CN105849093A - 卡巴他赛无水结晶形式、其制备方法和药用组合物 - Google Patents
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Abstract
本发明涉及式(I)的卡巴他赛的新的无水晶型,称为H型。本发明的另一个目的是上述H型的制备方法,通过将卡巴他赛在癸酰基‑和辛酰基甘油三酯的混合物中或者在三辛酸甘油酯中重结晶制备。卡巴他赛的H型用于制备卡巴他赛、卡巴他赛盐及其多晶型。其也可以特别用作药物,尤其是用于治疗癌症。
Description
技术领域
本发明涉及卡巴他赛的新的无水结晶形式、其制备方法及其药用组合物。
背景技术
卡巴他赛为天然紫杉烷10-脱乙酰基巴卡丁III的半合成衍生物,其在商业上为丙酮溶剂化物形式。其能够稳定微管,最终导致增殖细胞的有丝分裂阻滞。其在美国已经被批准用于多西他赛类治疗后的耐激素性前列腺癌的二线治疗药物。
卡巴他赛具有下列结构式(I):
其化学名为4α-乙酰氧基-2α-苯甲酰氧基-5β,20-环氧-1β-羟基-7β,10β-二甲氧基-9-氧代-11-紫杉烯(taxen)-13α-基(2R,3S)-3-叔-丁氧基羰基氨基-2-羟基-3-苯基丙酸酯。
卡巴他赛及其制备方法公开于WO 96/30355和WO 99/25704。
WO 2005/028462描述了卡巴他赛的丙酮溶剂化物,有时也称为A型。尽管丙酮溶剂化物的结晶是除去杂质的有效方法,然而更好的药物形式应当是不含结晶溶剂的纯卡巴他赛。
被称为I型(甲苯溶剂化物)、II型(甲基叔丁基醚溶剂化物)、III型(2-异丙醇溶剂化物)、IV型(1-丁醇溶剂化物)、V型(1-丙醇溶剂化物)和无定形的卡巴他赛的其它结晶溶剂化物形式的粉末状、非泡沫状形式公开于WO 2012/142117(Teva)。溶剂化物很少用于制药,因为溶剂化物具有挥发性,所以在结晶中难以保持溶剂。如果API由于储存条件或其它因素去溶剂化,则可能导致具有不同物理性质的多晶型物的形成。此外,无定形固体是亚稳态的,可能随着时间的推移而形成具有不同物理性质的多晶型物。
WO 2009/115655(Sanofi)公开了5种无水形式的化合物,称为B、C、D、E和F型;三种乙醇溶剂化物,称为乙醇化的B、D、E型;乙醇/水混合溶剂化物F型;一水合物-无溶剂C型和二水合物-无溶剂C型。这些形式达到高纯度的唯一可能性是通过其它技术预先纯化API,例如通过丙酮溶剂化物(如本申请中所述)。然而采用其它纯化技术可能由于较长的生产时间和较低的收率而影响了生产过程的效率。
WO 2013/134534公开了卡巴他赛溶剂化物结晶,其包含:
-烷基乙酸酯类,例如含有乙酸乙酯(VII型)、乙酸异丙酯(VIII型)、乙酸甲酯(XVII型)、乙酸丁酯(XVIII型)和乙酸异丁酯(XXI型)的溶剂化物;
-酮类,例如含有甲基乙基酮(IX型)和甲基异丁基酮(X型)的溶剂化物;
-醇类,例如含有2-丁醇(XI型)、异丁醇(XII型)和戊醇(XIII型)的溶剂化物。
WO 2013/134534还公开了含有二氧戊环(XIV型)、1,4-二氧六环(XV型)、1,2-丙二醇(XIX型)、丙三醇(XX型)和1,3-二甲基-2-咪唑烷酮(XXII型)的溶剂化物。还公开了被称为XVI型的结晶的卡巴他赛形式,其可以是无水的。
卡巴他赛的结晶的乙酸乙酯溶剂化物也公开于WO 2013/088335中。
W O2009/115655公开了该化合物的两种水合物形式,特别是一水和二水合物,两种水合物形式均通过暴露于水分而获自无水C型。只能通过丙酮溶剂化物获得高纯度的上述无水C型。
通过丙酮/水获得的卡巴他赛的晶型公开于CN 102675257A中。
被称为C1、C2、C3、C4、C5、C6、C7、C8、C8b、C9和C9p的卡巴他赛的晶型(包括无水物形式)公开于WO 2013/034979。
最后,被称为晶型-1、晶型-2、晶型-3、晶型-4、晶型-5、晶型-6、晶型-7、晶型-8、晶型-9、晶型-10、晶型-11、晶型-12和晶型13的13种晶型公开于WO 2013/0109870。
人们仍然需要发现能够解决上述问题的新的晶型。
发明内容
发明简述
本发明的目的是卡巴他赛的新的无水晶型,称为H型。本发明的另一个目的是制备上述晶型及其药用组合物的方法。
在本发明中,术语“无水”是指含有低于1%的被吸附水分(通过KarlFisher分析测定)的卡巴他赛的晶型。
H型为卡巴他赛的无水晶型,其通过使得卡巴他赛在已知商品名为812的癸酰基-和辛酰基甘油三酯(CAS number 52622-27-2)的混合物中结晶获得,或者在甘油三辛酸酯中结晶获得。
附图说明
图1卡巴他赛的结晶H型的X-RPD图谱
图2在4000-550cm-1光谱范围内的卡巴他赛的无水结晶H型的FTIR光谱
图3卡巴他赛的无水结晶H型的TG和DTA图谱
图4卡巴他赛的无水结晶H型的DSC图谱
发明详述
本发明的卡巴他赛H型特征在于采用铜波长分别为和的λ1和λ2获得的X-射线粉末衍射(X-RPD)图谱,基本上如图1所示。X-RPD图谱显示晶体结构,以2-θ角的值表示,在下列位置具有独特的反射:5.8、6.5、8.1、9.5、10.9、11.5、12.2、13.0、14.1、14.8、16.8、17.2、19.0、19.4、20.1、21.9和24.0±0.2。
如图1中表示的X-RPD图谱通过TOPAS采用正交晶单胞和可能的空间群P212121编录索引。Pawley精修获得Rwp=7.065%,具有下列晶胞参数:α=β=γ=90°、 和空间群P212121,与该晶胞中存在4个分子一致。
H型还可以通过傅里叶变换红外光谱法(FTIR)的光谱在4000-550cm-1光谱范围内以ATR模式表征,基本上如图2所示。H型的FTIR光谱在下列频率具有特征吸收:3615、3449、3060、2982、2939、2893、2826、1742、1711、1489、1450、1390、1368、1315、1273、1263、1247、1172、1098、1071、1027、989、947、919、883、832、802、781、718、704、675和637±4cm-1。
H型还可以通过热重分析(TG)和差热分析(DTA)图谱定性,如图3所示。DTA图谱通过熔化峰表征,起始于约184℃,最高为192.9℃,随后由于分解而出现强烈的放热峰。
在TG图谱中,直到融化开始才出现失重现象与无残留溶剂的无水产物一致。
H型还可以通过DSC图谱进一步表征,如图4所示。DSC图谱与DT信号一致,显示通过熔化峰定性的热图谱,该峰起始于187.4℃,最高为192.5℃,ΔH=-41.03J/g,随后分解发生于200℃以上。
当本发明的卡巴他赛晶型在本文中通过基本上如图谱例如X-RPD衍射图、TG/DTA图谱、DSC图谱和FTIR光谱所示的图谱数据表征时,技术人员应当理解此类数据的图示可能会受到细微变化的影响,所述变化可能是影响仪器响应和/或样品浓度和纯度的实验变异性引起的。这些变化是技术人员熟知的,它们不会影响技术人员对本文附图中的图解数据与未知晶型产生的图解数据的比较,也不会影响对同样晶型的或两种不同晶型的两组图解数据的定性评价。
本发明的卡巴他赛的无水结晶H型可以采用卡巴他赛在癸酰基-和辛酰基甘油三酯的混合物中和在三辛酸甘油酯中的溶液开始制备,分别如实施例1或2所述。无水H型结晶的沉淀自发地出现,通过加入反溶剂如庚烷完成。然后通过过滤收集获得的结晶,采用新制备的反溶剂洗涤并干燥。
因此,本发明的另一个目的是卡巴他赛的无水结晶H型的制备方法,该方法包括下列步骤:
a)将卡巴他赛于20-25℃溶于癸酰基-和辛酰基甘油三酯的混合物中或者溶于三辛酸甘油酯中;
b)搅拌步骤a)中获得的溶液,其中产物开始结晶;
c)向步骤b)获得的浆液中加入庚烷;
d)将步骤c)中获得的沉淀过滤并干燥,获得卡巴他赛的结晶H型。
当如实施例1-2所述获得时,获得的本发明的无水结晶H型的纯度高于99%。
与先前公开的卡巴他赛形式相比,本发明的无水晶型具有多个有益的特点,例如无需另外结晶即具有高纯度、转化为其它多晶型的稳定性、更易于处理以及提高的可加工性。
鉴于上述优点,本发明的卡巴他赛无水结晶H型可以用于制备卡巴他赛、卡巴他赛盐及其多晶型物。
此外,本发明的无水结晶H型特别可用作药物,尤其是用于治疗癌症,特别是前列腺癌,例如耐激素性前列腺癌。
卡巴他赛的无水结晶H型的上述用途是本发明的另一个目的。
为了实现治疗用途,本发明的无水结晶H型可以制成含有至少一种适合于药物用途的赋形剂的常规药物组合物,这是本发明另一个目的。
通过下列实施例进一步阐明本发明,其中粗品卡巴他赛用作起始物料。
实施例1
通过粗品卡巴他赛在812中重结晶制备卡巴他赛的无水结晶H型
将粗品卡巴他赛(1g)于室温下溶于812(28g)。将溶液放置结晶,然后加入庚烷(112mL)。过滤沉淀,采用庚烷洗涤,于约60℃真空干燥16小时。获得纯度高于99%的卡巴他赛。收率85%。
实施例2
通过粗品卡巴他赛在三辛酸甘油酯中重结晶制备卡巴他赛的无水结晶H型
将粗品卡巴他赛(1g)于室温下溶于三辛酸甘油酯(28g)。将溶液放置结晶,然后加入庚烷(112mL)。过滤沉淀,采用庚烷洗涤,于约60℃真空干燥16小时。获得纯度高于99%的卡巴他赛。收率84%。
实施例3
根据实施例1-2获得的化合物采用下述技术定性。
X-射线粉末衍射(X-RPD)(图1)
X-RPD图谱在Bruker D2-Phaser衍射仪上收集。x-射线发生器于30kV和10mA操作,采用CuKα线作为辐射源。将样品填充到适当的狭缝中,辐射长度为10mm。在2-50度2θ之间收集数据,步长为0.02度2θ,计数时间为每步3秒。
傅里叶变换红外光谱(FTIR)(图2)
红外光谱以衰减全反射比(ATR)模式采用傅里叶转换光谱仪PerkinElmer Spectrum One记录,其配备Specac ATR Golden Gate配件。光谱是在4000-550cm-1光谱区以4cm-1的分辨率16附加扫描(co-added scans)获得和转换的结果。
热重分析(TG)和差热分析(DTA)(图3)
该分析采用配备开放式铝盘(40μl体积)的Seiko TG/DTA7200同步系统进行。TG/DT信号记录于30-300℃,线性升温速率(10℃/min),氮气流速为200ml/min。采用约10mg粉末用于测定。
差示扫描量热法(DSC)(图4)
该分析采用Mettler DSC1系统进行。热流量记录于30-300℃,线性升温速率(10℃/min),氮气流速为50ml/min。采用约5mg粉末用于测定,在有小孔的密封的铝坩埚(40μl体积)中进行。
Claims (4)
1.式(I)的卡巴他赛的无水晶型,称为H型:
其中无水晶型具有下列一或多个特征:
-采用铜波长分别为和的λ1和λ2获得的X-RPD图谱,以2-θ角的值表示,在下列位置具有独特的反射:5.8、6.5、8.1、9.5、10.9、11.5、12.2、13.0、14.1、14.8、16.8、17.2、19.0、19.4、20.1、21.9和24.0±0.2;
-采用铜波长分别为和的λ1和λ2获得的X-RPD图谱,基本上如图1所示;
-采用线性升温速率10℃/min获得的TG和DTA图谱,基本上如图3所示;
-采用线性升温速率10℃/min获得的DSC图谱,基本上如图4所示。
2.权利要求1的卡巴他赛的晶型,用于制备卡巴他赛、卡巴他赛盐及其多晶型物。
3.药用组合物,其含有权利要求1的无水结晶H型以及与之混合的至少一种适合于药物用途的赋形剂。
4.制备权利要求1的无水结晶H型的方法,该方法包括使得卡巴他赛在癸酰基-和辛酰基甘油三酯的混合物中或者在三辛酸甘油酯中重结晶。
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