WO2019057165A1 - 盐酸伊达比星一水合物的晶型 - Google Patents

盐酸伊达比星一水合物的晶型 Download PDF

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WO2019057165A1
WO2019057165A1 PCT/CN2018/107008 CN2018107008W WO2019057165A1 WO 2019057165 A1 WO2019057165 A1 WO 2019057165A1 CN 2018107008 W CN2018107008 W CN 2018107008W WO 2019057165 A1 WO2019057165 A1 WO 2019057165A1
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idarubicin
hydrochloride
crystalline form
monohydrate
crude
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PCT/CN2018/107008
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English (en)
French (fr)
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徐丹
葛书旺
苏进财
吴舰
王华萍
柴雨柱
朱春霞
田舟山
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南京正大天晴制药有限公司
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Priority to CN201880057475.0A priority Critical patent/CN111094313B/zh
Publication of WO2019057165A1 publication Critical patent/WO2019057165A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins

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  • the present application belongs to the field of pharmaceutical synthesis, and in particular to a crystalline form of idarubicin monohydrate hydrochloride, a preparation method thereof and use thereof.
  • Idarubicin hydrochloride 4-demethoxydaunorubicin hydrochloride, is a semi-synthetic anthracycline antitumor drug that is clinically used to treat acute myeloid leukemia (AML). Its mechanism of action is the insertion of NDA with a rigid structure to interfere with nucleic acid synthesis, and idarubicin can also interact with topoisomerase II to further interfere with nucleic acid synthesis. At present, the combination of idarubicin hydrochloride and cytarabine is the first choice for the treatment of AML.
  • idarubicin hydrochloride The structural formula of idarubicin hydrochloride is as follows:
  • the method for preparing idarubicin hydrochloride disclosed in the document CN85103835A is to acidify the crude idarubicin to pH 3.5 with an anhydrous methanol solution of hydrogen chloride, and then add an excess of diethyl ether to precipitate a solid, and the obtained idarubicin hydrochloride has a melting point of 183 ° C. ⁇ 185 ° C.
  • the solid obtained by crystallization from diethyl ether was determined to be amorphous idarubicin hydrochloride by X-ray powder diffraction.
  • Document CN103906757A discloses a method for preparing a crystalline form of idarubicin hydrochloride (hereinafter referred to as Form II) using a mixed solvent of 1-butanol, 2-butanol or 1-pentanol and water as a recrystallization solvent, but the method The solution needs to be heated to about 80 ° C, while idarubicin hydrochloride is unstable at high temperatures.
  • Polish patent PL195417B1 discloses a crystal form of idarubicin monohydrate hydrochloride (hereinafter referred to as crystal form I) which is prepared by recrystallization from a mixed solvent of water and isopropanol, and has a melting point of 190.1 ° C to 199.6. °C. It has been found that edababixin is partially degraded by recrystallization in a mixed solvent of water and an organic solvent.
  • crystal form III idarubicin monohydrate hydrochloride
  • the X-ray powder diffraction pattern of Form III expressed in terms of 2 ⁇ angle has characteristic peaks at 2 ⁇ values of 5.80 ⁇ 0.2°, 9.09 ⁇ 0.2°, and 15.04 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III expressed in 2 ⁇ angle is 2.81 ⁇ 0.2 °, 7.17 ⁇ 0.2 °, 9.09 ⁇ 0.2 °, 9.78 ⁇ 0.2 °, 14.10 ⁇ 0.2. Characteristic peaks at °, 15.04 ⁇ 0.2 °, 17.01 ⁇ 0.2 °, and 21.45 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form III expressed in 2 ⁇ angle is 2.81 ⁇ 0.2 °, 7.17 ⁇ 0.2 °, 9.09 ⁇ 0.2 °, 9.78 ⁇ 0.2 °, 11.60 ⁇ .
  • the crystalline form III of the present application has two endothermic peaks at temperatures of about 100 ° C to 130 ° C and about 188 ° C to 195 ° C, respectively.
  • the DSC pattern of Form III of the present application is shown in FIG.
  • An endothermic peak appeared in the range of 100 ° C to 130 ° C and 188 ° C to 193 ° C, and the peak temperatures were about 118.2 ° C and 192.1 ° C, respectively.
  • the mass fraction of the weight loss of Form III of the present application is about 3.4% to 4.0% as determined by thermogravimetric analysis (TGA).
  • the TGA profile of Form III of the present application is shown in FIG.
  • the present application also provides a method for preparing crystalline form III of idarubicin monohydrate, which is prepared by dissolving crude idarubicin hydrochloride in anhydrous methanol, and then adding ethyl acetate to crystallize and dissolve therein.
  • water is added to the anhydrous methanol before or after the step, and the sum of the amount of water contained in the crude idarubicin hydrochloride and the amount of water optionally added is ⁇ 5 wt% of the crude idarubicin hydrochloride, and ⁇ 2 wt% of the crude idarubicin hydrochloride.
  • the crude idarubicin hydrochloride contains ⁇ 5% by weight of the crude idarubicin hydrochloride and ⁇ 2% by weight of the crude idarubicin hydrochloride.
  • the mass to volume ratio of crude idarubicin hydrochloride to anhydrous methanol is from 1:10 to 20. More preferably, the mass to volume ratio of crude idarubicin hydrochloride to anhydrous methanol is 1:14.
  • the volume ratio of ethyl acetate to anhydrous methanol is from 1 to 5:1. More preferably, the volume ratio of ethyl acetate to anhydrous methanol is 3:1.
  • the method of preparation further comprises a filtration, washing and drying step.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Form III of idarubicin monohydrate hydrochloride and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers include, but are not limited to, glycerin, gelatin, sodium alginate, dextran, water, or mixtures thereof, or pH adjusting agents.
  • the present application also provides the use of Form III of idarubicin monohydrate hydrochloride for the preparation of a medicament for anti-tumor disease.
  • the neoplastic disease is preferably acute myeloid leukemia and acute lymphocytic leukemia.
  • the present application also provides a method for preventing and/or treating a neoplastic disease and a disease state, comprising administering to a subject in need thereof Form III of idarubicin hydrochloride monohydrate of the present application or the present application Pharmaceutical composition.
  • the neoplastic disease is preferably acute myeloid leukemia and acute lymphocytic leukemia.
  • the present application also provides Form III of the idarubicin hydrochloride monohydrate of the present application for preventing and/or treating a neoplastic disease and a disease state, or a pharmaceutical composition of the present application.
  • the neoplastic disease is preferably acute myeloid leukemia and acute lymphocytic leukemia.
  • the inventors of the present application found that the water content in the system prior to recrystallization is critical to the formation of Form III and the effect of different water contents on the crystalline product was investigated.
  • the inventors of the present application also found that the water content in the system prior to recrystallization also affects the stability of idarubicin monohydrate hydrochloride. Tests have shown that in the process of the present application, the stability of Form III of idarubicin monohydrate hydrochloride can be maintained when the water content in the system before recrystallization is ⁇ 5 wt%. As shown in the table below, in the recrystallization system of the present application, the total impurity content does not increase with time:
  • the present application provides a new crystalline form of idarubicin monohydrate, which is different from the crystalline forms already disclosed in the prior literature.
  • the crystalline form III of the present application has one or more of the following surprising advantages: the crystalline form III of the present application maintains good stability under high temperature and high humidity conditions. It is advantageous for the storage of the drug substance; in terms of solubility, the crystal form III of the present application also has a significant advantage compared with the crystal form I and the crystal form II, and is suitable for forming a pharmaceutical preparation. Therefore, the crystalline form III of the present application has good drug-forming properties.
  • the diffraction spectrum obtained from the crystalline compound is often characteristic for a specific crystallization, wherein the relative intensity of the band (especially at low angles) may be due to The dominant orientation effect due to the difference in crystallization conditions, particle diameter, and other measurement conditions varies. Therefore, the relative intensity of the diffraction peaks is not characteristic for the crystals that are targeted.
  • the relative positions of the peaks are not their relative intensities. Furthermore, there may be slight errors in the position of the peak for any given crystallization, which is also well known in the field of crystallography.
  • the position of the peak can be shifted due to changes in temperature during sample analysis, sample movement, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2°. Therefore, this error should be taken into account when determining each crystal structure.
  • the peak positions of the XRPD spectrum have similarities as a whole, and the relative intensity error may be large.
  • DSC provides an auxiliary method for identifying different crystals. Different crystalline forms can be identified based on different transition temperature characteristics. It should be noted that for the mixture, the DSC peak may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance. For the same crystallization of the same compound, the thermal transition temperature error is typically within about 5 °C, typically within about 3 °C, in a continuous analysis.
  • Figure 1 is an X-ray powder diffraction pattern of Form III of idarubicin hydrochloride monohydrate of the present application.
  • Figure 3 is a TGA pattern of Form III of idarubicin hydrochloride monohydrate of the present application.
  • Figure 4 is an X-ray powder diffraction pattern of amorphous idarubicin monohydrate hydrochloride.
  • the crude raw material idarubicin hydrochloride can be prepared by the method disclosed in the literature "Semi-synthesis of idarubicin hydrochloride, Chinese Journal of Antibiotics, 2006, 31(3): 181-183" or CN85103835A or PL195417B1.
  • the powder diffractometer is produced by the manufacturer ARL of Switzerland, the instrument model: X'TRA, The tube voltage is 40KV, the tube current is 30mA, and the scanning speed is 8°/min.
  • the water content of the crude material before crystallization was determined by Karl Fischer moisture measurement.
  • the DSC spectrum is shown in Figure 2. There is an endothermic peak at 118 °C, water molecules are lost, and 192 °C is the melting peak.
  • the Karl Fischer moisture meter measured a moisture content of 3.60% by weight.
  • the XRPD pattern is shown in Figure 4 and is shown to be amorphous.
  • the XRPD pattern indicates an amorphous mixture.
  • Form II was prepared according to the method described in Example 1 of Patent Application CN103906757A.
  • Test conditions Form III of Example 1 of the present application, amorphous form of Comparative Example 1, Form I prepared in Comparative Example 3, and Form II sample prepared in Comparative Example 4 were placed in a holding chamber at 60 ° C for 30 days. , samples were taken on days 0, 5, 10, and 30.
  • the test results show that the amorphous form prepared in Comparative Example 1 is unstable under high temperature conditions, and the chemical purity of idarubicin hydrochloride is less than 95% after 30 days, which is not conducive to the storage of the drug substance.
  • the crystal form I prepared in Comparative Example 3 had a partial crystal transformation phenomenon under high temperature conditions, and the XRPD pattern showed a change after being left for 30 days.
  • Form III was significantly more pure than Form I and Form II after standing for 30 days at a high temperature of 60 °C.
  • Test conditions Form III of Example 1 of the present application, amorphous form of Comparative Example 1, Form I prepared in Comparative Example 3, and Form II sample prepared in Comparative Example 4 were placed at room temperature and the humidity was 92.5%. The samples were taken on days 0, 5, 10, and 30 for 30 days in the environment.
  • test results show that under high humidity conditions, amorphous form will be converted to Form I, and after 30 days of Form I, the XRPD pattern shows a change, indicating that partial crystal transformation has occurred; and Form I and Form II The chemical purity is slightly reduced.
  • the clinically approved idarubicin hydrochloride is a lyophilized powder injection.
  • the raw material drug idarubicin hydrochloride is first dissolved in water and then lyophilized. Therefore, the solubility of the drug substance idarubicin hydrochloride is very important for the preparation process.
  • Example 1 100 mg of the sample of Example 1, Comparative Example 3, and Comparative Example 4 was placed in 5 mL of water at 25 ° C, and the dissolution was observed at the same magnetic stirring speed. If the solute particles were not visually observed, they were considered to be completely dissolved.

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Abstract

本发明公开了盐酸伊达比星一水合物的新晶型，新晶型的制备方法，包含该新晶型的药物组合物以及其在预防和/或治疗肿瘤疾病中的医药用途。

Description

盐酸伊达比星一水合物的晶型
相关申请的交叉引用
本申请要求于2017年09月22日向中华人民共和国知识产权局提交的申请号为201710864412.3的中国发明专利申请的优先权。在此通过引用方式将其全部内容以其整体并入本文。
技术领域
本申请属于药物合成领域，具体而言，涉及盐酸伊达比星一水合物的晶型、其制备方法以及用途。
背景技术
盐酸伊达比星，即4-脱甲氧柔红霉素盐酸盐，属于半合成的蒽环类抗肿瘤药物，临床上用于治疗急性骨髓性白血病(AML)。其作用机制为具有刚性结构的伊达比星插入NDA从而干扰核酸合成，并且伊达比星还可以与拓扑异构酶II相互作用而进一步干扰核酸合成。目前盐酸伊达比星与阿糖胞苷联合使用是治疗AML的首选方案。
盐酸伊达比星的结构式如下式所示：
Figure PCTCN2018107008-appb-000001
文献“盐酸伊达比星的半合成研究，中国抗生素杂志，2006，31(3):181-183公开了盐酸伊达比星的制备方法，将伊达比星粗品溶解于氯化氢的甲醇溶液，向其中滴加无水二氯甲烷，从而析出橙色固体，所得盐酸伊达比星的熔点为184℃～185℃。经X射线粉末衍射测定，从二氯甲烷中析晶制备得到的该固体为无定形的盐酸伊达比星。
文献CN85103835A公开的盐酸伊达比星的制备方法是将伊达比星粗品用氯化氢的无水甲醇溶液酸化至pH 3.5，再加入过量乙醚析出固体，得到的盐酸伊达比星的熔点为183℃～185℃。经X射线粉末衍射测定，从乙醚中析晶制备得到的该固体为无定形的盐酸伊达比星。
文献CN103906757A公开了采用1-丁醇、2-丁醇或1-戊醇与水的混合溶剂 作为重结晶溶剂制备盐酸伊达比星晶型(下文称为晶型II)的方法，但是该方法需将溶液加热至80℃左右，而盐酸伊达比星在高温下不稳定。
波兰专利PL195417B1公开了盐酸伊达比星一水合物的晶型(下文简称晶型I)，该晶型是采用水和异丙醇的混合溶剂重结晶制备得到的，其熔点为190.1℃～199.6℃。实验发现，伊达比星在水和有机溶剂的混合溶剂中重结晶会发生部分降解。
因此，仍需要新的稳定的盐酸伊达比星的晶型以及温和的制备该新晶型的方法。
发明详述
本申请提供了具有如下结构的盐酸伊达比星一水合物的新晶型(下文简称晶型III)：
Figure PCTCN2018107008-appb-000002
使用Cu-Ka辐射，晶型III的以2θ角度表示的X射线粉末衍射图在2θ值为5.80±0.2°、9.09±0.2°、15.04±0.2°处具有特征峰。
优选地，使用Cu-Ka辐射，晶型III的以2θ角度表示的X射线粉末衍射图在2θ值为5.80±0.2°、7.17±0.2°、9.09±0.2°、9.78±0.2°、14.10±0.2°、15.04±0.2°、17.01±0.2°、21.45±0.2°处具有特征峰。
更优选地，使用Cu-Ka辐射，晶型III的以2θ角度表示的X射线粉末衍射图在2θ值为5.80±0.2°、7.17±0.2°、9.09±0.2°、9.78±0.2°、11.60±0.2°、14.10±0.2°、15.04±0.2°、15.42±0.2°、16.51±0.2°、17.01±0.2°、17.64±0.2°、18.22±0.2°、19.91±0.2°、21.45±0.2°、22.09±0.2°、22.34±0.2°、23.46±0.2°、24.63±0.2°、25.87±0.2°、27.87±0.2°、30.36±0.2°、31.44±0.2°、38.09±0.2°处具有特征峰，如图1所示。
在差示扫描量热法(DSC)测得的热分析图中，本申请的晶型III分别在约100℃～130℃和约188℃～195℃的温度处有两个吸热峰。
在一个优选的实施方案中，本申请的晶型III的DSC图谱如图2所示。在100℃～130℃和188℃～193℃范围内出现吸热峰，峰值温度分别为约118.2℃和192.1℃。
经热重分析(TGA)测定，本申请的晶型III的重量损失的质量分数为约 3.4％～4.0％。
在一个优选的实施方案中，本申请的晶型III的TGA图谱如图3所示。在90℃～130℃范围内出现重量损失，重量损失的质量分数为3.6％；卡尔费休水分仪测得其含水量也为3.6wt％，与理论计算的一水合物的含水量3.4wt％相符。
另一方面，本申请还提供了盐酸伊达比星一水合物的晶型III的制备方法，将盐酸伊达比星粗品溶解于无水甲醇中，然后加入乙酸乙酯析晶，其中在溶解步骤之前或之后向无水甲醇中任选地添加水，并且所述盐酸伊达比星粗品含有的水量与任选添加的水量之和≤所述盐酸伊达比星粗品的5wt％，并且≥所述盐酸伊达比星粗品的2wt％。
优选地，在一个实施方案中，盐酸伊达比星粗品含有的水量≤所述盐酸伊达比星粗品的5wt％，并且≥所述盐酸伊达比星粗品的2wt％。
优选地，盐酸伊达比星粗品与无水甲醇的质量体积比为1:10～20。更优选地，盐酸伊达比星粗品与无水甲醇的质量体积比为1:14。
优选地，乙酸乙酯与无水甲醇的体积比为1～5:1。更优选地，乙酸乙酯与无水甲醇的体积比为3:1。
在一个实施方案中，所述制备方法还包括过滤、洗涤和干燥步骤。
另一方面，本申请还提供药物组合物，其包含盐酸伊达比星一水合物的晶型III和药学上可接受的载体。在一个实施方案中，所述药学上可接受的载体的实例包括但不限于甘油、明胶、海藻酸钠、葡聚糖、水或其混合物或pH调节剂。
另一方面，本申请还提供了盐酸伊达比星一水合物的晶型III在制备抗肿瘤疾病的药物中的用途。在一个实施方案中，所述肿瘤疾病优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
再一方面，本申请还提供了用于预防和/或治疗肿瘤疾病和疾病状态的方法，其包括向有需要的个体给予本申请的盐酸伊达比星一水合物的晶型III或本申请的药物组合物。在一个实施方案中，所述肿瘤疾病优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
还一方面，本申请还提供了用于预防和/或治疗肿瘤疾病和疾病状态的本申请的盐酸伊达比星一水合物的晶型III或本申请的药物组合物。在一个实施方案中，所述肿瘤疾病优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
(一)含水量研究
1.本申请的发明人发现，重结晶前体系中的含水量对晶型III的形成至关重要，并研究了不同的含水量对结晶产品的影响。
Figure PCTCN2018107008-appb-000003
将不同含水量的盐酸伊达比星1g溶于无水甲醇10mL，任选地添加水以获得具有如下表所示的含水量的体系，再加入10mL乙酸乙酯以析晶，结果如下表所示：
重结晶前体系中的含水量(wt％) 2 5 7 10
结晶产品 晶型III 晶型III 晶型I 晶型I
该试验表明当重结晶前体系中的含水量大于5wt％时，重结晶后得不到本申请的晶型III，而是得到晶型I。
2.本申请的发明人还发现，重结晶前体系中的含水量也影响盐酸伊达比星一水合物的稳定性。试验表明，在本申请的方法中，当重结晶前体系中的含水量≤5wt％，可以保持盐酸伊达比星一水合物的晶型III的稳定性。如下表所示，在本申请的重结晶体系中，总杂质含量并不会随着时间延长而有所增加：
Figure PCTCN2018107008-appb-000004
但是如果增加重结晶前体系中的含水量，则总杂质含量将会随着时间延长而逐渐增加，如下表所示：
Figure PCTCN2018107008-appb-000005
本申请提供了新的盐酸伊达比星一水合物的晶型，其不同于现有文献中已经公开的晶型。与现有文献中公开的晶型相比，本申请的晶型III具有如下一种或多种令人惊讶的优势：在高温高湿条件下，本申请的晶型III均能保持良好的稳定性，有利于原料药的储存；在溶解性方面，本申请的晶型III与晶型I和晶型II相比也具有显著的优势，适合于形成药物制剂。因此，本申请的晶型III具有良好的成药性。
需要说明的是，在X射线粉末衍射光谱(XRPD)中，由结晶化合物得到的衍射谱图对于特定的结晶往往是特征性的，其中谱带(尤其是在低角度)的相对强度可能会因为结晶条件、粒径和其它测定条件的差异而产生的优势取向效果而变化。因此，衍射峰的相对强度对所针对的结晶并非是特征性的。判断是否与已知的结晶相同时，更应该注意的是峰的相对位置而不是它们的相对强度。此外，对任何给定的结晶而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品移动、或仪器的标定等，峰的位置可以移动，2θ值的测定误差有时约为±0.2°。因此，在确定每种结晶结构时，应该将 此误差考虑在内。在XRPD图谱中通常用2θ角或晶面距d表示峰位置，两者之间具有简单的换算关系：d＝λ/2sinθ，其中d代表晶面距，λ代表入射X射线的波长，θ为衍射角。对于同种化合物的同种结晶，其XRPD谱的峰位置在整体上具有相似性，相对强度误差可能较大。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的结晶是特征性的。
DSC提供了一种辨别不同结晶的辅助方法。不同的结晶形态可根据不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。对于同种化合物的同种结晶，在连续的分析中，热转变温度误差典型的在约5℃以内，通常在约3℃以内。
附图说明
图1为本申请的盐酸伊达比星一水合物的晶型III的X射线粉末衍射图谱。
图2为本申请的盐酸伊达比星一水合物的晶型III的DSC图谱。
图3为本申请的盐酸伊达比星一水合物的晶型III的TGA图谱。
图4为无定形的盐酸伊达比星一水合物的X射线粉末衍射图谱。
实施例
下面结合具体实施例进一步说明本申请的实施方案，但并不限定本发明。
原料盐酸伊达比星粗品可以采用文献“盐酸伊达比星的半合成研究，中国抗生素杂志，2006，31(3):181-183”或者CN85103835A或PL195417B1中公开的方法制备。
1.粉末衍射仪是由制造厂商瑞士ARL公司生产的，仪器型号：X'TRA，
Figure PCTCN2018107008-appb-000006
管电压40KV，管电流30mA，扫描速度8°/min。
2.差示扫描量热仪和热重分析仪由美国PerKinElmer公司生产，仪器型号：Pyris 1 DSC，采用氮气气氛，升温速率20℃/min。
3.卡尔费休水分测试仪型号：Mettler Toledo V30 Volumetric KF Titrator
4. HPLC测定采用以下色谱条件：仪器：Agilent 1260型；色谱柱：C18柱；检测波长：254nm；流速：1.0ml/min；柱温：30℃；进样量：10μL；流动相：甲醇-水-30％磷酸溶液(790:210:1)，每1000mL中含十二烷基硫酸钠4.0g。
5.结晶前原料粗品的含水量采用卡尔费休水分测定法测定。
实施例1 晶型III的制备
将10g盐酸伊达比星粗品(含水量5wt％)在室温下溶于无水甲醇(140mL)中， 加入420mL乙酸乙酯析晶，搅拌半小时，过滤，于45℃下真空干燥3h，得到橘红色晶体9.4g，HPLC纯度99.90％。
XRPD图谱见图1所示。
DSC图谱如图2所示，在118℃处有吸热峰，失去水分子，192℃为熔化峰；
TGA图谱如图3所示，在加热至130℃时，有3.658％的失重，由热重数据分析得知一分子盐酸伊达比星中含有一个水分子；
卡尔费休水分仪测得水分含量为3.60wt％。
实施例2 晶型III的制备
将10g盐酸伊达比星粗品(含水量2wt％)在室温下溶于无水甲醇(100mL)中，加入500mL乙酸乙酯析晶，10℃下搅拌半小时，过滤，于45℃下真空干燥3h，得到橘红色晶体9.3g，HPLC纯度99.91％。XRPD图谱、DSC图谱、TGA图谱与实施例1一致。
实施例3 晶型III的制备
将10g盐酸伊达比星粗品(含水量4wt％)在室温下溶于无水甲醇(200mL)中，加入200mL乙酸乙酯析晶，0℃下搅拌半小时，过滤，于45℃下真空干燥3h，得到橘红色晶体9.1g，HPLC纯度99.93％。XRPD图谱、DSC图谱、TGA图谱与实施例1一致。
实施例4 晶型III的制备
将无水甲醇180ml与纯化水0.35ml加入反应瓶，开启搅拌，室温下加入10g盐酸伊达比星粗品(含水量0.9wt％)，搅拌至基本溶清，滴加900ml乙酸乙酯，滴加完毕后，降温至5℃，搅拌析晶1h。过滤，滤饼于30℃下真空干燥3h，得到橘红色晶体9g。XRPD图谱、DSC图谱、TGA图谱与实施例1一致。
对比例1 参照文献CN85103835A方法制备
将伊达比星粗品5克溶于125mL冰冷的0.1M氯化氢的甲醇溶液中，加入过量乙醚，析出固体，抽滤即得。熔点184～185℃。
XRPD图谱如图4所示，表明为无定形。
对比例2 参照文献“盐酸伊达比星的半合成研究，中国抗生素杂志，2006，31(3):181-183”所描述的方法制备
将伊达比星粗品5克溶于125mL冰冷的0.1M氯化氢的甲醇溶液中，滴加1000mL无水二氯甲烷，析出橙色固体，抽滤即得。熔点184～185℃。
XRPD图谱表明为无定形混合物。
对比例3 参照文献PL195417B1方法制备晶型I
将盐酸伊达比星粗品用水和异丙醇(v:v＝1:3)的混合溶剂重结晶，制备晶型I。
对比例4 参照CN103906757A方法制备晶型II
按照专利申请CN103906757A中的实施例1记载的方法制备晶型II。
实施例5 稳定性试验
(1)高温试验
试验条件：将本申请实施例1的晶型III、对比例1的无定形、对比例3制备的晶型I以及对比例4制备的晶型II样品敞口放在60℃的保温室内30天，于第0、5、10、30天取样测定。
试验结果如下表所示：
Figure PCTCN2018107008-appb-000007
该试验结果表明对比例1制备的无定形在高温条件下不稳定，在30天后盐酸伊达比星的化学纯度还不到95％，不利于原料药的储存。对比例3制备的晶型I在高温条件下存在部分转晶的现象，放置30天后，XRPD图谱显示有变化。晶型III在60℃的高温下放置30天后纯度显著高于晶型I和晶型II。
(2)高湿试验
试验条件：将本申请实施例1的晶型III、对比例1的无定形、对比例3制备的晶型I以及对比例4制备的晶型II样品敞口放在室温且湿度为92.5％的环境下30天，于第0、5、10、30天取样测定。
试验结果如下表所示：
Figure PCTCN2018107008-appb-000008
该试验结果表明在高湿条件下，无定形会转化成晶型I，而晶型I放置30天后，XRPD图谱显示有变化，这表明发生了部分转晶；并且晶型I和晶型II的化学纯度都稍有下降。
实施例6 溶解性比较试验
目前临床上批准的盐酸伊达比星是冻干粉针剂，在制剂过程中需要先将原料药盐酸伊达比星溶于水，再进行冻干。故原料药盐酸伊达比星的溶解性对于制剂工艺十分重要。
取实施例1、对比例3、对比例4的样品100mg于25℃下置于5mL水中，以相同的磁力搅拌速度，观察溶解情况，如无目视可见的溶质颗粒即视为完全溶解。
结果如下表所示：
Figure PCTCN2018107008-appb-000009
该结果表明，本申请的晶型III在溶解性方面显著优于晶型I和晶型II。

Claims (16)

  1. 盐酸伊达比星一水合物的晶型，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射图在2θ值为5.80±0.2°、9.09±0.2°、15.04±0.2°处具有特征峰。
  2. 根据权利要求1所述的盐酸伊达比星一水合物的晶型，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射图在2θ值为5.80±0.2°、7.17±0.2°、9.09±0.2°、9.78±0.2°、14.10±0.2°、15.04±0.2°、17.01±0.2°、21.45±0.2°处具有特征峰。
  3. 根据权利要求2所述的盐酸伊达比星一水合物的晶型，其特征在于，使用Cu-Ka辐射，以2θ角度表示的X射线粉末衍射图还在2θ值为11.60±0.2°、15.42±0.2°、16.51±0.2°、17.64±0.2°、18.22±0.2°、19.91±0.2°、22.09±0.2°、22.34±0.2°、23.46±0.2°、24.63±0.2°、25.87±0.2°、27.87±0.2°、30.36±0.2°、31.44±0.2°、38.09±0.2°处具有特征峰。
  4. 根据权利要求2所述的盐酸伊达比星一水合物的晶型，其特征在于所述晶型具有如图1所示的X射线粉末衍射图谱。
  5. 根据权利要求1～4中任一项所述的盐酸伊达比星一水合物的晶型，其特征在于所述晶型在约100℃～130℃和约188℃～195℃的温度处有两个吸热峰。
  6. 根据权利要求1～5中任一项所述的盐酸伊达比星一水合物的晶型，其特征在于所述晶型具有如图2所示的DSC图谱。
  7. 根据权利要求1～6中任一项所述的盐酸伊达比星一水合物的晶型，其特征在于所述晶型的重量损失的质量分数为约3.4％～4.0％。
  8. 根据权利要求1～7中任一项所述的盐酸伊达比星一水合物的晶型，其特征在于所述晶型具有如图3所示的TGA图谱。
  9. 制备权利要求1～8中任一项所述的盐酸伊达比星一水合物的晶型的方法，其特征在于将盐酸伊达比星粗品溶解于无水甲醇中，然后加入乙酸乙酯析晶，其中在溶解步骤之前或之后向无水甲醇中任选地添加水，并且所述盐酸伊达比星粗品含有的水量与任选添加的水量之和≤所述盐酸伊达比星粗品的5wt％，并且≥所述盐酸伊达比星粗品的2wt％。
  10. 根据权利要求9所述的制备方法，其特征在于所述盐酸伊达比星粗品含有的水量≤所述盐酸伊达比星粗品的5wt％，并且≥所述盐酸伊达比星粗品的2wt％。
  11. 根据权利要求9或10所述的制备方法，其特征在于所述盐酸伊达比星粗品与无水甲醇的质量体积比为1:10～20。
  12. 根据权利要求9-11中任一项所述的制备方法，其特征在于所述无水甲醇与乙酸乙酯的体积比为1:1～5。
  13. 药物组合物，其含有权利要求1～8中任一项所述的盐酸伊达比星一水合物的晶型与药学上可接受的载体。
  14. 权利要求1～8中任一项所述的盐酸伊达比星一水合物的晶型或权利要求13所述的药物组合物在制备抗肿瘤疾病的药物中的用途，其中所述肿瘤疾病优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
  15. 用于预防和/或治疗肿瘤疾病和疾病状态的方法，其包括向有需要的个体给予权利要求1～8中任一项所述的盐酸伊达比星一水合物的晶型或权利要求13所述的药物组合物，其中所述肿瘤疾病和疾病状态优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
  16. 用于预防和/或治疗肿瘤疾病和疾病状态的权利要求1～8中任一项所述的盐酸伊达比星一水合物的晶型或权利要求13所述的药物组合物，其中所述疾病和疾病状态优选为急性骨髓粒细胞白血病和急性淋巴性白血病。
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