WO2019091373A1 - 一种盐酸苯达莫司汀的晶体及其制备方法 - Google Patents

一种盐酸苯达莫司汀的晶体及其制备方法 Download PDF

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WO2019091373A1
WO2019091373A1 PCT/CN2018/114148 CN2018114148W WO2019091373A1 WO 2019091373 A1 WO2019091373 A1 WO 2019091373A1 CN 2018114148 W CN2018114148 W CN 2018114148W WO 2019091373 A1 WO2019091373 A1 WO 2019091373A1
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bendamustine hydrochloride
crystal
hydrochloride
angle
bendamustine
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PCT/CN2018/114148
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French (fr)
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王立坤
杜振兴
高猛
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江苏恒瑞医药股份有限公司
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Priority to CN201880059253.2A priority Critical patent/CN111093654B/zh
Publication of WO2019091373A1 publication Critical patent/WO2019091373A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a crystal of bendamustine hydrochloride and a process for the preparation thereof, which are useful in the preparation of a medicament for treating diseases such as cancer.
  • Bendamustine hydrochloride is an alkylated antitumor drug developed and marketed by Cephalon in the United States under the trade name
  • the dosage form has a lyophilized powder preparation and a concentrate preparation, and is clinically used for the single treatment or combined use of breast cancer, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, plasmacytoma.
  • Clinical application shows that the treatment of breast cancer alone or in combination is effective, can significantly reduce the recurrence rate and mortality, and has small adverse reactions and good safety.
  • Bendamustine hydrochloride has a variety of crystalline forms.
  • CN101980698A discloses crystalline forms 1, 2, 3 and 4 of bendamustine hydrochloride. Wherein the crystal forms of 1, 3 and 4 are in the form of an anhydride and the form 2 is in the form of a monohydrate.
  • CN102351799A discloses crystal form I of bendamustine hydrochloride.
  • One aspect of the present invention provides a crystal of bendamustine hydrochloride having an angle of repose ⁇ of not more than 45°, for example, an angle of repose of not less than 44°, 43°, 42°, 41°, 40°, 39°, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26 or 25.
  • the crystal has a shape factor of from 0.4 to 1, preferably from 0.6 to 1.
  • the crystal is spherical or ellipsoidal.
  • the bendamustine hydrochloride is an anhydrate.
  • the bendamustine hydrochloride is a hydrate, such as a monohydrate.
  • the bendamustine hydrochloride crystal is characterized by: using Cu-K ⁇ radiation, obtaining an X-ray powder diffraction pattern expressed by a diffraction angle 2 ⁇ angle, which is 10.010, 10.503 at a 2 ⁇ angle, There are characteristic peaks at 11.273, 12.372, 13.543, 14.983, 19.990, 20.102, 20.655 and 22.831.
  • an X-ray powder diffraction pattern at an angle of diffraction 2 ⁇ is obtained, which is 10.010, 10.503, 11.273, 12.372, 13.543, 14.983, 19.990, 20.102 at 2 ⁇ angles, There are characteristic peaks at 20.655, 22.831, 24.911, 26.116, 27.311, 28.632, 30.214, 30.556, 31.472, 34.540 and 40.825.
  • Cu-K ⁇ radiation is used and the resulting X-ray powder diffraction pattern is shown in FIG.
  • the bendamustine hydrochloride may be a crystal form of bendamustine hydrochloride 1, a crystal form, a 3-crystal form, a 4-crystal form, a 4-crystal form, or the like, preferably a 2-crystal form.
  • the amount of bendamustine hydrochloride (in percent by weight) of the bendamustine hydrochloride crystals may be greater than 90%, or greater than 92%, or greater than 93%, or greater than 94. %, or greater than 95%, or greater than 96%, or greater than 97%, or greater than 98%, or greater than 99%.
  • the present invention provides a bendamustine hydrochloride crystal having an angle of repose ⁇ of no greater than 45°, preferably no greater than 35°, more preferably no greater than 30°, and a shape factor of 0.4- 1, preferably 0.6-1, wherein the bendamustine hydrochloride is in the form 2, wherein the content of bendamustine hydrochloride (in weight percent) is greater than 95%, preferably greater than 97%.
  • Another aspect of the present invention provides a method for preparing crystals of bendamustine hydrochloride, which comprises mixing bendamustine hydrochloride with a solvent under stirring to precipitate crystals of bendamustine hydrochloride.
  • the solvent may be one or more of a C 1 -C 6 alkyl alcohol (for example, methanol, ethanol, isopropanol, etc.), water, and isopropyl acetate.
  • a C 1 -C 6 alkyl alcohol for example, methanol, ethanol, isopropanol, etc.
  • water for example, water, and isopropyl acetate.
  • the bendamustine hydrochloride is first dissolved in an A solvent, which may be one or more of a C 1 -C 6 alkyl alcohol and water, and then mixed with the B solvent.
  • the B solvent may be isopropyl acetate, and the crystal of bendamustine hydrochloride is precipitated.
  • the bendamustine hydrochloride is first dissolved in an A solvent, which may be one or more of a C 1 -C 6 alkyl alcohol and water, and the B solvent is added to the system.
  • the B solvent may be isopropyl acetate, and the crystal of bendamustine hydrochloride is precipitated.
  • the concentration of the added bendamustine hydrochloride may be from 1 to 500 mg/ml, preferably from 50 to 150 mg/ml.
  • the stirring speed may be from 100 r/min to 1000 r/min.
  • the reaction temperature of the process may range from 0 °C to 60 °C, preferably from 0 °C to 40 °C.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the bendamustine hydrochloride crystals of the invention, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a pharmaceutical composition prepared by mixing crystals of bendamustine hydrochloride according to the invention with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the invention further relates to a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal of bendamustine hydrochloride according to the invention, which comprises crystallizing bendamustine hydrochloride according to the invention with one or more pharmaceutically An acceptable carrier, diluent or excipient is mixed.
  • compositions of the present invention can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the crystal or pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, crystals, solutions, suspensions, syrups, injections (including injections, sterile powder for injection and concentrated solutions for injection) , suppositories, inhalants or sprays.
  • the present invention further relates to a drug substance of bendamustine hydrochloride comprising the crystal of bendamustine hydrochloride according to the present invention.
  • the content of the bendamustine hydrochloride crystals may be greater than 50%, preferably greater than 70%, more preferably greater than 80%, and most preferably greater than 90%, based on the total weight of the drug substance.
  • Another aspect of the present invention provides a powder-liquid multi-chamber infusion bag product comprising at least one powder chamber and at least one liquid chamber, wherein the powder chamber comprises bendamustine hydrochloride according to the present invention
  • the crystal, liquid chamber comprises one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the powder chamber and the liquid chamber may be separated by a plurality of weakly welded separator strips.
  • the present invention further relates to the use of the bendamustine hydrochloride crystal, pharmaceutical composition or drug substance of the present invention for the preparation of a medicament for treating cancer, such as chronic lymphocytic leukemia, Hodgkin's disease, Non-Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma or breast cancer.
  • cancer such as chronic lymphocytic leukemia, Hodgkin's disease, Non-Hodgkin's lymphoma, mantle cell lymphoma, multiple myeloma or breast cancer.
  • the crystal obtained by the present invention was subjected to structure measurement and crystal form study by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the starting material used in the crystal preparation method of the present invention may be any form of bendamustine hydrochloride, and specific forms include, but are not limited to, amorphous, any crystal form, any hydrate or solvate, and the like.
  • the "differential scanning calorimetry or DSC” as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change to get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" as used in the present invention means the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.3 or ⁇ 0.2 or ⁇ 0.1.
  • the "plane spacing or interplanar spacing (d value)" means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points.
  • the parallelepiped unit which is divided into juxtapositions, is called the interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice.
  • the lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different; Or ang.
  • the "rest angle” as used in the present invention refers to the maximum angle measured by the gravity and the friction between the particles when the particles slide on the free slope of the powder accumulation layer in the gravitational field.
  • the angle of repose of the particles is determined by a funnel method, and the particulate material falls from the funnel and falls on the plane to form a cone, and the cone bottom angle is the angle of repose.
  • the calculation formula is:
  • h and r are the height and radius of the cone, respectively.
  • the "form factor” according to the present invention is a parameter reflecting the shape of the particle, that is, reflecting the degree of the difference between the cross-sectional shape of the particle and the circle, and the degree of irregularity.
  • the calculation formula is:
  • Area represents the cross-sectional area of the particle and Perimeter represents the perimeter of the cross-section of the particle.
  • Perimeter represents the perimeter of the cross-section of the particle.
  • the bendamustine hydrochloride crystal prepared by the invention has good fluidity, good solubility, rapid reconstitution, high crystal form purity, good crystal form stability under illumination, high temperature and high humidity conditions, in preparation, storage and It is stable in the drying process and has excellent biocompatibility. It can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable, reproducible and controllable, and can be adapted to industrial production.
  • the crystal of bendamustine hydrochloride can be quickly dissolved in the liquid diluent, which avoids the disadvantages of time-consuming and easy contamination of the drug during the preparation of the injection, and can be better applied to the clinic.
  • Example 1 is an XRPD pattern of crystal form of bendamustine hydrochloride obtained in Example 1;
  • Example 2 is a DSC chart of crystal form of bendamustine hydrochloride obtained in Example 1;
  • Example 3 is a TGA pattern of crystal form of bendamustine hydrochloride obtained in Example 1;
  • Example 4 is a photomicrograph of the crystal of bendamustine hydrochloride obtained in Example 1;
  • Figure 5 is a photomicrograph of the crystalline form of bendamustine hydrochloride 2 prepared according to the method of CN101980698A.

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Abstract

本发明涉及一种盐酸苯达莫司汀的晶体及其制备方法。本发明的晶体具备优异的流动性，可更好地用于生产和临床治疗。

Description

一种盐酸苯达莫司汀的晶体及其制备方法
本申请要求申请日为2017年11月07日的中国专利申请CN201711084907.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种盐酸苯达莫司汀的晶体及其制备方法，其在制备用于治疗癌症等疾病的药物中的用途。
背景技术
盐酸苯达莫司汀(bendamustine hydrochloride)是一种烷化抗肿瘤药物，在美国由Cephalon公司开发并上市，商品名为
Figure PCTCN2018114148-appb-000001
剂型有冻干粉制剂以及浓缩液制剂，临床用于乳腺癌、慢性淋巴细胞性白血病、非霍奇金淋巴瘤、霍奇金病、浆细胞瘤的单独治疗或联合用药。临床应用表明，其单独治疗或联合用药治疗乳腺癌，疗效确切，能明显降低复发率与死亡率，且不良反应小，安全性好。
Figure PCTCN2018114148-appb-000002
盐酸苯达莫司汀具有多种晶体形式。CN101980698A公开了盐酸苯达莫司汀的1、2、3和4晶型。其中1、3和4晶型是无水物形式，2晶型是一水合物形式。CN102351799A公开了盐酸苯达莫司汀的晶体I晶型。通过对专利报道的这些盐酸苯达莫司汀晶型进行研究，发现这些晶型大多为条状或粉末状晶体，普遍存在流动性差、稳定性不高的问题，这些缺点增加了制剂产品的制备难度。
发明内容
本发明的目的在于提供一种盐酸苯达莫司汀的新的晶体形式，该晶体具备良好的流动性，可更好地应用于药物的制备和临床使用。
本发明一方面提供了一种盐酸苯达莫司汀晶体，其休止角θ不大于45°，例如其休止角可以不大于44°、43°、42°、41°、40°、39°、38°、37°、36°、35°、34°、33°、32°、31°、30°、29°、28°、27°、26°或25°。
在某些实施方式中，所述晶体的形状因子为0.4-1，优选0.6-1。
在某些实施方式中，所述晶体为球形或椭球形。
在某些实施方式中，所述的盐酸苯达莫司汀为无水物。
在某些实施方式中，所述的盐酸苯达莫司汀为水合物，例如一水合物。
在某些实施方式中，所述的盐酸苯达莫司汀晶体特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在2θ角为10.010、10.503、11.273、12.372、13.543、14.983、19.990、20.102、20.655和22.831处有特征峰。
在一个优选的实施方案中，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在2θ角为10.010、10.503、11.273、12.372、13.543、14.983、19.990、20.102、20.655、22.831、24.911、26.116、27.311、28.632、30.214、30.556、31.472、34.540和40.825处有特征峰。
在一个优选的实施方案中，使用Cu-Kα辐射，得到的X-射线粉末衍射图谱如图1所示。
在某些实施方式中，所述的盐酸苯达莫司汀可以是盐酸苯达莫司汀1晶型、2晶型、3晶型、4晶型、I晶型等，优选2晶型。
在某些实施方式中，所述的盐酸苯达莫司汀晶体中盐酸苯达莫司汀的含量(以重量百分比计)可以大于90％，或大于92％，或大于93％，或大于94％，或大于95％，或大于96％，或大于97％，或大于98％，或大于99％。
在某些优选的实施方式中，本发明提供一种盐酸苯达莫司汀晶体，其休止角θ为不大于45°，优选不大于35°，更优选不大于30°，形状因子为0.4-1，优选0.6-1，所述盐酸苯达莫司汀为2晶型，其中盐酸苯达莫司汀的含量(以重量百分比计)大于95％，优选大于97％。
本发明另一方面提供一种制备盐酸苯达莫司汀晶体的方法，所述方法包括：在搅拌条件下将盐酸苯达莫司汀与溶剂混合，析出盐酸苯达莫司汀晶体。
其中，所述溶剂可以是C 1-C 6烷基醇(例如甲醇、乙醇、异丙醇等)、水和醋酸异丙酯中的一种或多种。
在某些实施方式中，先将盐酸苯达莫司汀溶于A溶剂中，所述A溶剂可以是C 1-C 6烷基醇和水中的一种或多种，再与B溶剂混合，所述B溶剂可以是醋酸异丙酯，析出盐酸苯达莫司汀晶体。
在某些实施方式中，先将盐酸苯达莫司汀溶于A溶剂中，所述A溶剂可以是C 1-C 6烷基醇和水中的一种或多种，再将B溶剂加入体系中，所述B溶剂可以是醋酸异丙酯，析出盐酸苯达莫司汀晶体。
所述加入的盐酸苯达莫司汀的浓度可以为1-500mg/ml，优选50-150mg/ml。
所述的搅拌速度可以是100r/min-1000r/min。
所述方法的反应温度可以为0℃-60℃，优选0℃-40℃。
本发明进一步涉及一种药物组合物，其包含本发明所述的盐酸苯达莫司汀晶体，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明进一步涉及一种药物组合物，其由本发明所述的盐酸苯达莫司汀晶体，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合制得。
本发明进一步涉及一种包含本发明所述的盐酸苯达莫司汀晶体的药物组合物的制备方法，其包括将本发明所述的盐酸苯达莫司汀晶体与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
本发明所述药物组合物可以制成药学上可接受的任一剂型。例如，本发 明的晶体或药物制剂可以配制为片剂、胶囊剂、丸剂、晶体剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本发明进一步涉及一种盐酸苯达莫司汀的原料药，其包含本发明所述的盐酸苯达莫司汀晶体。基于原料药的总重量，所述盐酸苯达莫司汀晶体的含量可以大于50％，优选大于70％，更优选大于80％，最优选大于90％。
本发明另一方面提供了一种粉-液多室输液袋产品，其包括至少一个粉体腔室和至少一个液体腔室，其中粉体腔室包含本发明所述的盐酸苯达莫司汀晶体，液体腔室包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
其中，所述粉体腔室和所述液体腔室可以通过若干条弱焊分隔条隔离。
本发明进一步涉及本发明所述的盐酸苯达莫司汀晶体、药物组合物或原料药在制备用于治疗癌症的药物中的用途，所述癌症例如慢性淋巴细胞白血病、霍奇金氏病、非霍奇金氏淋巴瘤、套细胞淋巴瘤、多发性骨髓瘤或乳腺癌。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对本发明所得到晶体进行结构测定、晶型研究。
本发明晶体制备方法中所用的起始原料可以是任意形式的盐酸苯达莫司汀，具体形式包括但不限于：无定形、任意晶型、任意水合物或溶剂合物等。
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2018114148-appb-000003
衍射的级数n为任何正整 数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方程，从而测得了这组X射线粉末衍射图。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.3或±0.2或±0.1。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2018114148-appb-000004
或埃。
本发明所述的“休止角”是指在重力场中，粒子在粉体堆积层的自由斜面上滑动时所受重力和粒子之间摩擦力达到平衡而处于静止状态下测得的最大角。采用漏斗法测定粒子的休止角，微粒物料由漏斗流出落于平面上形成圆锥体，锥底角即为休止角。计算公式为：
Figure PCTCN2018114148-appb-000005
其中，h和r分别为圆锥的高和半径。
本发明所述的“形状因子”(Form factor)是反映粒子形状的参数，即反映粒子截面形状与圆相差的程度及不规则程度，计算公式为：
Figure PCTCN2018114148-appb-000006
其中，Area表示粒子截面积，Perimeter表示粒子截面周长。当粒子呈圆形时，形状因子为1.0，当粒子形状偏离圆形时，其值小于1.0。粒子的形 状越不规则，形状因子数值就越小，即表示粒子偏离圆形越远。
发明的有益效果
本发明制备的盐酸苯达莫司汀晶体具有流动性好，溶解性好，复溶迅速，晶型纯度高，在光照、高温、高湿的条件下晶型稳定性好，在制备、存储和干燥过程中很稳定，生物相容性优异，能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。当用于粉液双室袋制剂时，盐酸苯达莫司汀晶体可快速溶于液体稀释剂，避免了注射剂配置过程中的耗时和容易污染药品等缺点，能够更好的应用于临床。
附图说明
图1为实施例1所得的盐酸苯达莫司汀晶体晶型的XRPD图谱；
图2为实施例1所得的盐酸苯达莫司汀晶体晶型的DSC图谱；
图3为实施例1所得的盐酸苯达莫司汀晶体晶型的TGA图谱；
图4为实施例1所得盐酸苯达莫司汀晶体的显微照片；
图5为根据CN101980698A方法制备的盐酸苯达莫司汀2晶型的显微照片。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
试验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 3 +STAR e System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：BRUKER D8 Discover A25X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40°
电压：40KV，电流：40mA
3、热重分析仪(Thermal Gravimetric Analyzer)
仪器型号：Mettler Toledo TGA
升温速率：10℃/min
氮气吹扫速度：60mL/min
4、光学显微镜(Optical Microscope)
仪器型号：Nikon高通量显微成像平台Ti-E
实施例1
将盐酸苯达莫司汀20mg加入到200μl的甲醇和水的混合溶剂中溶解，其中甲醇和水的体积比为1:1，将上述溶液在搅拌下滴加3ml的醋酸异丙酯，保持室温，析出盐酸苯达莫司汀晶体。该晶体样品的X-射线衍射图谱见图1，其DSC谱图见图2，其TGA谱图见图3，显微照片见图4。经测定确认为盐酸苯达莫司汀2晶型，其特征峰位置如下表所示：
表1、盐酸苯达莫司汀晶体晶型特征峰
Figure PCTCN2018114148-appb-000007
Figure PCTCN2018114148-appb-000008
实施例2
将盐酸苯达莫司汀2.5mg加入到100μl的乙醇和水的混合溶剂中溶解，其中乙醇和水的体积比为1:1，将上述溶液在搅拌下滴加3ml的醋酸异丙酯，保持室温，析出盐酸苯达莫司汀晶体。该晶体经XRPD检测确定产物为2晶型。
实施例3
根据CN101980698A的方法，采用快速蒸发进行苯达莫司汀的晶体，溶剂为乙酸，得到盐酸苯达莫司汀2晶型，其显微照片如图5所示。
实施例4
根据国家标准GB11986-89关于《表面活性剂粉体和颗粒休止角的测量》 的规定(粉体和颗粒的休止角均可参照此规定测量)，搭建休止角测试装置。三次平行测试，测得实施例1所得盐酸苯达莫司汀晶体的休止角分别为：29.84°，27.05°和25.55°；而实施例3所得盐酸苯达莫司汀晶体的休止角分别为：48.21°，49.22°和49.64°。

Claims (18)

  1. 一种盐酸苯达莫司汀晶体，其休止角θ不大于45°。
  2. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，所述晶体的形状因子为0.4-1，优选0.6-1。
  3. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，所述的晶体为球形或椭球形。
  4. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在2θ角为10.010、10.503、11.273、12.372、13.543、14.983、19.990、20.102、20.655和22.831处有特征峰。
  5. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在2θ角为10.010、10.503、11.273、12.372、13.543、14.983、19.990、20.102、20.655、22.831、24.911、26.116、27.311、28.632、30.214、30.556、31.472、34.540和40.825处有特征峰。
  6. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，使用Cu-Kα辐射，得到的X-射线粉末衍射图谱如图1所示。
  7. 根据权利要求1所述的盐酸苯达莫司汀晶体，其特征在于，所述的盐酸苯达莫司汀晶体中盐酸苯达莫司汀的含量(以重量百分比计)大于90％，优选大于95％，更优选大于97％，最优选大于99％。
  8. 一种盐酸苯达莫司汀晶体，其休止角θ不大于45°，优选不大于35°，更优选不大于30°；形状因子为0.4-1，优选0.6-1；其中，所述盐酸苯达莫司汀晶体使用Cu-Kα辐射，得到的X-射线粉末衍射图谱如图1所示；盐酸苯达莫司汀的含量(以重量百分比计)大于95％，优选大于97％。
  9. 一种制备如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体的方法，其包括：在搅拌条件下将盐酸苯达莫司汀与溶剂混合，其中，所述溶 剂选自C 1-C 6烷基醇、水和醋酸异丙酯中的一种或多种，优选甲醇、乙醇、水和醋酸异丙酯中的一种或多种。
  10. 根据权利要求9所述的制备方法，其特征在于，所述的盐酸苯达莫司汀的浓度为1-500mg/ml，优选50-150mg/ml。
  11. 根据权利要求9所述的制备方法，其特征在于，所述方法的反应温度为0℃-60℃。
  12. 一种药物组合物，其包含如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
  13. 一种药物组合物，其由权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合制得。
  14. 一种盐酸苯达莫司汀的原料药，其包含如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体，基于原料药的总重量，所述盐酸苯达莫司汀晶体的含量大于50％，优选大于70％，更优选大于80％，最优选大于90％。
  15. 一种包含盐酸苯达莫司汀的药物组合物的制备方法，其包括将如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体，与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
  16. 一种如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体、如权利要求12和13中任意一项所述的药物组合物或如权利要求14所述的盐酸苯达莫司汀的原料药在制备用于治疗癌症的药物中的用途，所述癌症优选慢性淋巴细胞白血病、霍奇金氏病、非霍奇金氏淋巴瘤、套细胞淋巴瘤、多发性骨髓瘤或乳腺癌。
  17. 一种粉-液多室输液袋产品，其包括至少一个粉体腔室和至少一个液体腔室，其中粉体腔室包含如权利要求1-8中任意一项所述的盐酸苯达莫司汀晶体，液体腔室包含一种或多种药学上可接受的载体、稀释剂或赋形剂。
  18. 根据权利要求17所述的粉-液多室输液袋产品，其特征在于，所述粉体腔室和所述液体腔室通过若干条弱焊分隔条隔离。
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Publication number Priority date Publication date Assignee Title
CN101980698A (zh) * 2008-03-26 2011-02-23 赛福伦公司 新的盐酸苯达莫司汀固体形式

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CN101980698A (zh) * 2008-03-26 2011-02-23 赛福伦公司 新的盐酸苯达莫司汀固体形式

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