1, 1640cm -1, 1523cm -1, 1257cm -1, 1220cm -1, 982cm -1, 653cm - 1 , 575cm -1 and 535cm -1 .
  • the infrared absorption spectrum of the romidepsin crystal form O also has characteristic peaks at the following positions: 1440 cm -1 , 1385 cm -1 , 1301 cm -1 , 1180 cm -1 , 1107 cm -1 , 1028 cm -1 , 1002 cm -1 , 915 cm -1 , 891 cm -1 , 848 cm -1 , 802 cm -1 and 752 cm -1 .
  • the differential scanning calorimetry (DSC) pattern of the romidepsin crystal form O of the present invention has two exothermic peaks at 190.3 ⁇ 2 ° C and 260.8 ⁇ 2 ° C.
  • Another object of the present invention is to provide a method for preparing a crystalline form O of romidepsin, the method comprising the steps of:
  • the halogenated alkane is selected from the group consisting of chloroform, dichloromethane or a mixture thereof
  • the lower alcohol is selected from the group consisting of methanol, ethanol or a mixture thereof
  • the anti-solvent is acetonitrile.
  • the volume ratio of the halogenated alkane to the lower alcohol is from 15 to 5:1, preferably from 10 to 7:1.
  • the volume content of the anti-solvent in the mixed solution is from 75 to 99%, preferably from 85 to 96%, more preferably from 90 to 95%.
  • the temperature of the mixed solution obtained in the step (2) is controlled to be -10 ° C to 30 ° C, preferably -5 ° C to 25 ° C.
  • the step of adding a seed crystal of the romidepsin crystal form O to the mixed solution obtained in the step (2) is further included.
  • the invention further relates to a pharmaceutical composition comprising romidepsin crystal form O, the pharmaceutical composition comprising a therapeutically effective amount of romidepsin crystal form O, and one or more pharmaceutically acceptable carriers.
  • the romidepsin-type O drug substance is lyophilized to obtain a acetonitrile residue-qualified preparation product.
  • the pharmaceutical compositions of the invention may also comprise one or more additional pharmaceutically active ingredients.
  • the invention relates to the use of romidepsin crystal form O for the preparation of a pharmaceutical composition for the treatment of tumors.
  • tumors include, but are not limited to, breast cancer, non-Hodgkin's lymphoma, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer and lymphoma.
  • the inventors of the present invention have found that the romidepsin crystal form O has filled a gap in the prior art.
  • the crystal form of the invention has good stability and is left at room temperature for several months. No crystal transformation phenomenon is found, the crystal grain size is large and the filter is easy to be filtered, and the drying is performed by ordinary vacuum drying, and the industrial operation is more convenient.
  • Example 1 is an X-ray powder diffraction pattern of a novel crystalline form O of romidepsin obtained in Example 1.
  • Example 2 is an infrared absorption spectrum of a novel crystalline form O of romidepsin obtained in Example 1.
  • Example 3 is a DSC chart of the novel crystalline form O of romidepsin obtained in Example 1.
  • Example 4 is a TGA pattern of the novel crystalline form O of romidepsin obtained in Example 1.
  • the raw material of romidepsin used in the present invention is prepared in accordance with Example 5 and Example 6 of Chinese Patent No. CN201310087484.3.
  • the X-ray powder diffraction apparatus and test conditions according to the present invention are: X-diffraction instrument model Rigaku D/max-2200Cu target; operation method: scanning speed 4 ° / min, scanning step width 0.01 °.
  • the infrared spectrophotometer and the test conditions of the invention are: infrared spectrophotometer model: BRWKER VECTOR 22; operation method: KBr tableting method, scanning range 400-4000 cm -1 .
  • the DSC detector and the test conditions of the invention are: SERKIN detector model: PERKIN ELMER DSC8000; operation method: heating rate 10 ° C / min, temperature range: 20 ° C ⁇ 280 ° C.
  • TGA detector and test conditions of the invention are: TGA detector model: PerkinElmer TGA400; operation method: heating rate 10 ° C / min, temperature range: 30 ° C ⁇ 300 ° C.
  • romidepsin HPLC purity greater than 99%
  • the crystals obtained were then placed in a refrigerator at 4 ° C in the dark, filtered after 24 h, and dried under vacuum at 45 ° C for 48 h to give 0.95 g of solid, yield 95%. Upon detection, it was confirmed that romidepsin crystal form O was obtained.
  • Example 4 10 g of a sample of romidepsin crystal form O was prepared, and then 1 g/bag was dispensed, placed in a double-layer PE bag, heat-sealed, and then placed in an aluminum foil bag, and heat-sealed. Then, the experiment was accelerated under the condition of 40 ⁇ 2° C. and humidity: 75 ⁇ 5%. After 6 months, the data was basically stable, and the data is shown in Table 3 below.

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Abstract

本发明涉及一种罗米地辛的新晶型O，它可以通过X-射线粉末衍射（XRPD）谱图，差示扫描量热（DSC）谱图，红外（IR）吸收谱图等来表征。同时，本发明还涉及该罗米地辛晶型O的药物组合物、制备方法和用途。

Description

一种罗米地辛的新晶型及其药物组合物、制备方法和用途 技术领域
本发明涉及制药领域。更具体的说，本发明涉及一种罗米地辛的新晶型以及含有该新晶型的药物组合物、制备方法和用途。
技术背景
恶性肿瘤是威胁人类健康的最严重疾病之一。长期以来，肿瘤治疗一直是医学界研究的重大课题，寻找治疗恶性肿瘤的新药更是药物研究人员的首要任务。在抗肿瘤药物中，研究和开发非细胞毒的具有选择性的抑制癌细胞生长的药物是目前抗肿瘤药物的研究重点。近年来，一类锌离子依赖性的金属蛋白酶——组蛋白脱乙酰基酶(histone deacetylases，HDACs)成为抗肿瘤药物研究的热点。
罗米地辛(Romidepsin)又名FK228或FR901228，是一种HDAC抑制剂。HDACs在组蛋白中催化从乙酰化赖氨酸残基去除乙酰基，导致基因表达的调节。HDACs还脱去乙酰基非-组蛋白蛋白，例如转录因子。在体外，罗米地辛引起乙酰化组蛋白的蓄积，并且诱导细胞周期停止和某些癌症细胞株凋亡，IC50值在以纳克计的范围内。2009年11月9日，美国食品药品监督管理局批准罗米地辛注射药物上市销售，用于治疗皮肤T细胞淋巴瘤(Cutaneous T-Cell Lymphoma，CTCL)。其他适应症，如乳腺癌、非霍奇金淋巴瘤、骨髓瘤、卵巢癌、胰腺癌、前列腺癌和肾癌，处于II期临床研究阶段。
罗米地辛是由四个氨基酸基团(D-缬氨酸、D-半胱氨酸、脱氢α-氨基丁酸和L-缬氨酸)和3-羟基-7-疏基-4-庚烯酸组成的，包含酰胺和酯键的缩酚酸肽类天然产物，其结构式如下：
Figure PCTCN2015088109-appb-000001
1994年，Ueda等(J.Antibiot.1994，47(3)：301-10.)首次从青紫色素杆菌(Chromobacterium violaceum)发酵液中分离得到的。中国发明专利CN201310087484.3公开了一种新的产罗米地辛的紫色杆菌菌株，该菌株命名为紫色杆菌(Chromobacterium sp.)HS-13-94，保藏编号为CGMCC No.6247。罗米地辛除了利用上述发酵制备得到外，还可以通过合成或半合成的方法来制备得到。Kahn等人(J.Am.Chem.Soc.1996，118：7237-7238)报道的罗米地辛全合成涉及14个步骤，总收率为18％。中国发明专利CN201210579007.4公开的罗米地辛制备方法所制备的产品纯度大于99％，总收率大于30％。
美国专利US761172482公开了罗米地辛的晶型A和晶型B。国际专利申请WO 2012009336公开了罗米地辛的晶型C、D、E、F、H、I、J、K、L和N，同时还公开了其非晶形式和得到上述晶型的各种方法。除此之外，国际专利申请WO 2012009336还公开了在一定条件下，晶型B、C、D、E和H容易转变为晶型A。晶型A是目前药用的晶型，国际专利申请WO 2008083288公开了其完整的制备方法，将罗米地辛晶体粗品溶解在85％丙酮水溶液(约13L/kg罗米地辛晶体粗品)中，然后在搅拌下。缓慢加入纯化水(约65L/kg罗米地辛晶体粗品)进行沉淀。通过过滤得到沉淀的晶体，并且用15％丙酮水溶液(约5L/kg罗米地辛晶体粗品)洗涤。最后，将湿晶体在＜-70℃真空干燥。该制备过程中需要使用＜-70℃真空干燥技术，因此工业化生产成本较高。
对于多晶型药物而言，不同的晶型可以具有不同的物理化学性质，包括熔点、化学稳定性、表观溶解度、溶解速率、光学和机械性质，这些直接影响到原料药和制剂的质量。因此，尽管已报道了罗米地辛的诸多晶型，但仍有必要进一步开 发在某些方面具有更加优异性质的新晶体。
本发明的发明人经过大量研究发现罗米地辛晶型O。该晶型稳定性好，在室温下放置几个月，未发现转晶现象，晶体颗粒度大更易过滤，干燥采用普通真空干燥即可，产业化操作更方便，成本更低。
发明内容
本发明的目的之一在于提供一种新颖的、稳定的罗米地辛晶型，命名为晶型O。
本发明所述的罗米地辛晶型O，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：8.82±0.20°、9.69±0.20°、10.86±0.20°、11.12±0.20°、18.43±0.20°、18.65±0.20°、21.30±0.20°和23.91±0.20°。
优选地，使用Cu-Kα辐射，本发明所述的罗米地辛晶型O以2θ角度表示的X-射线粉末衍射图谱进一步在以下位置具有特征峰：14.34±0.20°、17.55±0.20°、19.56±0.20°、20.23±0.20°、21.93±0.20°、24.31±0.20°、26.46±0.20°和26.99±0.20°。
更优选地，使用Cu-Kα辐射，本发明所述的罗米地辛晶型O以2θ角度表示的X-射线粉末衍射图谱进一步在以下位置具有特征峰：9.33±0.20°、13.49±0.20°、14.64±0.20°、20.73±0.20°、20.99±0.20°、21.58±0.20°、27.87±0.20°、29.28±0.20°、29.77±0.20°、30.65±0.20°、33.92±0.20°和35.74±0.20°。
优选地，本发明所述的罗米地辛晶型O的2θ角度、d值和相对强度数据如下表1所示：
表1
峰编号 2θ(°) d(晶面间距) 相对强度(％)
1 8.82 10.0172 93.5
2 9.33 9.4711 30.5
3 9.69 9.1200 55.8
4 10.86 8.1396 71.3
5 11.12 7.9505 71.5
6 13.49 6.5583 16.3
7 14.34 6.1717 25.2
8 14.64 6.0460 17.2
9 17.55 5.0493 40.3
10 18.43 4.8101 60.6
11 18.65 4.7537 69.8
12 19.56 4.5347 33.7
13 20.23 4.3860 27.9
14 20.73 4.2813 15.6
15 20.99 4.2288 72.0
16 21.30 4.1679 100.0
17 21.58 4.1144 93.3
18 21.93 4.0497 30.4
19 23.91 3.7185 55.3
20 24.31 3.6583 27.6
21 26.46 3.3658 32.4
22 26.99 3.3009 32.6
23 27.87 3.1986 12.1
24 29.28 3.0477 16.4
25 29.77 2.9987 16.5
26 30.65 2.9144 13.1
27 33.92 2.6406 16.2
28 35.74 2.5101 17.6
更优选地，本发明所述罗米地辛晶型O的XRPD图谱如图1所示。
此外，本发明所述的罗米地辛晶型O，可以用KBr压片测得的红外吸收图谱表征，根据所述图谱，其在以下位置处有特征峰：3369cm-1、3316cm-1、3295cm-1、2962cm-1、2930cm-1、2876cm-1、1741cm-1、1692cm-1、1661cm-1、1640cm-1、1523cm-1、1257cm-1、1220cm-1、982cm-1、653cm-1、575cm-1和535cm-1。
优选地，所述罗米地辛晶型O的红外吸收谱图还在以下位置处有特征峰：1440cm-1、1385cm-1、1301cm-1、1180cm-1、1107cm-1、1028cm-1、1002cm-1、915cm-1、891cm-1、848cm-1、802cm-1和752cm-1。
本发明所述的罗米地辛晶型O的红外谱图如图2所示。
本发明所述的罗米地辛晶型O的差示扫描量热(DSC)图谱在190.3±2℃和260.8±2℃有两个放热峰。
本发明所述的罗米地辛晶型O的DSC图谱如图3所示。
本发明所述的罗米地辛晶型O的TGA图谱如图4所示。
本发明另一目的还在于提供一种制备罗米地辛晶型O的方法，该方法包括如下步骤：
(1)将罗米地辛溶于含有卤代烷烃和低级醇的混合溶剂中，形成一种溶液；
(2)向步骤(1)所得溶液中加入一种反溶剂，得混合溶液；
(3)沉淀、过滤并干燥得到罗米地辛晶型O。
其中，所述卤代烷烃选自氯仿、二氯甲烷或它们的混合物，所述低级醇选自甲醇、乙醇或它们的混合物，所述反溶剂为乙腈。所述卤代烷烃和低级醇的体积比为15～5∶1，优选10～7∶1。
步骤(1)所得溶液中加入反溶剂后，反溶剂在混合溶液中的体积含量为75～99％，优选为85～96％，更优选为90～95％。
其中，将步骤(2)所得混合溶液的温度控制在-10℃～30℃，优选-5℃～25℃。
任选地，在步骤(3)之前，还包括在步骤(2)所得混合溶液中加入罗米地辛晶型O的晶种的步骤。
本发明还涉及含有罗米地辛晶型O的药物组合物，所述药物组合物包含治疗有效量的罗米地辛晶型O，以及一种或多种药学上可接受的载体。
在一个具体的实施方案中，将罗米地辛品型O原料药冻干得到乙腈残留合格的制剂产品。本发明所述药物组合物还可以包含一种或多种其它的药物活性成分。
此外，本发明还涉及罗米地辛晶型O在制备用于治疗肿瘤的药物组合物中的用途。所述的肿瘤包括但不限于乳腺癌、非霍奇金淋巴瘤、骨髓瘤、卵巢癌、胰腺癌、前列腺癌和肾癌和淋巴瘤。
本发明的发明人经过大量研究发现罗米地辛晶型O，填补了现有技术存在的空白。本发明的晶型稳定性好，在室温下放置几个月，未发现转晶现象，晶体颗粒度大更易过滤，干燥采用普通真空干燥即可，产业化操作更方便。
附图说明
图1为实施例1所得罗米地辛新晶型O的X-射线粉末衍射图谱。
图2为实施例1所得罗米地辛新晶型O的红外吸收光谱。
图3为实施例1所得罗米地辛新晶型O的DSC图谱。
图4为实施例1所得罗米地辛新晶型O的TGA图谱。
具体实施例
以下实施例进一步解释说明本发明，但是，对本发明并不构成限制。
本发明所用的罗米地辛原料是按照中国发明专利CN201310087484.3中的实施例5和实施例6制备得到的。
本发明所涉及的X-射线粉末衍射仪器及测试条件为：X-衍射仪器型号Rigaku D/max-2200Cu靶；操作方法：扫描速度4°/min，扫描步宽0.01°。
本发明所涉及的红外分光光度仪及测试条件为：红外分光光度仪型号：BRWKER VECTOR 22；操作方法：采用KBr压片法，扫描范围400～4000cm-1。
本发明涉及的DSC检测仪及测试条件为：DSC检测仪型号为：PERKIN ELMER DSC8000；操作方法：升温速率10℃/min，温度范围：20℃～280℃。
本发明涉及的TGA检测仪及测试条件为：TGA检测仪型号：PerkinElmer TGA400；操作方法：升温速率10℃/min，温度范围：30℃～300℃。
本发明涉及的液相测试条件为：色谱柱为：Eclipse XDB-C18，9.4mm×250mm；流动相为：甲醇∶水＝70∶30；检测波长：210nm；流速：1.5ml/min；柱温：室温。
实施例1
将2.0g罗米地辛(HPLC纯度大于99％)溶于5ml氯仿∶甲醇＝9/1(体积比)的混合溶剂中，形成饱和溶液(有固体未溶解完全)，过滤得滤液。取滤液3ml，然后往滤液中加入27ml乙腈，混合均匀后置于4℃的冰箱中避光放置，72h后过滤得晶体，晶体45℃真空干燥48h，得到罗米地辛晶型O。取样品检测，其X-射线粉末衍射图谱如图1所示，红外吸收图谱如图2所示，DSC图谱如图3所示，TGA图谱如图4所示。
实施例2
将10.0g罗米地辛(HPLC纯度大于99％)溶于25ml氯仿∶甲醇＝9/1(体积比)的混合溶剂中，形成饱和溶液(有固体未溶解完全)，过滤得滤液。取9份1ml滤液，然后往滤液中分别加入1ml、2ml、3ml、4ml、5ml、6ml、7ml、8ml、9ml乙腈，混合均匀后置于4℃的冰箱中避光放置，48h后过滤得晶体，晶体45℃真空干燥48h。经检测，各溶剂体系得到的晶型如下表2所示。
表2
乙腈(ml) 1 2 3 4 5 6 7 8 9
晶型 L L L+O L+O O O O O O
实施例3
将1.0g罗米地辛(HPLC纯度大于99％)溶于2.5ml二氯甲烷∶乙醇＝9/1(体积比)的混合溶剂中，接着加入35ml乙腈，室温搅拌过夜，过滤，45℃真空干燥48h，得到0.92g固体，收率92％。经检测，确认得到罗米地辛晶型O。
实施例4
将1.0g罗米地辛(HPLC纯度大于99％)溶于2.5ml二氯甲烷∶乙醇＝9/1(体积比)的混合溶剂中，接着加入25ml乙腈，混合均匀后，加入10mg实施例1中得到的晶体然后置于4℃的冰箱中避光放置，24h后过滤，45℃真空干燥48h，得到0.95g固体，收率95％。经检测，确认得到罗米地辛晶型O。
实施例5
将1.0g罗米地辛(HPLC纯度大于99％)溶于3.0ml氯仿∶甲醇＝7/1(体积比)的混合溶剂中，接着加入57ml乙腈，混合均匀后，置于室温条件下(25℃)避光放置，48h后过滤，45℃真空干燥48h，得到0.85g固体，收率85％。经检测，确认得到罗米地辛晶型O。
实施例6
将1.0g罗米地辛(HPLC纯度大于99％)溶于2.0ml氯仿∶甲醇＝10/1(体积比)的混合溶剂中，接着加入48ml乙腈，混合均匀后，置于-5℃条件下避光放置，48h后过滤，45℃真空干燥48h，得到0.82g固体，收率82％。经检测， 确认得到罗米地辛晶型O。
实施例7
将1.0g罗米地辛(HPLC纯度大于99％)溶于2.0ml氯仿∶甲醇＝10/1(体积比)的混合溶剂中，接着加入68ml乙腈，混合均匀后，置于-5℃条件下避光放置，48h后过滤，45℃真空干燥48h，得到0.53g固体，收率53％。经检测，确认得到罗米地辛晶型O。
实施例8
将1.0g罗米地辛(HPLC纯度大于99％)溶于3.0ml氯仿∶甲醇＝9/1(体积比)的混合溶剂中，接着加入27ml乙腈，混合均匀后置于4℃的冰箱中避光放置，72h后过滤得晶体，晶体45℃真空干燥48h，得到0.90g固体，收率90％。经检测，确认得到罗米地辛晶型O。
实施例9
按照实施例4的条件，制备得到罗米地辛晶型O样品10g，然后1g/袋分装，将其装入双层PE袋内，电热封口，然后装入铝箔袋中，电热封口。然后将其放入40±2℃，湿度：75±5％条件下加速实验，6个月后数据基本稳定，数据见下表3。
表3
Figure PCTCN2015088109-appb-000002
实施例10
将2.0g聚维酮K17溶于342ml叔丁醇∶注射用水＝45/55(体积比)的混合溶剂中，然后加入按照实施例1方法得到的罗米地辛晶型O1.0g(HPLC纯度大于99％)，室温搅拌至完全溶解，然后用PTFE滤膜(0.22μm，颇尔，美国)过滤得滤液。滤液按照如下表4冻干工艺进行冻干。冻干成品的质量达到美国药 典要求。
表4
Figure PCTCN2015088109-appb-000003

Claims (11)

  1. 一种罗米地辛晶型O，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱在以下位置具有特征峰：8.82±0.20°、9.69±0.20°、10.86±0.20°、11.12±0.20°、18.43±0.20°、18.65±0.20°、21.30±0.20°和23.91±0.20°。
  2. 根据权利要求1所述的罗米地辛晶型O，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱进一步在以下位置具有特征峰：14.34±0.20°、17.55±0.20°、19.56±0.20°、20.23±0.20°、21.93±0.20°、24.31±0.20°、26.46±0.20°和26.99±0.20°。
  3. 根据权利要求1或2所述的罗米地辛晶型O，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射图谱进一步在以下位置具有特征峰：9.33±0.20°、13.49±0.20°、14.64±0.20°、20.73±0.2°、20.99±0.20°、21.58±0.20°、27.87±0.20°、29.28±0.20°、29.77±0.2°、30.65±0.20°、33.92±0.20°和35.74±0.20°。
  4. 一种制备根据权利要求1-3任一项所述的罗米地辛晶型O的方法，其特征在于，所述方法包括如下步骤：
    (1)将罗米地辛溶于含有卤代烷烃和低级醇的混合溶剂中，形成一种溶液；
    (2)向步骤(1)所得溶液中加入一种反溶剂，得混合溶液；
    (3)沉淀、过滤并干燥得到罗米地辛晶型O。
  5. 根据权利要求4所述的方法，其特征在于，所述卤代烷烃选自氯仿、二氯甲烷或它们的混合物，所述低级醇选自甲醇、乙醇或它们的混合物，所述反溶剂为乙腈。
  6. 根据权利要求4或5所述的方法，其特征在于，所述卤代烷烃和低级醇的体积比为15～5∶1，优选10～7∶1。
  7. 根据权利要求4-6任一项所述的方法，其特征在于，步骤(1)所得溶液中加入反溶剂后，反溶剂在混合溶液中的体积含量为75～99％，优选为85～96％，更优选为90～95％。
  8. 根据权利要求4-7任一项所述的方法，其特征在于，在步骤(3)之前，还包括在步骤(2)所得混合溶液中加入罗米地辛晶型O的晶种的步骤。
  9. 根据权利要求4-8任一项所述的方法，其特征在于，将步骤(2)所得混合溶液的温度控制在-10℃～30℃，优选-5℃～25℃。
  10. 一种含有权利要求1-3任一项所述的罗米地辛晶型O的药物组合物。
  11. 权利要求1-3任一项所述的罗米地辛晶型O在制备用于治疗肿瘤的药物中的用途。
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