CN115417812B - 一种阿西替尼-烟酰胺共晶及其制备方法和应用 - Google Patents
一种阿西替尼-烟酰胺共晶及其制备方法和应用 Download PDFInfo
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- CN115417812B CN115417812B CN202210939048.3A CN202210939048A CN115417812B CN 115417812 B CN115417812 B CN 115417812B CN 202210939048 A CN202210939048 A CN 202210939048A CN 115417812 B CN115417812 B CN 115417812B
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- axitinib
- nicotinamide
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
Abstract
本发明提供了一种阿西替尼共晶及其制备方法,所述阿西替尼共晶是由阿西替尼与烟酰胺按照摩尔比1:1结合形成;使用Cu‑kα辐射,阿西替尼共晶X射线粉末衍射谱具有明显区别于阿西替尼和烟酰胺的尖锐新衍射峰;晶体学参数为:三斜晶系,空间群为P‑1;晶胞参数为:α=101.866(5)°,β=94.807(4)°,γ=101.579(4)°本发明所述的共晶显著地改善阿西替尼的溶解度,稳定性,堆密度,休止角,压片裂片率,片剂硬度和粘冲性。本发明工艺简单,适合制药工业大规模生产。
Description
技术领域
本发明属于结晶技术领域,涉及一种阿西替尼-烟酰胺共晶及其制备方法和应用。
背景技术
据统计,有90%的药物活性成分(API)属于BCSⅡ药物,由于它们不理想的溶解度和溶解速率,临床中的生物利用度受到严重的限制;此外,药物需要有足够的化学稳定性和晶型稳定性以应对制剂和生产过程中的环境影响;大多数药物倾向于制备固体制剂,如颗粒剂,片剂等,因此如何优化结晶工艺,制备出具有良好流动性,堆密度和压片性能的原料药是制药行业的共性难题。
阿西替尼是辉瑞开发的抗肿瘤药物,以血管内皮生长因子(VEGF)为靶点,通过阻断肿瘤血管生成来阻止癌细胞的生长和增殖,在许多靶标组织和器官的癌症治疗中显示出了希望,结构如下式所示:
阿西替尼于2012年1月27日获得FDA批准用于早期至晚期肾癌的治疗,同年9月获得 EMA批准其在欧洲上市。目前,该药物在多个国家被用于治疗晚期肾细胞癌,FDA、EMEA公布,目前只有阿西替尼片剂上市销售,片剂规格为1mg和5mg。US20060094763公开了阿西替尼的晶型I、II、III、IV、VI、VII、VIII等多种晶型;CN103626739公开了阿昔替尼的晶型XXV、XVI、VIII、XLI、IX、XII、XV及多种溶剂化物。虽然目前阿西替尼有5种无溶剂晶型和近70种溶剂化物,但只有无溶剂晶型IV、晶型XXV及晶型XLI可以满足生物利用度,稳定性和临床安全性要求。但阿西替尼属于BCSⅡ类药物,常温下晶型IV在水中的溶解度仅为5μg/mL。此外,阿西替尼对光高度敏感,容易降解,在潮湿、阳光、高温等条件下易产生2+2二聚物、不对称二聚物、顺式异构物等杂质。对于粉体药物,一般认为休止角小于40°时粉体的流动性良好,可满足压片过程中对流动性的要求,休止角大于40°,则要通过修饰颗粒表面或添加辅料等方式来改善,阿西替尼粉体流动性差(休止角大于50°),堆密度低(低于0.5g/cm3),压片过程容易粘冲和裂片,亟待改善。
据专利人研究结果和已有文献报道,在绝大多数溶剂中结晶阿西替尼都会形成相应的溶剂化物,不可药用,现有阿西替尼精致结晶工艺制备无溶剂晶型都需要经过高温脱溶剂转晶, CN106883212A公布了晶型XLI制备方法,工艺冗长,需要多步重结晶,且需要在50-70℃高温下进行,安全性低,操作步骤复杂;CN104140414A公布的晶型IV工艺使用烷烃,醚类和酯类等低沸点溶剂,回流温度高达80-90℃,安全性低,能耗高。因此迫切需要开发一种条件温和,可直接制备无溶剂药用阿西替尼晶体的制备方法。
总结来说,阿西替尼溶解度低,生物利用度差,光稳定性和晶型稳定性差,堆密度低,流动性差,裂片率和粘性性高,在固体制剂中面临巨大挑战和改进的空间,因此需要开发更多固体形态以解决临床和生产问题,此外,也要开发适合工业化,工艺简洁,能耗低的无溶剂阿西替尼晶体的绿色制备工艺以满足经济和环保需求。
共晶的使用是提高生物利用度的一种可能,且除生物利用度外,还可以改善若干其他性质,例如溶出度、物理稳定性、机械特性、吸湿性、化学稳定性、流动性和纯化加工能力。
发明内容
为了解决现有技术的不足,本发明的目的是提供一种阿西替尼共晶及其制备方法,将阿西替尼与可药用小分子烟酰胺形成共晶,在保证稳定性的同时,显著提高阿西替尼的溶解度,生物利用度,稳定性,粉体性能和压片性能。
为了解决上述技术问题,本发明采用如下技术方案:
第一方面,本发明提供了一种阿西替尼-烟酰胺共晶,所述的一种阿西替尼-烟酰胺共晶的基本结构单元由一个阿西替尼分子和一个烟酰胺分子构成;
烟酰胺,分子式为C6H6N2O,结构式为:
阿西替尼-烟酰胺共晶的晶胞参数为晶胞参数为 ,α=101.866(5)°,β=94.807(4)°,γ=101.579(4)°,Z=2,三斜晶系,P-1。
阿西替尼-烟酰胺共晶的X射线衍射图谱,以衍射角2θ表示为:在5.9°、7.9°、8.7°、11.9°、12.7°、13.9°、15.8°、18.0°、21.4°、22.4°、23.4°、23.9°、25.1°、25.8°、 28.0°、28.9°、31.0°和31.7°处各有特征衍射峰,其中每个衍射峰的处的误差为±0.2°。
阿西替尼-烟酰胺共晶的傅里叶固体红外测试中,在3145.7cm-1、3112.7cm-1、3044.7 cm-1、2972.6cm-1、2916.3cm-1、2903.5cm-1、2840.6cm-1、2784.9cm-1、1694.5cm-1、 1630.5cm-1、1585.2cm-1和1560.5cm-1波长处有吸收峰,其中,每个吸收峰处的误差范围为±2cm-1。
阿西替尼-烟酰胺共晶,使用差式扫描量热法测定DSC曲线进行测试时,所得共晶体存在一个吸热峰,对应的温度是175.21~186.45℃,其峰值为183.24℃。
本发明第二方面提供了本发明第一方面所述的阿西替尼-烟酰胺共晶的制备方法,所述制备方法包括悬浮结晶和研磨结晶:
Ⅰ悬浮结晶步骤:
将阿西替尼原料和烟酰胺按照摩尔比为1:1~3置于有机溶剂中,20-50℃悬浮结晶18-48 h,得到所述阿西替尼-烟酰胺共晶。
优选地,所述阿西替尼原料包括阿西替尼晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI、阿西替尼乙醇溶剂化物、阿西替尼水合物、阿西替尼异丙醇溶剂化物、阿西替尼丙酮溶剂化物、阿西替尼乙腈溶剂化物、阿西替尼乙酸乙酯溶剂化物、阿西替尼二甲基亚砜溶剂化物、阿西替尼N,N-二甲基甲酰胺溶剂化物、阿西替尼N-甲基吡咯烷酮溶剂化物或阿西替尼四氢呋喃溶剂化物中的任意一种或至少两种的组合;
优选地,有机溶剂包括C1-C6醇类溶剂、苯类溶剂、醚类溶剂、腈类溶剂、酯类溶剂、酰胺类溶剂或C3-C6酮类溶剂中的任意一种或至少两种的组合;
优选地,所述有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、正己醇、甲苯、苯、***、苯甲醚、乙腈、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯、甲酰胺、N,N-二甲基甲酰胺、丙酮、丁酮、甲基异丁基酮或环己酮中的任意一种或至少两种的组合;
优选地,所述制备方法还包括将悬浮结晶后得到的混合物依次进行固液分离以及干燥;
优选地,所述固液分离的方式包括过滤;
优选地,所述干燥的温度为40-50℃,干燥的时间为12-24h。
Ⅱ研磨结晶步骤:
将阿西替尼原料和烟酰胺按照摩尔比为1:1~1.5滴加到有机溶剂中,球磨,得到所述阿西替尼-烟酰胺共晶。
优选地,所述阿西替尼原料包括阿西替尼晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI、阿西替尼乙醇溶剂化物、阿西替尼水合物、阿西替尼异丙醇溶剂化物、阿西替尼丙酮溶剂化物、阿西替尼乙腈溶剂化物、阿西替尼乙酸乙酯溶剂化物、阿西替尼二甲基亚砜溶剂化物、阿西替尼N,N-二甲基甲酰胺溶剂化物、阿西替尼N-甲基吡咯烷酮溶剂化物或阿西替尼四氢呋喃溶剂化物中的任意一种或至少两种的组合;
优选地,以阿西替尼和烟酰胺质量之和的添加量计,所述有机溶剂的添加量为0.05-0.1 mL/g;
优选地,有机溶剂包括C1-C6醇类溶剂、苯类溶剂、醚类溶剂、腈类溶剂、酯类溶剂、酰胺类溶剂或C3-C6酮类溶剂中的任意一种或至少两种的组合;
优选地,所述有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、正己醇、甲苯、苯、***、苯甲醚、乙腈、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯、甲酰胺、N,N-二甲基甲酰胺、丙酮、丁酮、甲基异丁基酮或环己酮中的任意一种或至少两种的组合;
优选地,所述制备方法还包括将球磨后得到的混合物进行干燥12-24h。
进一步,阿西替尼与烟酰胺的摩尔比为1:1;
进一步,所述阿西替尼选自阿西替尼晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI、乙醇溶剂化物、水合物、异丙醇溶剂化物、丙酮溶剂化物、乙腈溶剂化物、乙酸乙酯溶剂化物、二甲基亚砜溶剂化物、N,N-二甲基甲酰胺溶剂化物、N-甲基吡咯烷酮溶剂化物或四氢呋喃溶剂化物中的一种或几种的混合物。
进一步,所述溶剂为C1~C6醇类溶剂,苯类溶剂,醚类溶剂,腈类溶剂,酯类溶剂,酰胺类溶剂,烷类溶剂,C3~C6酮类溶剂的单一溶剂或混合溶剂;
进一步,所述溶剂的用量为0.05~0.4mL/g。
本发明第三方面提供了一种药物制剂,所述药物组合物包括有效量的本发明第一方面所述的阿西替尼-烟酰胺共晶。
进一步,所述药物组合物还包含药学上可接受的稀释剂、赋形剂或载体。
进一步,所述“组合物”打算包括包含规定组分的产物以及其直接或间接由以规定量的规定组分的组合生成的任何产物。所谓“药学上可接受的稀释剂、赋形剂或载体”意指稀释剂、赋形剂或载体必须与剂型中的其它组分可适配并且对其接受者无害。
进一步,上述药物组合物可制成一定的剂型,通过适合的途径给药。例如口服、肠胃外 (包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂,根据需要,可适于药物活性成分的快速释放、延迟释放或调节释放;适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液;适合直肠给药的剂型包括栓剂或灌肠剂;适合透皮给药的剂型包括软膏、霜剂、贴剂;适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂;适合***给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地,由于本发明的共晶具有优异的水溶性和在水溶液中的稳定性,因此,尤其适合制备成片剂、胶囊剂、崩解片、即释、缓释和控释片剂;进一步优选为片剂和胶囊剂。
进一步,上述药物组合物中药学上可接受的赋形剂,在固体口服剂型的情况下,包括但不限于:稀释剂,例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等;粘合剂,例如***胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等;崩解剂,例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等;润滑剂,例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等;助流剂,例如胶体二氧化硅等;复合物形成剂,例如各种级别的环糊精和树脂;释放速度控制剂,例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地,对片剂涂覆包衣层,例如提供虫胶隔离包衣、糖衣或聚合物包衣,包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉,还可以包括抗粘着剂如二氧化硅、滑石粉,乳浊剂如二氧化钛,着色剂如氧化铁类着色剂。在液体口服剂型的情况下,合适的赋形剂包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂等;水或非水的无菌混悬剂可含有悬浮剂和增稠剂;适用于水性混悬剂的赋形剂包括合成胶或天然胶例如***树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下,水或非水的无菌注射溶液的赋形剂通常为无菌水、生理盐水或葡萄糖水溶液,可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质。每一种赋形剂必须是可接受的,能与配方中的其他成分兼容并且对于患者无害。
进一步,所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备药物组合物时,将本发明共晶与一种或多种药学上可接受的赋形剂相混合,任选地与一种或多种其他的药物活性成分相混合。例如,片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备;粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备;溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备;混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
本发明提供的共晶具有适用于上述剂型的有利性质。
本发明第四方面提供了本发明第一方面所述的阿西替尼-烟酰胺共晶或本发明第三方面所述的药物组合物在制备抗肿瘤药物/预防肿瘤药物中的应用。
进一步,包括早期肾细胞癌、全身治疗失败的晚期肾细胞癌、单独治疗或辅助其他药物治疗甲状腺癌、非小细胞肺癌、黑素瘤、结肠直肠癌、肉瘤、乳腺癌、肾上腺皮质癌、肝细胞癌、间皮瘤、***癌、类癌瘤和多形成性胶质细胞瘤。
本发明的优点和有益效果:
1、本发明中的阿西替尼共晶晶体相较于现有技术的阿西替尼无溶剂晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI晶体,水溶性好,光稳定性高,晶型稳定性好,堆密度高,流动性好,裂片率低,不易粘冲。
2、本发明中的阿西替尼晶体制备方法,条件温和,操作时间短,可一步制备无溶剂阿西替尼晶体,无需再经过脱溶剂过程,明显降低工艺难度和提高安全性。
3、本发明提供使用的共晶试剂价格便宜,且共晶制备采用悬浮结晶工艺简单,能耗低因此生产成本较低,本发明使用的球磨方法主要消耗二次能源电能,绿色环保,因此制备的共晶具有较高溶解度且生产成本较低,环境友好。
附图说明
图1是阿西替尼-烟酰胺共晶的PXRD衍射图;
图2是阿西替尼-烟酰胺共晶的FTIR光谱图;
图3是阿西替尼-烟酰胺共晶的DSC图;
图4是阿西替尼-烟酰胺共晶的TG图;
图5是阿西替尼-烟酰胺共晶的晶胞结构图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅是帮助理解本发明,不应视为对本发明的具体限制。
实施例1
精确称取阿西替尼晶型XLI386.5mg,烟酰胺原料122.12mg,将样品置于RetschMM400 研磨仪,6mm钢球一个,频率为20Hz,添加甲醇38μL,研磨10min,25℃恒温干燥12h,得到阿西替尼-烟酰胺共晶。
实施例2
精确称取阿西替尼晶型Ⅰ386.47mg,烟酰胺原料183.18mg,将样品置于RetschMM400 研磨仪,6mm钢球一个,频率为25Hz,添加丁酮20μL,乙腈37μL,研磨10min,25℃恒温干燥18h,得到阿西替尼-烟酰胺共晶。
实施例3
精确称取阿西替尼丙酮溶剂化物444.55mg,烟酰胺原料122.12mg,将样品置于Retsch MM400研磨仪,6mm钢球一个,频率为25Hz,添加甲苯19μL,甲酰胺10μL研磨10min,25℃恒温干燥24h,得到阿西替尼-烟酰胺共晶。
实施例4
精确称取阿西替尼乙腈溶剂化物427.52mg,烟酰胺原料146.54mg,将样品置于Retsch MM400研磨仪,6mm钢球一个,频率为25Hz,添加正戊醇5μL,乙酸丁酯30μL研磨10min, 25℃恒温干燥16h,得到阿西替尼-烟酰胺共晶。
实施例5
精确称取阿西替尼乙酸乙酯溶剂化物237.29mg,烟酰胺原料61.06mg,将样品置于10ml 烧杯中,添加***2mL,乙酸正丙酯2mL,20℃恒温悬浮搅拌18h后过滤,40℃烘箱恒温干燥12h,得到阿西替尼-烟酰胺共晶。
实施例6
精确称取阿西替尼二甲基亚砜溶剂化物1.8584g,烟酰胺原料0.9770g,将样品置于10ml 烧杯中,添加乙酸乙酯3mL,N,N-二甲基甲酰胺1mL,30℃恒温悬浮搅拌24h后过滤,45℃烘箱恒温干燥18h,得到阿西替尼-烟酰胺共晶。
实施例7
精确称取阿西替尼四氢呋喃溶剂化物917.16mg,烟酰胺原料610.06mg,将样品置于10ml 烧杯中,添加甲基异丁基酮3mL,环己酮1mL,40℃恒温悬浮搅拌36h后过滤,50℃烘箱恒温干燥20h,得到阿西替尼-烟酰胺共晶。
实施例8
精确称取阿西替尼晶型IV386.47mg,烟酰胺原料366.36mg,将样品置于10ml烧杯中,添加二甲基亚砜1mL,正丁醇5mL,50℃恒温悬浮搅拌48h后过滤,45℃烘箱恒温干燥24h,得到阿西替尼-烟酰胺共晶。
对比实施例1:
参照专利CN103626739A公开的方法,制备阿昔替尼晶型XXV
对比实施例2:
参照专利US20060094763中公开的方法,制备阿昔替尼晶型IV。
对比实施例3:
参照专利CN103626739A公开的方法,制备阿昔替尼晶型XLI。
下列分析方法和设备用于表征本发明的阿西替尼-烟酰胺共晶体:
1、X-射线粉末衍射(PXRD):
采用的粉末衍射仪为日本理学株式会社生产的D/MAX2500型,测试条件为:采用CuKα靶测试,电压40kV,电流100mA,扫描波长,采用连续扫描测试,扫描速度为8°/min。收集完数据后采用Jade7.0软件进行数据分析。
将由实施例1制备得到阿西替尼-烟酰胺共晶进行测试,阿西替尼-烟酰胺共晶的X射线衍射图谱如图1和表一所示:
表1实施例1制得的阿西替尼-烟酰胺共晶的PXRD数据
实施例1~8具有一致的PXRD试验结果。
2、固体红外(FTIR):
FTIR采用(Bio-Rad,FTS3000MXIR光谱仪)得到。溴化钾压片制样,采用透射方式测定,测试波长为4000~400cm-1。
将由实施例1制备得到阿西替尼-烟酰胺共晶进行测试,阿西替尼-烟酰胺共晶的FTIR图谱如图2所示,在3145.7cm-1、3112.7cm-1、3044.7cm-1、2972.6cm-1、2916.3cm-1、2903.5cm-1、 2840.6cm-1、2784.9cm-1、1694.5cm-1.、1630.5cm-1、1585.2cm-1和1560.5cm-1波长处有吸收峰。
实施例1~8具有一致的FTIR试验结果。
3、差式扫描量热仪(DSC):
采用梅特勒托利多公司的DSC1/500型仪器测试,将5-20mg样品加入40μL的标准铝坩埚中,密封坩埚,放入炉体。炉体内用高纯氮气做保护气(气速为50mL/min)和反应气 (气速为200mL/min)。测量温度范围30~250℃,升温速率5~10℃·min-1。测定加热过程中样品的温度和热量变化,程序控制、数据记录和分析均由梅特勒公司开发的STAReSoftware10.0软件完成。
将由实施例1制备得到阿西替尼-烟酰胺共晶进行测试,结果如图3所示,差示扫描热量仪(DSC)显示,在测试温度范围内,所得共晶体存在一个吸热峰,对应的温度是175.21~ 186.45℃,其峰值为183.24℃。
实施例1~8具有一致的DSC试验结果。
4、热重分析(TGA):
热重分析数据由梅特勒托利多公司的MettlerTG/DSC1STARe型热重分析仪完成测定。测试条件:样品量:3-5mg;温度范围:25-400℃;升温速率:10℃/min;气体:氮气;流速:20mL/min。
热重分析(TGA)结果如图4所示,在测试温度范围内观察到阿西替尼的分解与烟酰胺的分解。
实施例1~8具有一致的TGA试验结果。
5、X-射线单晶衍射(SXRD):
本研究采用日本理学株式会社生产的X射线单晶衍射仪(RigakuR_AXISRapidII),MoKα靶产生射线,波长为,测试电压50kV,电流为90mA。借助Rapidauto(Rigaku,2004) 进行数据收集,单晶解析和精修运用SHELXS-97软件。
图5是阿西替尼-烟酰胺共晶的晶体晶胞图,基本结构单元由一个阿西替尼分子和一个烟酰胺分子构成;阿西替尼-烟酰胺共晶的晶胞参数为: ,α=101.866(5)°,β=94.807(4)°,γ=101.579(4)°,Z=2,三斜晶系,P-1。
6、高效液相色谱(HPLC):
阿西替尼在水中的浓度,使用美国安捷伦1260高效液相色谱测定,UV检测波长为330 nm,采用AgilentODS-C18(5μm,4.6mm×250mm)液相色谱柱,柱温设置为40℃,流速为1mL/min,采取机器自动进样进行测试,每次采样20μL。流动相由比例为60:40(v/v)的乙腈和0.03M乙酸钠水溶液(用乙酸调节至pH4.6)组成。DMSO和0.01NHCl水溶液作为稀释剂用于制备标准溶液。
分别取实施例1和对比例1~3制备得到的阿昔替尼过量,加入到去离子水中,25℃下搅拌72小时。重复取样三次,过滤,取滤液,采用HPLC检测纯度方法检测含量,得出溶解度如表二所示:
表二不同阿西替尼固体形态在水中的溶解度
溶解度实验表明,本发明制备的阿西替尼-烟酰胺共晶相较于对比例1~3有明显的水溶性的提高,本发明制备的阿西替尼-烟酰胺共晶的溶解度是市售稳定晶型XLI的3.12倍,亚稳晶型IV的2.70倍,XXV的3.86倍,具有明显的进步,不仅如此,本发明的显著进步还体现在下文表征的粉体性能和压片性能上。
实施例1~8具有一致的溶解度试验结果。
7、粉体性能测试仪:
应用BT-1001智能粉体特性测试仪对阿西替尼和共晶进行休止角和振实堆密度的测定,将5~10g粉体过100目筛后,装填入粉体测试仪容器,测定休止角,再设定量筒上下振动,振幅5~10mm,测定粉体振实堆密度,重复三次,取平均值,结果如表三所示。
表三粉体堆密度和休止角测试结果
粉体测试表明,本发明的阿西替尼-烟酰胺共晶相比于对比例1~3具有更优越的粉体性能,一般认为休止角小于40°时粉体的流动性良好,可满足压片过程中对流动性的要求,本发明中的阿西替尼-烟酰胺共晶流动性好,将阿西替尼原药在不添加辅料的情况下,将休止角从市售晶型XLI的50.2°降低到35.2°,满足制剂部门对于流动性的要求;不仅如此,本发明的阿西替尼-烟酰胺共晶对于粉体堆密度具有明显的提升,相较于晶型XLI提高了65%,相较于晶型IV提高了53%,相较于XXV提高了69%,具有明显的进步。
实施例1~8具有一致的堆密度和休止角试验结果。
8、光稳定性实验
分别取实施例1和对比例1~3制备得到的阿西替尼及阿西替尼-烟酰胺共晶,在25℃ (RH45%)暴露于强光照射(4500Lx±500Lx)下储存15天,分别于第0天和第15天取样,采用 HPLC检测纯度。结果见表四:
表四阿西替尼和阿西替尼-烟酰胺共晶光稳定性实验结果
光照稳定性实验表明,本发明的阿西替尼-烟酰胺共晶相比于对比例1~3具有明显的稳定性优势,15天光照后对比例1~3降解率均超过了5%,远远高于阿西替尼-烟酰胺共晶,因此本发明中的阿西替尼-烟酰胺共晶具有显著提高的光照稳定性。
实施例1~8具有一致的光稳定性试验结果。
9、压片性实验
压片性能测试方案依据文献报道方法(Cryst.GrowthDes.2021,21,12,6655–6659),详细地,首先在压实压力为300MPa下制备片剂,压实速度为4mm/min,原药量400mg/片,由黏附在冲头上的药物质量占投药量的百分数表征黏粘冲性;去除片剂边缘的毛刺后,用卡尺测量片的尺寸。采用结构分析仪,由断裂时的压力F计算出片材的抗拉强度,实验重复20次,根据压片后带有裂纹/碎裂的片剂数量计算裂片率,实验结果如表五所示:
表五阿西替尼和阿西替尼-烟酰胺共晶片剂抗拉强度和粘冲性实验结果
压片性实验表明,本发明的阿西替尼-烟酰胺共晶相比于对比例1~3具有更优越的压片性能,在300MPa的压力下,实施例1片剂的抗拉强度是XXV的3.03倍,IV的2.28倍,XLI的3.06倍,裂片率仅有5%,而对比例1~3都高于20%,黏附率也显著低于对比例1~3,由此可以看出本发明的阿西替尼-烟酰胺共晶的压片性能相比于对比例1~3具有明显的提升。
实施例1~8具有一致的压片性能试验结果。
10、共晶中阿西替尼与烟酰胺结合比例测定:
(1)阿西替尼的含量测定法(HPLC):使用美国安捷伦1260高效液相色谱测定,UV检测波长为330nm,采用AgilentODS-C18(5μm,4.6mm×250mm)液相色谱柱,柱温设置为 40℃,流速为1mL/min,采取机器自动进样进行测试,每次采样20μL。流动相由比例为60:40 (v/v)的乙腈和0.03M乙酸钠水溶液(用乙酸调节至pH4.6)组成。
(2)供试品溶液:取20~30mg阿西替尼共晶,精密称定,置50mL量瓶中,加DMSO 溶解并稀释至刻度,摇匀0.22μm微孔滤膜过滤,取续滤液20μL注入液相色谱仪,记录阿西替尼峰面积。
(3)对照品溶液:取步骤(2)共晶相同摩尔当量的阿西替尼对照品,精密称定,置50mL 量瓶中,加DMSO溶解并稀释至刻度,摇匀,0.22μm微孔滤膜过滤,取续滤液20μL注入液相色谱仪,记录阿西替尼峰面积。
(4)计算步骤(2)和(3)中的峰面积的比值,结果显示比值处于于0.995~1.008之间,证明本专利所述阿西替尼共晶中阿西替尼与烟酰胺比例为1:1。
本发明中通过烟酰胺与原料药阿西替尼组成的共晶晶体形态和分子层次的组装完全不用于现有技术的阿西替尼晶体溶解度高,堆密度高,流动性好,稳定性优,可以长期保存,压片过程裂片率和粘冲率低,抗拉强度大,在产品性能上有显著优势,此外,本发明制备工艺简洁,能耗低,条件温和,安全易控制,成本低廉,可进一步开发适用于大规模生产。
申请人声明,以上所述仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,所属技术领域的技术人员应该明了,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,均落在本发明的保护范围和公开范围之内。
Claims (16)
1.一种阿西替尼-烟酰胺共晶,其特征在于,所述阿西替尼-烟酰胺共晶是由阿西替尼与烟酰胺按照摩尔比1:1结合形成;
所述阿西替尼-烟酰胺共晶的基本结构单元由一个阿西替尼分子和一个烟酰胺分子构成;晶胞参数包括;α=101.866(5)°,β=94.807(4)°,γ=101.579(4)°,Z=2,三斜晶系,P-1;
使用Cu-kα辐射,所述阿西替尼-烟酰胺共晶的X射线粉末衍射谱具有区别于阿西替尼和烟酰胺的尖锐新衍射峰;
所述阿西替尼-烟酰胺共晶的X射线衍射图谱,以衍射角2θ表示为:在5.9°、7.9°、8.7°、11.9°、12.7°、13.9°、15.8°、18.0°、21.4°、22.4°、23.4°、23.9°、25.1°、25.8°、28.0°、28.9°、31.0°和31.7°处各有特征衍射峰,其中每个衍射峰的处的误差为±0.2°。
2.根据权利要求1所述的阿西替尼-烟酰胺共晶,其特征在于,所述阿西替尼-烟酰胺共晶,使用差式扫描量热法测定DSC曲线进行测试时,所得共晶体存在一个吸热峰,对应的温度是175.21~186.45℃,其峰值为183.24℃。
3.根据权利要求1所述的阿西替尼-烟酰胺共晶,其特征在于,所述阿西替尼-烟酰胺共晶的傅里叶固体红外测试中,在3145.7cm-1、3112.7cm-1、3044.7cm-1、2972.6cm-1、2916.3cm-1、2903.5cm-1、2840.6cm-1、2784.9cm-1、1694.5cm-1、1630.5cm-1、1585.2cm-1和1560.5cm-1波长处有吸收峰,其中,每个吸收峰处的误差范围为±2cm-1。
4.根据权利要求1-3任一项所述的阿西替尼-烟酰胺共晶的制备方法,其特征在于,所述制备方法包括悬浮结晶法或研磨结晶法。
5.根据权利要求4所述的制备方法,其特征在于,所述悬浮结晶法包括:
将阿西替尼原料和烟酰胺按照摩尔比为1:1~3置于有机溶剂中,20-50℃悬浮结晶18-48h,得到所述阿西替尼-烟酰胺共晶。
6.根据权利要求5所述的制备方法,其特征在于,所述阿西替尼原料包括阿西替尼晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI、阿西替尼乙醇溶剂化物、阿西替尼水合物、阿西替尼异丙醇溶剂化物、阿西替尼丙酮溶剂化物、阿西替尼乙腈溶剂化物、阿西替尼乙酸乙酯溶剂化物、阿西替尼二甲基亚砜溶剂化物、阿西替尼N,N-二甲基甲酰胺溶剂化物、阿西替尼N-甲基吡咯烷酮溶剂化物或阿西替尼四氢呋喃溶剂化物中的任意一种或至少两种的组合。
7.根据权利要求5所述的制备方法,其特征在于,有机溶剂包括C1-C6醇类溶剂、苯类溶剂、醚类溶剂、腈类溶剂、酯类溶剂、酰胺类溶剂或C3-C6酮类溶剂中的任意一种或至少两种的组合。
8.根据权利要求7所述的制备方法,其特征在于,所述有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、正己醇、甲苯、苯、***、苯甲醚、乙腈、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯、甲酰胺、N,N-二甲基甲酰胺、丙酮、丁酮、甲基异丁基酮或环己酮中的任意一种或至少两种的组合。
9.根据权利要求5所述的制备方法,其特征在于,所述制备方法还包括将悬浮结晶后得到的混合物依次进行固液分离以及干燥;
所述固液分离的方式包括过滤;
所述干燥的温度为40-50℃,干燥的时间为12-24h。
10.根据权利要求4所述的制备方法,其特征在于,所述研磨结晶法包括:
将阿西替尼原料和烟酰胺按照摩尔比为1:1~1.5滴加到有机溶剂中,球磨,得到所述阿西替尼-烟酰胺共晶。
11.根据权利要求10所述的制备方法,其特征在于,所述阿西替尼原料包括阿西替尼晶型Ⅰ、晶型IV、晶型Ⅵ、晶型XXV、晶型XLI、阿西替尼乙醇溶剂化物、阿西替尼水合物、阿西替尼异丙醇溶剂化物、阿西替尼丙酮溶剂化物、阿西替尼乙腈溶剂化物、阿西替尼乙酸乙酯溶剂化物、阿西替尼二甲基亚砜溶剂化物、阿西替尼N,N-二甲基甲酰胺溶剂化物、阿西替尼N-甲基吡咯烷酮溶剂化物或阿西替尼四氢呋喃溶剂化物中的任意一种或至少两种的组合。
12.根据权利要求10所述的制备方法,其特征在于,以阿西替尼原料和烟酰胺质量之和的添加量计,所述有机溶剂的添加量为0.05-0.1mL/g。
13.根据权利要求10所述的制备方法,其特征在于,所述有机溶剂包括甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、正戊醇、正己醇、甲苯、苯、***、苯甲醚、乙腈、乙酸甲酯、乙酸乙酯、乙酸正丙酯、乙酸异丙酯、乙酸丁酯、甲酰胺、N,N-二甲基甲酰胺、丙酮、丁酮、甲基异丁基酮或环己酮中的任意一种或至少两种的组合。
14.根据权利要求10所述的制备方法,其特征在于,所述制备方法还包括将球磨后得到的混合物进行干燥12-24h。
15.根据权利要求1-3任一项所述的阿西替尼-烟酰胺共晶作为活性成分在制备抗肿瘤/预防肿瘤药物中的应用。
16.一种药物制剂,其特征在于,所述药物制剂包括权利要求1-3任一项所述的阿西替尼-烟酰胺共晶以及药学上可接受的辅料和/或载体。
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