WO2015117538A1 - 达格列净新特晶型及其制备方法 - Google Patents

达格列净新特晶型及其制备方法 Download PDF

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WO2015117538A1
WO2015117538A1 PCT/CN2015/071009 CN2015071009W WO2015117538A1 WO 2015117538 A1 WO2015117538 A1 WO 2015117538A1 CN 2015071009 W CN2015071009 W CN 2015071009W WO 2015117538 A1 WO2015117538 A1 WO 2015117538A1
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dapagliflozin
crystalline form
preparation
drying
crystal form
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PCT/CN2015/071009
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English (en)
French (fr)
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朱希风
李孝壁
张添程
袁阜平
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江苏豪森药业股份有限公司
江苏豪森医药集团连云港宏创医药有限公司
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Priority to CN201580006892.9A priority Critical patent/CN106170482B/zh
Priority to US15/117,533 priority patent/US9550747B2/en
Publication of WO2015117538A1 publication Critical patent/WO2015117538A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the technical field of polymorphic drug preparation, and in particular relates to a novel crystal form of dapagliflozin and a preparation method thereof.
  • Dapagliflozin is a drug developed by Bristol-Myers Squibb/AstraZeneca for the treatment of type 2 diabetes (sodium-glucose cotransporter-2 (SGLT-2) inhibitor).
  • Dapagliflozin chemical name 2-chloro-5-( ⁇ -D-glucopyranosyl-1-yl)-4'-ethoxydiphenylmethane, has the following chemical structure:
  • XRPD X-ray powder diffraction
  • the crystal form has a characteristic absorption peak at about 4.318 (20.45) in an X-ray powder diffraction pattern expressed at 2 ⁇ angle and interplanar spacing (d value).
  • Another object of the present invention is to provide a process for preparing a novel crystalline form of dapagliflozin according to the present invention, which comprises the preparation of daclixene in an organic solvent system at a temperature of from 0 ° C to 30 ° C.
  • dapagliflozin is dissolved in a benign organic solvent, a poor solvent is added, and then stirred and crystallized, filtered, and dried at 0 to 30 ° C to obtain a target crystal form.
  • the benign organic solvent is selected from the group consisting of ether solvents, preferably diethyl ether or methyl tert-butyl ether.
  • the poor organic solvent is selected from the group consisting of alkane solvents, preferably n-hexane or n-heptane.
  • the reaction temperature is 10 to 20 °C.
  • the stirring crystallization time is 1.5 to 2 hours.
  • the drying temperature is 10 to 30 °C.
  • the drying is vacuum drying.
  • the method for preparing the dapagliflozin crystal form is as follows: dissolving dapagliflozin in a benign organic solvent, adding daggliflozin poor solvent, stirring and crystallization, filtering and drying to obtain dadgliflozin crystal type.
  • the specific scheme adopted is as follows: dissolving dapagliflozin in a benign organic solvent, and then adding a poor solvent of dapagliflozin. After the addition, stirring and crystallization is continued for 5 to 2 hours at 30 ° C or lower, and filtration, 0 to Drying at 30 ° C in vacuo yielded a sample of the granules.
  • the invention provides a novel method for preparing a crystalline form of dapagliflozin, which has good solubility, small wettability, stable process, strong operability, high yield, good reproducibility, and obtained crystals.
  • the type is stable and suitable for medical development and application.
  • Figure 1 is an X-ray powder diffraction spectrum of a new crystalline form of dapagliflozin.
  • Figure 2 is an X-ray powder diffraction spectrum of the new crystalline form of dapagliflozin after tableting.
  • Example 1 The crystal form sample obtained in Example 1 was placed under accelerated test conditions for 6 months, and the quality indexes of the samples did not change significantly, which met the quality standard, and the maximum single impurity range was 0.02% to 0.05%, and the total impurity range was 0.10. % ⁇ 0.14%, the content range is 99.3% ⁇ 99.7%.
  • the specific data is shown in Table 1.
  • Example 2 The crystal form sample obtained in Example 1 was placed under long-term test conditions for 6 months, and the quality indexes of the samples did not change significantly, which met the quality standard: the maximum single impurity range was 0.02% to 0.05%%, and the total miscellaneous range was 0.10% to 0.15%, and the content ranges from 99.3% to 99.7%.
  • the specific data is shown in Table 2.
  • Example 3 The crystal form sample obtained in Example 1 was subjected to a wettability test, and the results are shown in Table 3 below.

Abstract

本发明涉及式(I)所示的达格列净的新晶型，这种晶型在以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱中在约4.318(20.45)处具有特征吸收峰，可以通过将达格列净溶解在良性有机溶剂中，再加入不良溶剂搅拌析晶，过滤，干燥而制得。本发明的达格列净新晶型具有以下优良特性：溶解性好，引湿性小，稳定性高，制备可重现性好。

Description

达格列净新特晶型及其制备方法 技术领域
本发明属于多晶型药物制备技术领域，具体涉及一种达格列净的新晶型及其制备方法。
背景技术
达格列净(Dapagliflozin)是由Bristol-Myers Squibb/AstraZeneca开发的，用于治疗II型糖尿病的药物(钠-葡萄糖协同转运蛋白-2(SGLT-2)抑制剂)。
2010年12月，Bristol-Myers Squibb/AstraZeneca向EMA提交申请。2012年4月，欧洲人用药务委员会推荐批准达格列净用于治疗II型糖尿病的申请。
2010年12月，同样向FDA提交申请。2012年1月，FDA发出回应函，要求增加临床数据。
达格列净(Dapagliflozin)，化学名为2-氯-5-(β-D-吡喃葡萄糖-1-基)-4’-乙氧基二苯甲烷，其化学结构如下：
Figure PCTCN2015071009-appb-000001
到目前为止，在有关达格列净晶型方面的报道中，仅有原研晶型专利(CN101479287)报道了9种晶型：其为达格列净溶剂化物和达格列净氨基酸络合物，均被保护。具体内容如下：
Figure PCTCN2015071009-appb-000002
Figure PCTCN2015071009-appb-000003
发明内容
本发明的目的在于提供一种新的、特异的达格列净晶型。
本发明的如式(I)所示的达格列净的新晶型的X-射线粉末衍射(XRPD)图谱如图1所示，
Figure PCTCN2015071009-appb-000004
该晶型在以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱中在约4.318(20.45)处具有特征吸收峰。
本发明的另一目的在于提供一种本发明所述的达格列净的新晶型的制备方法，包括在0℃～30℃温度，由达格列净在有机溶剂体系中制得。
在本发明的一个优选的实施方案中，将达格列净溶解在良性有机溶剂中，加入不良溶剂，然后搅拌析晶，过滤，于0～30℃干燥，即得目标晶型。
在本发明另一个优选的实施方案中，所述良性有机溶剂选自醚类溶剂，优选***或甲基叔丁基醚。
在本发明另一个优选的实施方案中，所述不良有机溶剂选自烷烃类溶剂，优选正己烷或正庚烷。
优选，反应温度为10～20℃。
优选，搅拌析晶时间为1.5～2小时。
优选，干燥温度为10～30℃。
优选，所述干燥为真空干燥。
进一步地，制备达格列净晶型的方法为：将达格列净溶解良性有机溶剂中，再加入达格列净不良溶剂，搅拌析晶，经过滤、干燥，制得达格列净晶型。
进一步地，采取的具体方案如下：将达格列净溶解在良性有机溶剂中，再加入达格列净不良溶剂，加完后在30℃以下继续搅拌析晶1.5～2小时，过滤，0～30℃真空干燥，即得达格列净晶型样品。
本发明提供了一种制备达格列净晶型的新方法，该方法具有溶解性好、引湿性小、工艺稳定、可操作性强、收率高、制备可重现性好，而且所得晶型性质稳定，适合医药开发应用等优点。
附图说明
图1为达格列净新晶型的X-射线粉末衍射谱图。
图2为达格列净新晶型在压片后的X-射线粉末衍射谱图。
具体实施方式
实施例1：达格列净新晶型的制备
称取达格列净(0.5g)，加入***(4.5ml)中，搅拌溶清，加入正己烷(20ml)，瓶壁有白色油状物粘附，继续搅拌，1.5h后过滤、抽干，得0.42g产物(白色粉末状固体)。经XRPD测定，图谱如图1所示。
实施例2：达格列净新晶型的制备
称取达格列净(0.5g)，加入甲基叔丁基醚(3ml)中，搅拌溶清，加入正己烷(10ml)，瓶壁有白色油状物粘附，继续搅拌，2h后过滤、抽干，得0.33g产物(白色粉末状固体)。经XRPD测定，图谱基本与图1吻合。
实施例3：达格列净新晶型的制备
称取达格列净(0.5g)，加入甲基叔丁基醚(3ml)中，搅拌溶清，加入正庚烷(10ml)，瓶壁有白色油状物粘附，继续搅拌，2h后过滤、 抽干，得0.35g产物(白色粉末状固体)。经XRPD测定，图谱基本与图1吻合。
实验例1：稳定性研究试验结果
1、加速试验
将实施例1所得晶型样品于加速试验条件下放置6个月，样品的各项质量指标未发生明显变化，符合质量标准规定，最大单杂范围为0.02％～0.05％，总杂范围为0.10％～0.14％，含量范围为99.3％～99.7％。具体数据见表1。
考察条件：30℃±2℃/RH 65％±5％
包装：两层药用低密度聚乙烯袋，分别热熔封口，加干燥剂，外加聚酯/铝/聚酰胺/流延聚丙烯药品包装用复合膜袋封口包装。
表1  加速试验考察结果
Figure PCTCN2015071009-appb-000005
2、长期试验
将实施例1所得晶型样品于长期试验条件下放置6个月，样品的各项质量指标未发生明显变化，符合质量标准规定：最大单杂范围为0.02％～0.05％％，总杂范围为0.10％～0.15％，含量范围为99.3％～99.7％。具体数据见表2。
考察条件：21℃±2℃/RH 45％±5％
包装：两层药用低密度聚乙烯袋，分别热熔封口，加干燥剂，外加聚酯/铝/聚酰胺/流延聚丙烯药品包装用复合膜袋封口包装。
表2  长期试验考察结果
Figure PCTCN2015071009-appb-000006
3、晶型研磨或压片后的稳定性比较研究
从图2可以看出，本发明晶型经过压片后未发生转晶，表明本发明晶型在压片条件下是稳定的，同样的试验中，晶型在研磨和粉碎后通过XRPD图谱显示，也未发生转晶。
实验例2 晶型引湿性效果
取实施例1所得晶型样品进行引湿性试验，其结果如下表3。
表3  吸湿增重试验考察结果
Figure PCTCN2015071009-appb-000007

Claims (9)

  1. 一种式(I)所示的达格列净的新晶型，
    Figure PCTCN2015071009-appb-100001
    其特征在于：所述晶型的X-射线粉末衍射图谱如图1所示，在以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱中在约4.318(20.45)处具有特征吸收峰。
  2. 一种如权利要求1所述的式(I)所示的达格列净的新晶型的制备方法，其特征在于：在0℃～30℃温度，由达格列净在有机溶剂体系中制得。
  3. 根据权利要求2所述的制备方法，其特征在于：将达格列净溶解在良性有机溶剂中，加入不良溶剂，然后搅拌析晶，过滤，于0～30℃干燥，即得目标晶型。
  4. 根据权利要求3所述的制备方法，其特征在于：所述良性有机溶剂选自醚类溶剂，优选***或甲基叔丁基醚。
  5. 根据权利要求3所述的制备方法，其特征在于：所述不良溶剂选自烷烃类溶剂，优选正己烷或正庚烷。
  6. 根据权利要求2所述的制备方法，其特征在于：反应温度为10～20℃。
  7. 根据权利要求3所述的制备方法，其特征在于：搅拌析晶时间为1.5～2小时。
  8. 根据权利要求3所述的制备方法，其特征在于：干燥温度为10～30℃。
  9. 根据权利要求3所述的制备方法，其特征在于：所述干燥为真空干燥。
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US10464915B2 (en) 2016-05-24 2019-11-05 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dapagliflozin crystal form and preparation method and use thereof
EP3466939A4 (en) * 2016-05-24 2019-12-18 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. NOVEL CRYSTALLINE FORM OF DAPAGLIFLOZIN, ITS PREPARATION METHOD AND ITS USE
JP7007300B2 (ja) 2016-05-24 2022-01-24 江▲蘇▼豪森▲薬▼▲業▼集▲団▼有限公司 ダパグリフロジンの新規な結晶形並びにその製造方法および用途
WO2018097570A3 (ko) * 2016-11-24 2018-08-09 한미약품 주식회사 다파글리플로진 l-프롤린을 포함하는 약제학적 제제

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