CN105229001B - 一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途 - Google Patents
一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途 Download PDFInfo
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- CN105229001B CN105229001B CN201580000670.6A CN201580000670A CN105229001B CN 105229001 B CN105229001 B CN 105229001B CN 201580000670 A CN201580000670 A CN 201580000670A CN 105229001 B CN105229001 B CN 105229001B
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Abstract
本发明涉及一种噁唑烷酮类抗生素的新晶型,所述新晶型在溶解度、吸湿性、结晶度和稳定性方面具有优势。本发明还涉及所述新晶型的制备方法、其药物组合物及其用于制备治疗和/或预防微生物感染疾病的药物中的用途。
Description
技术领域
本发明涉及药物化学结晶技术领域。具体而言,本发明涉及一种噁唑烷酮类抗生素TR-701FA的晶型及其制备方法、药物组合物和用途。
背景技术
TR-701FA是Trius制药公司开发的一种新型噁唑烷酮类衍生物,已进入III期临床试验,显示对广谱菌优异的抗菌活性和低毒性。TR-701FA的化学名称为(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯,其化学结构式如下所示;
TR-701FA是一种前体药物,是活性成分Tedizolid的二氢磷酸酯(TedizolidPhosphate)。Tedizolid又名TR-700或torezolid,化学名称为(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮,其化学结构式如下所示:
TR-701FA在体内通过血液中的酯酶和磷酸酯酶可转化成活性代谢物Tedizolid,发挥抗菌作用。TR-701FA比Tedizolid具有更优异的溶解性,在水或酸性溶液中稳定,由此被开发用于注射或口服的制剂。
专利文献WO2005/058886A1公开了Tedizolid、TR-701FA及其制备方法。
专利文献WO2010/091131A1公开了结晶态的TR-701FA(为了方便,在本发明中称其为“晶型I”)及其制备方法,并通过核磁共振氢谱图、X-射线粉末衍射图、傅立叶-拉曼光谱图、红外光谱图、差示扫描量热分析图和动态湿气吸附图对晶型I进行了表征。
本发明人研究发现,按照WO2010/091131A1实施例1描述方法制备得到的TR-701FA晶型I具有结晶度低、在水中溶解度低和易吸湿的缺点。为了满足药物开发对药物活性成分晶型的严苛要求,开发具有更多优势性能的TR-701FA新晶型具有十分重要的现实意义。
发明内容
针对现有技术的不足,本发明的目的是提供TR-701FA的新晶型,并提供其制备方法、药物组合物和用途。与已知晶型相比,本发明新晶型应具有一种或多种改进的特性,例如:稳定性好;溶解性好;溶出速度快;结晶度高;不易吸湿性;易于纯化和处理;化学纯度高;低残留溶剂;低毒性;颗粒形貌佳;适宜的制剂可加工性例如流动性好、有利的粉体粘度、紧密度和可压实性;改进制剂表观;改善生物利用度、制剂药效;延长制剂保存期;适合制剂新剂型应用等方面,特别是应具备更高的结晶度和更优良的溶解性能。
根据本发明的目的,本发明提供结构式如下所示的TR-701FA的晶型II(为了方便,在本发明中称其为“晶型II”):
使用Cu-Kα辐射,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰:10.5±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、21.0±0.2°和26.3±0.2°。
在本发明优选的一个实施方案中,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰:10.5±0.2°、12.1±0.2°、13.9±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、20.1±0.2°、21.0±0.2°、23.9±0.2°、24.5±0.2°、26.3±0.2°和27.6±0.2°。
在本发明更优选的一个实施方案中,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度:
非限制性地,所述晶型II的一个典型实例具有如图1所示的X-射线粉末衍射(XRPD)图谱。
所述晶型II的偏正光显微镜(PLM)图谱显示为片状晶体。
所述晶型II的热重分析(TGA)图谱显示:在150℃之前失重约0.41%,为无水物,分解温度约为226℃。
所述晶型II的差热分析(DSC)图谱显示:熔融温度约为233℃。
所述晶型II的等温吸附曲线显示:在20%~80%相对湿度范围内的重量变化约为0.49%。
根据本发明的目的,本发明提供所述TR-701FA的晶型II的制备方法,包括以下步骤:将TR-701FA溶解于溶剂中,所述溶剂选自胺、酰胺或其混合物,将所得溶液挥发至干,得到所述TR-701FA的晶型II。
优选地,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶或其混合物,更优选为N,N-二甲基甲酰胺。
优选地,所述挥发温度为25℃~80℃,更优选为60℃~80℃。“挥发”的具体操作是:将装有溶液的反应瓶在相应温度下敞口进行挥发结晶。
上述晶型II的制备方法中:起始原料TR-701FA可以是TR-701FA的已知的化合物或晶型,例如包括但不限于参照专利文献WO2005058886A1实施例58制备方法得到的TR-701FA化合物,或参照专利文献WO2010091131A1实施例1描述方法制备得到的TR-701FA晶型I;起始原料TR-701FA也可以是本发明开发的TR-701FA无定型物。
本发明的晶型II具有以下有益性质及应用效果:
1)本发明晶型II和已知晶型I在室温下的水中溶解度分别为168μg/mL和118μg/mL,因此,本发明晶型II比已知晶型I具有更好的水中溶解度。
2)由等温吸附曲线可知,本发明晶型II比已知晶型I具有更低的吸湿性。
3)由XRPD和PLM图可知,本发明晶型II具有较高的结晶度。
4)本发明晶型II在温度25℃、相对湿度60%的条件下保存6个月,纯度和晶型都保持不变;在80℃-6000lx的高温光照条件下保存10天后,其纯度的下降和最大单杂含量的增长都明显低于已知晶型I的数据。因此本发明晶型II具有较高的化学稳定性和晶型稳定性。
本发明晶型II的上述优势性质表明:与已知晶型I相比,本发明晶型II更适合药物制剂应用。可具有更好的颗粒流动性和更优良的后续加工特性,简化原料药后处理过程(如过滤操作等),提高制剂生产中由流动性引起的有效成分的均匀度,有利于制剂生产中的准确计量、提高效率和稳定质量;制剂具有更高的溶出度和生物利用度,抗菌效果更好;活性成分的稳定性好,能够更好地对抗药物制造和/或存储过程中由温度、湿度、光照等因素引起的含量不均匀、纯度下降、制剂可加工性降低等问题,减少由此带来的疗效下降风险和安全风险,也有利于后期的运输和储存。
本发明人在研究中还开发了TR-701FA的无定型物(为了方便,在本发明中称其为“无定型物”)及其制备方法。
非限制性地,所述无定型物的一个典型实例具有如图9所示的X-射线粉末衍射(XRPD)图谱,显示无特征峰。
所述无定型物的差热分析(DSC)图谱显示:在140-190℃有一宽大放热峰,熔融温度约为226℃。
所述无定型物的制备方法,包括以下步骤:将TR-701FA溶解于水和三氟乙醇的混合溶剂中,将所得溶液减压浓缩至干,得到所述无定型物。
优选地,所述水和三氟乙醇的混合溶剂中水和三氟乙醇的体积比为1∶2~1∶5,优选为1∶4。
优选地,所述浓缩的温度为40℃~60℃,优选为50℃。
所述“减压浓缩”的具体操作为:将装有溶液的容器置于旋蒸仪中,在室温至溶剂沸点的水浴温度下,小于大气压的压力下(优选压力小于0.08MPa),以10~180转/分的旋转速度(优选50~100转/分),将溶剂除尽。
无定型物的制备方法中:起始原料TR-701FA可以是TR-701FA的已知的化合物或晶型,例如包括但不限于参照专利文献WO2005/058886A1实施例58制备方法得到的TR-701FA化合物,或参照专利文献WO2010/091131A1实施例1描述方法制备得到的TR-701FA晶型I;起始原料TR-701FA也可以是本发明开发的TR-701FA晶型II。
本发明中,“室温”是指10-30℃。
本发明中,“晶型”是指被所示X-射线粉末衍射图表征所证实的。本领域技术人员公知,其中的实验误差取决于仪器条件、样品准备和样品纯度。图谱通常会随着仪器条件而有所改变:峰的相对强度可能随实验条件而变化,所以峰强度的顺序不能作为唯一或决定性因素;峰角度的实验误差也应被考虑进去,通常允许±0.2°的误差;样品高度等实验因素的影响会造成峰角度整体偏移,通常允许一定的偏移。因而,本领域技术人员可以理解的是,任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。所述“单一晶型”是指经X-射线粉末衍射检测为单一的晶型。
本发明的晶型II是纯的、单一的,基本没有混合任何其他晶型或非晶态。本发明中“基本没有”当用来指新晶型时,指这个新晶型中含有的其他晶型或非晶态少于20%(重量),更指少于10%(重量),尤其指少于5%(重量),特别是指少于1%(重量)。
本发明中,所述“无水物”指样品经TGA测量含有不多于1.5%(重量),或不多于1.0%(重量)的水。
根据本发明目的,本发明提供一种药物组合物,所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的TR-701FA晶型II或者由本发明制备方法制备得到的TR-701FA晶型II,以及至少一种药学上可接受的载体或助剂。此外,所述药物组合物还可以包含TR-701FA的可药用盐、其它晶型或无定型物。任选地,所述药物组合物还可以包含一种或多种其他的药物活性成分。
所述药物组合物可为固态、半固态或液态,可制备成合适的剂型例如固体剂型,包括片剂、颗粒剂、散剂、丸剂、粉末和胶囊剂;液体剂型,包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂;可注射制剂,包括溶液剂、分散剂、适于注射前在液体中溶解或悬浮的固体形式例如冻干剂。配方可适于活性成分的快速释放、持续释放或调节释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。给药途径包括口服、通过胃喂食管、通过十二指肠喂食管、静脉内、动脉内、肌肉内、皮下、骨内、皮肤内、阴道内、直肠内、腹膜内、透皮、鼻内、眼滴、耳滴等。
所述药物组合物中药学上可接受的载体或助剂,在固态制剂的情况下包括但不限于:稀释剂,例如淀粉、改性淀粉、乳糖、粉状纤维素、微晶纤维素、无水磷酸氢钙、磷酸三钙、甘露醇、山梨醇、蔗糖等;粘合剂,例如阿拉伯胶、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、共聚维酮等;崩解剂,例如淀粉、羧甲基淀粉钠、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。其他药学上可接受的载体或助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。口服片剂中,通常使用的载体或助剂包括糖比如乳糖、蔗糖、甘露醇或山梨醇,纤维素制品比如玉米淀粉、小麦淀粉、明胶、甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠和聚乙烯吡咯烷酮,还可以加入润滑剂比如硬脂酸镁、崩解剂比如交联聚乙烯吡咯烷酮,进一步地可对片剂核心进行包衣,例如形成糖衣层;口服胶囊剂中,有用的载体或助剂包括乳糖、高和低分子量聚乙二醇和干玉米淀粉;明胶胶囊剂的情况下,粉末载体例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸与类似物;软胶囊的情况下,活性化合物可以溶解或悬浮于合适的液体中,比如脂肪油、液体石蜡或液体聚乙二醇;当以混悬液口服给药时,所述活性成分与乳化剂和悬浮剂混合;如果需要,可以加入某些甜味剂和/或调味剂和/或着色剂。每一种载体或助剂必须是可接受的,能与配方中的其他成分兼容并且对于病患无害。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时,本发明的TR-701FA晶型II与一种或多种药学上可接受的载体或助剂相混合,任选地,与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。液体制剂可以通过溶解、分散等工艺来制备。
进一步地,本发明提供一种本发明TR-701FA晶型II或者由本发明制备方法得到的TR-701FA晶型II在制备用于治疗和/或预防微生物感染疾病的药物中的用途。
进一步地,本发明提供一种治疗和/或预防微生物感染疾病的方法,所述方法包括给予需要的患者治疗和/或预防有效量的本发明的TR-701FA晶型II或由本发明制备方法得到的TR-701FA晶型II或其药物组合物。所述患者是指哺乳动物例如人。对于本领域技术人员显而易见的是,施用的剂量和特定的给药方式将根据患者的年龄、体重、饮食、感染程度、同时使用的药物情况等因素而变化,治疗有效量是指有效预防、缓解或改善疾病症状,或延长治疗对象存活的化合物的量。对于成人患者,活性成分的每日口服剂量大约0.1mg到2000mg,优选地大约1mg到500mg,活性成分使用静脉、皮下或肌肉给药的剂量大约0.01mg到100mg,优选地大约0.1mg到60mg。
前述的微生物感染,包括但不限于皮肤感染,肺炎,病毒感染后感染,腹部感染,泌尿道感染,菌血症,败血病,心内膜炎,房室间隔感染,血管穿刺感染,脑膜炎,外科手术预防,腹膜感染,骨感染,关节感染,具有甲氧西林抗性的金黄色葡萄球菌感染,具有万古霉素抗性的肠球菌感染,具有利奈唑胺抗性的有机体感染以及肺结核。
附图说明
图1为本发明晶型II的XRPD图谱。
图2为本发明晶型II的PLM图谱。
图3为本发明晶型II的DSC图谱。
图4为本发明晶型II的TGA图谱。
图5为本发明晶型II的等温吸附曲线。
图6为参照WO2005/058886A1制备得到的已知晶型I的XRPD图谱。
图7为参照WO2005/058886A1制备得到的已知晶型I的PLM图谱。
图8为参照WO2005/058886A1制备得到的已知晶型I的等温吸附曲线。
图9为本发明无定型物的XRPD图谱。
图10为本发明无定型物的DSC图谱。
具体实施方案
通过下述实施例将有助于进一步理解本发明,但是不用于限制本发明的内容。
检测仪器及方法:
X-射线粉末衍射(XRPD):所使用的仪器为Bruker D8 Advance diffractometer,采用铜靶波长为1.54nm的KaX-射线,在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用金刚砂校准。采集软件是Diffrac Plus XRD Commander。样品在室温条件下测试,把需要检测的样品放在无反射板上。详细检测条件如下,角度范围:3-40°2θ,步长:0.02°2θ,速度:0.2秒/步。
偏振光显微镜(PLM)图谱采自于XP-500E偏振光显微镜(上海长方光学仪器有限公司)。取少量粉末样品置于载玻片上,滴加少量矿物油以更好地分散粉末样品,盖上盖玻片,然后将样品放置在载物台上,选择合适的放大倍数观测样品的形貌并拍照。
差热分析(DSC):数据采自于TA Instruments Q200 MDSC,仪器控制软件是Thermal Advantage,分析软件是Universal Analysis。通常取1~10毫克的样品放置于铝盘内,以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至300℃。
热重分析(TGA):数据采自于TA Instruments Q500 TGA,仪器控制软件是ThermalAdvantage,分析软件是Universal Analysis。通常取5~15mg的样品放置于白金坩埚内,采用分段高分辨检测的方式,以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至300℃。
等温吸附曲线(DVS):数据采自于TA Instruments Q5000 TGA,仪器控制软件是Thermal Advantage,分析软件是Universal Analysis。通常取1~10mg的样品放置于白金坩埚内,TA软件记录样品在相对湿度从0%到80%到0%变化过程中的重量变化。根据样品的具体情况,也会对样品采用不同的吸附和脱吸附步骤。
高效液相色谱(HPLC):分析数据采自于Agilent 1260,化学工作站是B.04。相应参数如下:色谱柱Eclipst XDB-C18,5μm,4.6×250mm,H-005#,柱温25℃,流速0.3ml/min,流动相为13%乙腈和87%水(0.0025M碳酸氢铵),波长254nm,进样量10μL和运行时间20分钟。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1 TR-701FA的制备
参照专利文献WO2005/058886A1实施例58的制备方法得到TR-701FA,具体操作如下:
1)将1g(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮溶于10mL混合溶剂(四氢呋喃∶二氯甲烷=1∶1)中。在室温下将0.6g四唑和2.3g双四丁基二异丙基磷酰胺加入溶液中并在室温下搅拌15小时。反应混合物冷冻至-78℃,加入0.7g间氯过苯甲酸并搅拌2小时。反应混合物搅拌2小时后,反应混合物升温至室温。将乙酸乙酯加入反应混合物中。用硫酸氢钠、碳酸氢钠和盐水洗涤分离所得的有机层、脱水、过滤并真空浓缩,随后通过色谱柱提纯,由此得到0.68g(R)-(3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-2-氧代-5-噁唑烷基)甲基磷酸双(四丁基酯),收率68%。
2)将0.6g上述制得的化合物溶于30mL二氯甲烷中。室温下将15mL三氟乙酸加入溶液中并搅拌1小时。将反应混合物真空浓缩,制得残留物。残留物用乙醇和乙醚结晶,得到320mg单-(R)-(3-(4-(2-(2-甲基四唑-5-基)吡啶-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)磷酸酯,即TR-701FA,产率为53%。
进一步检测表明,制备例1所得的TR-701FA即为专利文献WO2010/091131A1所述TR-701FA结晶,即TR-701FA晶型I。其XRPD图谱如图6所示;PLM图谱如图7所示,显示其为晶态,且颗粒较小,结晶度低;等温吸附曲线如图8所示,显示在20%~80%相对湿度范围内重量变化约为1.56%。
实施例1
取200mgTR-701FA,在80℃下用10mLN,N-二甲基甲酰胺溶清,恒温保持10min,之后置于80℃下挥发至干,得到196mg白色固体产物,产率98.0%。
产物的XRPD图谱如图1所示,显示为TR-701FA晶型II。
产物的PLM图谱如图2所示,显示为片状晶体。
产物的DSC图谱如图3所示,显示熔融温度约为233℃。
产物的TGA图谱如图4所示。显示在150℃之前失重约0.41%,为无水物,分解温度约为226℃。
产物的等温吸附曲线如图5所示,显示:20%RH~80%RH重量变化为0.49%。
实施例2
取100mgTR-701FA,在60℃下用8mL N,N-二甲基甲酰胺溶清,恒温保持10min,之后置于60℃下挥发至干,得到95mgTR-701FA晶型II,产率95.0%。
实施例3
取150mgTR-701FA,在25℃下用8mL吡啶溶清,过滤,滤液置于25℃下挥发至干,得到142mgTR-701FA晶型II,产率为94.7%。
实施例2、3制备的样品具有与实施例1样品相同或相似的XRPD图谱、PLM图谱、DSC图谱和TGA图谱(未示出)。说明实施例2、3样品与实施例1样品是相同的晶型。
实施例4
取100mgTR-701FA,在25℃下用100mL体积比为1∶4的水和三氟乙醇的混合溶剂溶清,过滤,滤液置于40℃下减压浓缩旋蒸至干,得到52mgTR-701FA无定型物,产率为52%。
无定型物具有如图9所示的X-射线粉末衍射(XRPD)图谱。
无定型物的差热分析(DSC)图谱如图10所示显示:在140-190℃有一宽大放热峰,熔融温度约为226℃。
实施例5
分别取制备例1制备的晶型I和实施例1制备的晶型II各20.0mg,分别加入100mL水在25℃搅拌10小时,分别过滤取清液,直接测定HPLC含量,结果为:晶型I的溶解度为118μg/mL,晶型II的溶解度为168μg/mL。
实施例6
制备含本发明TR-701FA晶型II作为药物活性成分的速释片剂,规格为含200mgTR-701FA。表1示出了该速释片剂生产中各成分的用量配方。表1包括药品生产过程中使用的所有成分,无论该成分是否包含在最终产品中,其中纯化水在生产过程中除去。
表1 速释片剂处方
制备步骤:
1:将TR-701FA晶型II、甘露醇、微晶纤维素和交联聚维酮过筛混合。
2:将聚维酮溶解于纯化水中得粘合剂溶液。
3:将步骤2的粘合剂溶液加入到步骤1的混合物中,进行湿法制粒并干燥。
4:将硬脂酸镁过筛后与步骤3中干颗粒混合,混合物于旋转压片机上压成片芯。
5:用欧巴代II黄涂膜材料的水溶液对步骤4的片芯持续涂膜,直到增加3.4%目标重量为止。
实施例7
制备含本发明TR-701FA晶型II作为药物活性成分的胶囊,规格为含182mgTR-701FA。表2示出了该胶囊生产中各成分的用量配方。表2包括药品生产过程中使用的所有成分,无论该成分是否包含在最终产品中,其中纯化水在生产过程中除去。
表2 胶囊剂处方
制备步骤:
1:将TR-701FA晶型II、微晶纤维素和交联聚维酮过筛混合。
2:将聚维酮溶解于纯化水中得粘合剂溶液。
3:将步骤2的粘合剂溶液加入到步骤1的混合物中,进行湿法制粒并干燥。
4:将硬脂酸镁过筛后与步骤3中干颗粒混合,混合物于胶囊填充机上进行胶囊填充。
对比例1
取制备例1制备的TR-701FA晶型I和本发明的TR-701FA晶型II,进行高温光照条件下放置10天的稳定性实验。高温条件为80℃,光照条件为6000lx照度。检测化合物在放置前后的HPLC纯度和最大单杂含量,结果见表3。
表3 稳定性实验的结果
由表3数据可知:在高温光照10天的条件下,TR-701FA晶型I的纯度降低了2.1%,最大单杂含量增加了1.2%,而本发明的TR-701FA晶型II的纯度基本无变化,最大单杂含量仅增加了0.1%。因此,本发明的TR-701FA晶型II在高温光照下的稳定性明显优于已知的TR-701FA晶型I。
本说明书中所引用的所有专利文献及非专利文献,均通过引用以其全文的方式并入本文中。
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,任何熟悉本领域的技术人员在本发明所揭露的技术范围内,可不经过创造性劳动想到的变化或替换,都应涵盖在本发明的保护范围之内。
Claims (12)
1.结构式如下所示的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯的晶型II:
使用Cu-Kα辐射,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰:10.5±0.2°、15.7±0.2°、16.5±0.2°、17.3±0..2°、21.0±0.2°和26.3±0.2°。
2.根据权利要求1所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II,其特征在于,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰:10.5±0.2°、12.1±0.2°、13.9±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、20.1±0.2°、21.0±0.2°、23.9±0.2°、24.5±0.2°、26.3±0.2°和27.6±0.2°。
3.根据权利要求2所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II,其特征在于,所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度:
4.权利要求1-3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II的制备方法,包括以下步骤:将(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯溶解于溶剂中,所述溶剂选自胺、酰胺或其混合物,将所得溶液挥发至干,得到所述晶型II。
5.根据权利要求4所述的制备方法,其特征在于,所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶或其混合物。
6.根据权利要求5所述的制备方法,其特征在于,所述溶剂为N,N-二甲基甲酰胺。
7.根据权利要求4所述的制备方法,其特征在于,所述挥发温度为25℃~80℃。
8.根据权利要求7所述的制备方法,其特征在于,所述挥发温度为60℃~80℃。
9.一种药物组合物,其包含治疗和/或预防有效量的选自权利要求1-3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II或根据权利要求4~8中任一项所述制备方法得到的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II,以及至少一种药学上可接受的载体或助剂。
10.根据权利要求9所述的药物组合物,其特征在于,所述药物组合物为注射剂、片剂或胶囊剂。
11.根据权利要求10所述的药物组合物,其特征在于,所述药物组合物为片剂。
12.权利要求1~3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II或根据权利要求4~8中任一项所述制备方法得到的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II在制备用于治疗和/或预防微生物感染疾病的药物中的用途;其中所述微生物感染选自于由下述所组成的组中的感染:皮肤感染,肺炎,病毒感染后感染,腹部感染,泌尿道感染,菌血症,败血病,心内膜炎,房室间隔感染,血管穿刺感染,脑膜炎,外科手术预防,腹膜感染,骨感染,关节感染,具有甲氧西林抗性的金黄色葡萄球菌感染,具有万古霉素抗性的肠球菌感染,具有利奈唑胺抗性的有机体感染以及肺结核。
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