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WO2008148260A1 - A novel crystal form of irinotecan hydrochloride and its preparation - Google Patents

A novel crystal form of irinotecan hydrochloride and its preparation Download PDF

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Publication number
WO2008148260A1
WO2008148260A1 PCT/CN2007/003071 CN2007003071W WO2008148260A1 WO 2008148260 A1 WO2008148260 A1 WO 2008148260A1 CN 2007003071 W CN2007003071 W CN 2007003071W WO 2008148260 A1 WO2008148260 A1 WO 2008148260A1
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irinotecan hydrochloride
crystal
ketone solvent
raw material
temperature
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PCT/CN2007/003071
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French (fr)
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Jinliang Li
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Shanghai Desano Pharmaceutical Holding Co., Ltd.
Shanghai Desano Chemical Pharmaceutical Co., Ltd.
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Publication of WO2008148260A1 publication Critical patent/WO2008148260A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the present invention relates to a novel crystalline form of irinotecan hydrochloride; in addition, the present invention also relates to a process for the preparation of the crystalline form. Background technique
  • Irinotecan is a camptothecin derivative jointly developed by Daiichi Seiyaku and Yakult Honsha in Japan. Since its initial market in Japan in 1994, it has attracted worldwide attention as an effective drug for metastatic colorectal cancer. Considering the water solubility problem, it is clinically used in the form of its hydrochloride salt (the trade name of irinotecan hydrochloride is Kaptor ® ), and the structural formula is as follows -
  • WO03074527 discloses a c-type crystal. Its 2 eigenvalue peaks and the corresponding intensity (%) are shown in Table II:
  • a first aspect of the present invention is to provide a novel irinotecan hydrochloride crystal form to overcome the above-mentioned drawbacks of the prior art.
  • the second aspect of the technical problem to be solved by the present invention is to provide a method for preparing the above irinotecan hydrochloride crystal form.
  • the crystal is at (2 ⁇ ) 7.836 under powder X-ray diffraction. , 9.965. , 11.264°, 14.128°, 14.813°, 15.609°, 20.001°, 21.312°, 22.202°, 22.685° have characteristic peaks.
  • the DSC plot shows that there is a large endothermic peak between about 50 and 150 ° C corresponding to the loss of crystallization.
  • Onset temperature is 119.6 ° C; between 200 220 ° C and 260 ⁇ 290 ° C there are two small exothermic peaks corresponding to the crystal transformation process, Onset temperature is 205.7 and 287.5 ° C ; a large endothermic peak between 3 ⁇ 4 300 ⁇ 340 °C corresponds to the process of sample decomposition, Onset temperature is 314.5 °C;
  • the Karl Fischer moisture meter measures the moisture content between 7.9 and 8.5% and should be trihydrate.
  • a method for preparing a novel crystalline form of irinotecan hydrochloride as a second aspect of the present invention which comprises the following
  • the raw material irinotecan hydrochloride (calculated as anhydrate): water: the ratio of the ketone solvent is 1: 5 to 15: 15 to 30 (g / ml / ml), wherein preferably 1: 9 ⁇ 12:18 ⁇ 22 (g/ml/ml).
  • the raw material irinotecan hydrochloride is an amorphous powder or a b-type crystal.
  • the ketone solvent is one of acetone, butanone, butanone or pentanone, of which acetone is preferred.
  • the dissolution temperature in the above step 1) is preferably 75 to 80 °C.
  • the temperature at which the ketone solvent is added in the above step 2) is preferably 20 to 22 °C.
  • the crystallization temperature in the above step 3) is preferably 4 to 6 ° C; the crystallization time is 8 to 16 hours, preferably 11 to 13 hours.
  • irinotecan hydrochloride (amorphous or b-type crystal) can be prepared by referring to J. Org. Chem., 1997, 62, 6588-97.
  • the novel crystalline form of irinotecan hydrochloride provided by the invention has high solubility in water and good storage stability.
  • the product obtained by the method for preparing irinotecan hydrochloride crystal provided by the invention has high purity and high content and less impurities.
  • the HPLC test method can be carried out by the method in the national drug standard.
  • Figure 1 is an X-ray diffraction pattern of irinotecan hydrochloride powder of the present invention
  • Figure 2 is a DSC chart of irinotecan hydrochloride of the present invention. detailed description
  • the crystal powder X-ray diffraction spectrum shows: (2 ⁇ ) 7.84°, 9.96°, 11.26°, 14.13°, 14.81°, 15.61°, 20.00°, 21.31. , 22.20°, 22.68° with characteristic peaks.
  • the DSC spectrum of the crystal shows that there is a large endothermic peak between about 50 and 150 ° C corresponding to the process of losing crystal water, and the Onset temperature is 119.6 ° C; at about 200 °
  • Onset temperature is 205.7 ° C and 287.5 ° C; between about 300 ⁇ 340 ° C a larger one
  • the endothermic peak corresponds to the process of sample decomposition, and the Onset temperature is 314.5° ( .

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Abstract

The invention discloses a novel crystal form of irinotecan hydrochloride which exhibits peaks (2θ) at 7.80°, 9.96°,13.28°,15.62°, 19.98°, 20.36°, 22.34°, 22.66°, 26.60°, 30.18° in powder X-ray diffractometry. Furthermore, the invention also discloses a process for preparing the novel crystal form of irinotecan hydrochloride. Irinotecan hydrochloride obtained by the process according to the invention has good solubility in water, excellent storage stability, high content and purity, and less contaminant.

Description

盐酸伊立替康新晶型及其制备方法 技术领域  Irinotecan hydrochloride new crystal form and preparation method thereof
本发明涉及一种盐酸伊立替康的新晶型； 此外， 本发明还涉及该晶 型的制备方法。 背景技术  The present invention relates to a novel crystalline form of irinotecan hydrochloride; in addition, the present invention also relates to a process for the preparation of the crystalline form. Background technique
伊立替康是日本 Daiichi Seiyaku和 Yakult Honsha公司联合开发的喜 树碱类衍生物， 自 1994年在日本首次上市后， 作为转移性结直肠癌的 有效药物引起全世界的广泛关注。 考虑到水溶性问题， 临床用其盐酸 盐形式 （盐酸伊立替康商品名为开普拓 ®)， 结构式如下所示-  Irinotecan is a camptothecin derivative jointly developed by Daiichi Seiyaku and Yakult Honsha in Japan. Since its initial market in Japan in 1994, it has attracted worldwide attention as an effective drug for metastatic colorectal cancer. Considering the water solubility problem, it is clinically used in the form of its hydrochloride salt (the trade name of irinotecan hydrochloride is Kaptor ® ), and the structural formula is as follows -
Figure imgf000003_0001
Figure imgf000003_0001
文锨 Chem. Pharm. Bull, 1991, 39(6), 1446-54.公开了一种制备盐酸 伊立替康三水合物（文献中简称为 CPT-11 )的合成方法， 产品是从水中 结晶得到的， 是一种淡黄色的针状结构或结晶性粉末， 该文献还公开了 CPT-11的晶体结构（后在 WO03074527中称此晶型为 b型结晶）。 b型 2Θ 值特征峰以及与之相对应的强度 （％) 如表 I所示- 表 I ：Wen. Chem. Pharm. Bull, 1991, 39(6), 1446-54. discloses a synthetic method for preparing irinotecan hydrochloride trihydrate (abbreviated as CPT-11 in the literature), which is obtained by crystallization from water. It is a pale yellow needle-like structure or a crystalline powder, and the literature also discloses the crystal structure of CPT-11 (hereinafter referred to as crystal form b in WO03074527). Type b 2Θ The value characteristic peak and the corresponding intensity (%) are shown in Table I - Table I:
Figure imgf000004_0001
Figure imgf000004_0001
WO03074527公开了一种 c型结晶。其 2Θ值特征峰以及与之相对应 的强度 （％) 如表 II所示：  WO03074527 discloses a c-type crystal. Its 2 eigenvalue peaks and the corresponding intensity (%) are shown in Table II:
表 II：
Figure imgf000004_0002
Table II:
Figure imgf000004_0002
b型结晶的溶解度较小， 不利于制剂。 c型结晶的溶解度大， 但稳定 性不太好。 发明内容 The solubility of type b crystals is small, which is not conducive to the preparation. The solubility of c-type crystals is large, but the stability is not so good. Summary of the invention
本发明要解决的技术问题第一方面在于提供一种新的盐酸伊立替康 晶型， 以克服现有技术存在的上述缺陷。  SUMMARY OF THE INVENTION A first aspect of the present invention is to provide a novel irinotecan hydrochloride crystal form to overcome the above-mentioned drawbacks of the prior art.
本发明要解决的技术问题第二方面在于提供上述盐酸伊立替康晶型 的制备方法。  The second aspect of the technical problem to be solved by the present invention is to provide a method for preparing the above irinotecan hydrochloride crystal form.
作为本发明第一方面的盐酸伊立替康晶型， 该结晶在粉末 X射线衍 射下在（2Θ) 7.836。， 9.965。， 11.264°, 14.128°, 14.813°, 15.609°, 20.001°, 21.312°， 22.202°, 22.685°具有特征峰。  As the crystal form of irinotecan hydrochloride of the first aspect of the present invention, the crystal is at (2Θ) 7.836 under powder X-ray diffraction. , 9.965. , 11.264°, 14.128°, 14.813°, 15.609°, 20.001°, 21.312°, 22.202°, 22.685° have characteristic peaks.
这些特征峰相对应的强度 （％) 如表 III所示：  The intensity (%) corresponding to these characteristic peaks is shown in Table III:
表 III：  Table III:
Figure imgf000005_0001
Figure imgf000005_0001
DSC 图显示在约 50〜150°C之间有一个大的吸热峰对应于失去结晶 水的过程， Onset温度为 119.6°C ; 在约 200 220 °C之间和 260〜290°C之 间有两个小的放热峰对应于转晶型的过程， Onset温度为 205.7 和 287.5 °C ; 在¾ 300〜340°C之间有一个较大的吸热峰对应于样品分解的过程， Onset温度为 314.5 °C ; The DSC plot shows that there is a large endothermic peak between about 50 and 150 ° C corresponding to the loss of crystallization. The water process, Onset temperature is 119.6 ° C; between 200 220 ° C and 260 ~ 290 ° C there are two small exothermic peaks corresponding to the crystal transformation process, Onset temperature is 205.7 and 287.5 ° C ; a large endothermic peak between 3⁄4 300~340 °C corresponds to the process of sample decomposition, Onset temperature is 314.5 °C;
卡氏水分测定仪测定水份含量在 7.9〜8.5%之间， 应为三水物。  The Karl Fischer moisture meter measures the moisture content between 7.9 and 8.5% and should be trihydrate.
作为本发明第二方面的盐酸伊立替康新晶型的制备方法， 包括下述  A method for preparing a novel crystalline form of irinotecan hydrochloride as a second aspect of the present invention, which comprises the following
1)用水溶解原料盐酸伊立替康， 溶解温度为 60〜90°C； 1) dissolving the raw material irinotecan hydrochloride with water, the dissolution temperature is 60~90 ° C;
2) 降温至 15〜25 °C后， 加入酮类溶剂；  2) After cooling to 15~25 °C, add ketone solvent;
3)继续降温至 0~10°C析晶。  3) Continue to cool down to 0~10 °C crystallization.
在上述制备方法中， 原料盐酸伊立替康 (按无水物计算)： 水： 酮类 溶剂的比例为 l :5〜15:15〜30(g/ml/ml)， 其中优选 l :9〜12:18〜22(g/ml/ml)。  In the above preparation method, the raw material irinotecan hydrochloride (calculated as anhydrate): water: the ratio of the ketone solvent is 1: 5 to 15: 15 to 30 (g / ml / ml), wherein preferably 1: 9 ~ 12:18~22 (g/ml/ml).
所述的原料盐酸伊立替康为.无定形粉末或 b型结晶。  The raw material irinotecan hydrochloride is an amorphous powder or a b-type crystal.
所述的酮类溶剂为丙酮、 丁酮、 丁酮或戊酮中的一种， 其中优选丙 酮。  The ketone solvent is one of acetone, butanone, butanone or pentanone, of which acetone is preferred.
在上述步骤 1)中溶解温度优选 75〜80°C。  The dissolution temperature in the above step 1) is preferably 75 to 80 °C.
在上述步骤 2)中加入酮类溶剂时的温度优选 20~22°C。  The temperature at which the ketone solvent is added in the above step 2) is preferably 20 to 22 °C.
在上述步骤 3)中析晶温度优选 4〜6°C ;析晶时间为 8~16小时，优选 11-13小时。  The crystallization temperature in the above step 3) is preferably 4 to 6 ° C; the crystallization time is 8 to 16 hours, preferably 11 to 13 hours.
本发明的原料盐酸伊立替康（无定形或 b型结晶） 可参照 J. Org. Chem., 1997, 62, 6588-97.制备得到。  The raw material of the present invention, irinotecan hydrochloride (amorphous or b-type crystal) can be prepared by referring to J. Org. Chem., 1997, 62, 6588-97.
本发明提供的盐酸伊立替康新晶型，水中溶解度大，储存稳定性好。 用本发明提供的制备盐酸伊立替康结晶的方法得到的产品纯度、 含量 高， 杂质少。 HPLC检验方法可采用国家药品标准中的方法。 附图说明 The novel crystalline form of irinotecan hydrochloride provided by the invention has high solubility in water and good storage stability. The product obtained by the method for preparing irinotecan hydrochloride crystal provided by the invention has high purity and high content and less impurities. The HPLC test method can be carried out by the method in the national drug standard. DRAWINGS
图 1为本发明盐酸伊立替康粉末 X射线衍射图；  Figure 1 is an X-ray diffraction pattern of irinotecan hydrochloride powder of the present invention;
图 2为本发明盐酸伊立替康 DSC图。 具体实施方式  Figure 2 is a DSC chart of irinotecan hydrochloride of the present invention. detailed description
下面结合附图和实施例对本发明作进一步详细的说明：  The present invention will be further described in detail below with reference to the accompanying drawings and embodiments:
实施例 1  Example 1
600.0g原料盐酸伊立替康（无定形或 b型结晶） 中加入 oL的水， 加热至 75°C固体完全溶解。 固体完全溶解后降温至 22 °C， 在搅拌状态 下逐步加入 12.0L丙酮。 加完后再降温至 5°C， 有晶体析出。 静置 12小 时后过滤， 35°C下真空干燥 12小时，得到 565.5g淡黄色针状结晶。 HPLC 检测含量和纯度均 99.5%。 卡氏水分测定仪测定水份 8.3%。  600.0 g of raw material irinotecan hydrochloride (amorphous or b-type crystal) was added with oL of water, and heated to 75 ° C to completely dissolve the solid. After the solid was completely dissolved, the temperature was lowered to 22 ° C, and 12.0 L of acetone was gradually added under stirring. After the addition was completed, the temperature was lowered to 5 ° C, and crystals were precipitated. After standing for 12 hours, it was filtered, and dried under vacuum at 35 ° C for 12 hours to obtain 565.5 g of pale yellow needle crystals. The HPLC content and purity were both 99.5%. The Karl Fischer moisture meter measured moisture 8.3%.
如附图 1所示，该结晶的粉末 X射线衍射谱图显示：在（2Θ) 7.84°， 9.96°, 11.26°, 14.13°, 14.81°, 15.61°, 20.00°, 21.31。， 22.20°, 22.68° 具有特征峰。  As shown in Fig. 1, the crystal powder X-ray diffraction spectrum shows: (2Θ) 7.84°, 9.96°, 11.26°, 14.13°, 14.81°, 15.61°, 20.00°, 21.31. , 22.20°, 22.68° with characteristic peaks.
如附图 2所示， 该结晶的 DSC谱图显示：在约 50~150°C之间有一个 大的吸热峰对应于失去结晶水的过程， Onset温度为 119.6 °C ; 在约 200〜220°C之间和 260~290°C之间有两个小的放热峰对应于转晶型的过 程， Onset温度为 205.7°C和 287.5°C ;在约 300~340°C之间有一个较大的 吸热峰对应于样品分解的过程， Onset温度为 314.5° ( 。 As shown in Fig. 2, the DSC spectrum of the crystal shows that there is a large endothermic peak between about 50 and 150 ° C corresponding to the process of losing crystal water, and the Onset temperature is 119.6 ° C; at about 200 ° There are two small exothermic peaks between 220 ° C and 260 ~ 290 ° C corresponding to the process of crystal transformation, Onset temperature is 205.7 ° C and 287.5 ° C; between about 300 ~ 340 ° C a larger one The endothermic peak corresponds to the process of sample decomposition, and the Onset temperature is 314.5° ( .
实施例 2  Example 2
6.0g原料盐酸伊立替康（无定形或 b型结晶） 中加入 50 ml的水， 加热至 90°C固体完全溶解。 固体完全溶解后降温至 15°C， 在搅拌状态 下逐步加入 150 ml丙酮。 加完后再降温至 5°C， 有晶体析出。 静置 16 小时后过滤， 35Ό下真空干燥 12小时，得到 5.8g淡黄色针状结晶。 HPLC 检测纯度 98.5%。 卡氏水分测定仪测定水份 8.1%。  6.0 g of raw material irinotecan hydrochloride (amorphous or b-type crystal) was added with 50 ml of water, and heated to 90 ° C to completely dissolve the solid. After the solid was completely dissolved, the temperature was lowered to 15 ° C, and 150 ml of acetone was gradually added under stirring. After the addition was completed, the temperature was lowered to 5 ° C, and crystals were precipitated. After standing for 16 hours, it was filtered, and dried under vacuum at 35 ° for 12 hours to obtain 5.8 g of pale yellow needle crystals. The purity of HPLC was 98.5%. The Karl Fischer moisture meter measured moisture 8.1%.
实施例 3  Example 3
6.0g原料盐酸伊立替康（无定形或 b型结晶） 中加入 70 ml的水， 加热至 80°C固体完全溶解。 固体完全溶解后降温至 20°C， 在搅拌状态 下逐步加入 180 ml丙酮。 加完后再降温至 0°C， 有晶体析出。 静置 15 小时后过滤， 35°C下真空干燥 12小时，得到 5.0g淡黄色针状结晶。 HPLC 检测纯度 99.2%。 卡氏水分测定仪测定水份 8.5%。  6.0 g of raw material irinotecan hydrochloride (amorphous or b-type crystal) was added with 70 ml of water, and heated to 80 ° C to completely dissolve the solid. After the solid was completely dissolved, the temperature was lowered to 20 ° C, and 180 ml of acetone was gradually added under stirring. After the addition was completed, the temperature was lowered to 0 ° C, and crystals were precipitated. After standing for 15 hours, it was filtered, and dried under vacuum at 35 ° C for 12 hours to obtain 5.0 g of pale yellow needle crystals. The purity of HPLC was 99.2%. The Karl Fischer moisture meter measures moisture by 8.5%.
实施例 4  Example 4
6.0g原料盐酸伊立替康（无定形或 b型结晶） 中加入 50 ml的水， 加热至 90°C固体完全溶解。 固体完全溶解后降温至 20 °C , 在搅拌状态 下逐步加入 90 ml丙酮。 加完后再降温至 10°C， 有晶体析出。 静置 8小 时后过滤， 35°C下真空干燥 12小时， 得到 5.5g淡黄色针状结晶。 HPLC 检测纯度 98.7%。 卡氏水分测定仪测定水份 7.9%。  6.0 g of raw material irinotecan hydrochloride (amorphous or b-type crystal) was added with 50 ml of water, and heated to 90 ° C to completely dissolve the solid. After the solid was completely dissolved, the temperature was lowered to 20 ° C, and 90 ml of acetone was gradually added under stirring. After the addition was completed, the temperature was lowered to 10 ° C, and crystals were precipitated. After standing for 8 hours, it was filtered, and dried under vacuum at 35 ° C for 12 hours to obtain 5.5 g of pale yellow needle crystals. The purity of HPLC was 98.7%. The Karl Fischer moisture meter measures moisture by 7.9%.
实施例 5  Example 5
6.0g原料盐酸伊立替康（无定形或 b型结晶） 中加入 60 ml的水， 加热至 80°C固体完全溶解。 固体完全溶解后降温至 20°C， 在搅拌状态 下逐步加入 180 ml丙酮。 加完后再降温至 5°C， 有晶体析出。 静置 12 小时后过滤， 35°C下真空干燥 12小时，得到 5.7g淡黄色针状结晶。 HPLC 检测纯度 99.1%。 卡氏水分测定仪测定水份 8.2%。 6.0 g of raw material irinotecan hydrochloride (amorphous or b-type crystal) was added with 60 ml of water, and heated to 80 ° C to completely dissolve the solid. After the solid is completely dissolved, it is cooled to 20 ° C, under stirring Add 180 ml of acetone gradually. After the addition was completed, the temperature was lowered to 5 ° C, and crystals were precipitated. After standing for 12 hours, it was filtered, and dried under vacuum at 35 ° C for 12 hours to obtain 5.7 g of pale yellow needle crystals. The purity of the HPLC was 99.1%. The Karl Fischer moisture meter measured moisture of 8.2%.

Claims

权利 要 求 Rights request
1、 一种盐酸伊立替康结晶， 其特征在于： 该结晶在粉末 X射线衍 射下在 (2Θ) 7.80。， 9.96°, 13.28。， 15.62°, 19.98。， 20.36°, 22.34°, 22.66°, 26.60°, 30.18°具有特征峰。 A irinotecan hydrochloride crystal characterized by: the crystal is (2Θ) 7.80 under powder X-ray diffraction. , 9.96°, 13.28. , 15.62°, 19.98. , 20.36°, 22.34°, 22.66°, 26.60°, 30.18° have characteristic peaks.
2、 根据权利要求 1所述的盐酸伊立替康结晶， 其特征在于，其结晶 的 DSC图在约 119.6°C， 205.7°C , 287.5 °C , 314.5°C有特征吸热峰。  The irinotecan hydrochloride crystal according to claim 1, wherein the crystalline DSC pattern has a characteristic endothermic peak at about 119.6 ° C, 205.7 ° C, 287.5 ° C, and 314.5 ° C.
3、 一种制备权利要求 1〜2所述的盐酸伊立替康结晶的方法， 其特 征在于， 包括下述步骤：  A method of preparing irinotecan hydrochloride crystals according to claims 1 to 2, which comprises the steps of:
1)用水溶解原料盐酸伊立替康， 溶解温度为 60〜90°C ; 1) Dissolving the raw material irinotecan hydrochloride with water, the dissolution temperature is 60~90 ° C ;
2) 降温至 15〜25°C后， 加入酮类溶剂；  2) After cooling to 15~25 ° C, add a ketone solvent;
3)继续降温至 0~10°C析晶。  3) Continue to cool down to 0~10 °C crystallization.
4、根据权利要求 3所述的方法，其特征在于，按无水物计算原料盐 酸伊立替康： 水： 酮类溶剂的比例为 l:5〜15:10〜30(g/ml/ml)。  The method according to claim 3, wherein the raw material irinotecan hydrochloride is calculated as an anhydride: water: ratio of ketone solvent is 1:5 to 15:10 to 30 (g/ml/ml) .
5、根据权利要求 3所述的方法， 其特征在于， 按无水物计算原料盐 酸伊立替康： 水： 酮类溶剂的比例为 l:9〜12:18~22(g/ml/ml)。  The method according to claim 3, wherein the raw material irinotecan hydrochloride is calculated as an anhydride: water: the ratio of the ketone solvent is 1:9 to 12:18 to 22 (g/ml/ml) .
6、根据权利要求 3所述的方法，其特征在于， 所述的原料盐酸伊立 替康为无定形粉末或 b型结晶。 - The method according to claim 3, wherein the raw material irinotecan hydrochloride is an amorphous powder or a b-type crystal. -
7、根据权利要求 3所述的方法， 其特征在于，所述的酮类溶剂为丙 酮、 丁酮、 丁酮或戊酮中的一种。 The method according to claim 3, wherein the ketone solvent is one of acetone, butanone, butanone or pentanone.
8、根据权利要求 3所述的方法， 其特征在于， 所述的酮类溶剂为丙 酮。 8. The method according to claim 3, wherein the ketone solvent is acetone.
9、 根据权利要求 3所述的方法， 其特征在于， 在上述步骤 1)中溶 解温度为 75~80°C。 9. The method according to claim 3, characterized in that the dissolution temperature in the above step 1) is from 75 to 80 °C.
10、 根据权利要求 3所述的方法， 其特征在于， 在上述步骤 2)中加 入酮类溶剂时的温度为 20~22°C。  The method according to claim 3, wherein the temperature at which the ketone solvent is added in the above step 2) is 20 to 22 °C.
11、 根据权利要求 3所述的方法， 其特征在于， 在上述步骤 3)中析 晶温度为 4〜6°C。  The method according to claim 3, wherein the crystallization temperature in the above step 3) is 4 to 6 °C.
12、 根据权利要求 3所述的方法， 其特征在于， 在上述步骤 3)中析 晶时间为 8~16小时。  12. The method according to claim 3, wherein the crystallization time in the above step 3) is 8 to 16 hours.
13、 根据权利要求 3所述的方法， 其特征在于， 在上述步骤 3)中析 晶时间为 11〜13小时。  13. The method according to claim 3, wherein the crystallization time in the above step 3) is 11 to 13 hours.
PCT/CN2007/003071 2007-06-07 2007-10-29 A novel crystal form of irinotecan hydrochloride and its preparation WO2008148260A1 (en)

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