CN117285458A - 一种无定型雷芬那辛及其制备方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种无定型形态的雷芬那辛及其制备方法。所述无定型形雷芬那辛稳定性良好、溶剂残留低,制得的制剂产品展示出较好的适用性。其制备方法步骤简单,易于生产操作,收率高,适合于工业化大规模生产。
Description
技术领域
本发明涉及雷芬那辛的新晶型,新晶型无定型形态,该药物可治疗慢性非阻塞及哮喘;本发明还涉及该晶型的表征及制备方法。
背景技术
雷芬那辛是长效毒蕈碱拮抗药,结构式如式1所示,其主要通过吸入给药,能显著改善肺功能,减少COPD的临床症状,并预防病变的进一步恶化,用于COPD患者的维持治疗。2018年,FDA批准雷芬那辛用于慢性阻塞性肺疾病(COPD)患者的维持治疗。COPD是一种非单一病因的进展性、不可逆转的持续性气道阻塞性肺部疾病,也是慢性支气管炎和肺气肿的总称。COPD被认为影响全球约3.28亿人,已经是美国第三大死因,到2020年已成为全球第三大死因,COPD治疗用药严重未满足需求。
中国专利文献CN101163677A披露了雷芬那辛二磷酸盐、单硫酸盐、草酸氢盐的晶型以及雷芬那辛游离碱晶型Ⅰ和晶型Ⅱ。该文献中雷芬那辛游离碱晶型Ⅰ使用水和乙腈制备得到,晶型Ⅱ使用乙腈和甲基叔丁基醚制备得到。中国专利文献CN102470130A披露了雷芬那辛游离碱晶型III和晶型Ⅳ。游离碱晶型III使用乙腈或乙酸异丙基酯制备得到。游离碱晶型Ⅳ由晶型III转化而来。在实际研究中,发明人发现雷芬那辛游离碱极易形成溶剂化物,在晶型制备过程中溶剂残留难以去除完全,晶型Ⅰ和晶型Ⅱ收率不高,并且稳定性较差。晶型Ⅳ的制备方法比较繁琐。上述晶型均不适用于商品化生产,目前仅有晶型III被用于上市制剂产品。
现有雷芬那辛上市制剂为吸入用雷芬那辛溶液,由爱尔兰Theravance生物制药公司与美国Mylan制药联合开发,并于2018年11月经美国FDA批准上市,商品名为Yupelri。
吸入溶液剂雾化后在肺部的沉积率非常低,仅为10%~20%,大部分患者只能在医院进行雾化治疗,设备体积较大,不方便携带,大大降低了给药的便捷性,影响治疗效果。吸入粉雾剂的肺部沉积率显著高于吸入溶液剂,可达50%以上,并且方便携带,可很好的满足临床给药需求。
吸入粉雾剂原料需性质稳定、具有良好的流动性和辅料相容性,现仅有晶型III用于上市制剂产品,亟需对雷芬那辛晶型进一步研究,以期获得适合粉雾剂需求的晶型。
发明内容
本发明针对现有技术不足,提供了一种雷芬那辛无定型新晶型,其生产方法步骤简单,易于生产操作,制备过程基本没有产品损失,收率高。本发明所述无定型的雷芬那辛具有较好的溶解性,同时原料及制剂产品稳定性好,具有较好的制剂适用性,较高的工业生产价值。本发明具体技术方案如下:
雷芬那辛无定型晶型,所述雷芬那辛结构式如下:
所述的雷芬那辛无定型晶型,为典型的弥散性峰,具有如图1所示的X-射线粉末衍射峰图谱。
所述的雷芬那辛无定型晶型,具有如图2所示的DSC图谱。
所述的雷芬那辛无定型晶型,具有如图3所示的红外图谱特征。所述晶型的红外图谱在3195±3cm-1、3057±3cm-1、1206±3cm-1、1009±3cm-1处有红外吸收。进一步在3419±3cm-1、2943±3cm-1、2806±3cm-1、1918±3cm-1、1731±3cm-1、1673±3cm-1、1615±3cm-1、1518±3cm-1、1493±3cm-1、1488±3cm-1、1401±3cm-1、1339±3cm-1、1141±3cm-1、1044±3cm-1、934±3cm-1、858±3cm-1、749±3cm-1、702±3cm-1、556±3cm-1处有红外吸收。
本发明另一目的在于提供所述的雷芬那辛无定型晶型的制备方法,包括:
a)将雷芬那辛游离碱加入相对应的有机溶剂中;
b)搅拌、升温溶解、过滤;
c)减压蒸除上述有机溶剂滤液制得无定型雷芬那辛。
无定型形态是物质存在多晶型现象中的一种形式,也是一种特殊的晶型状态。在制备无定型形态过程中,溶解溶剂的选择最为关键,直接影响到是否能制备出无定型晶型,经过对多种溶剂进行筛选,溶剂为乙酸乙酯、丙酮、无水乙醇中的一种或几种时,充分溶解后减压脱除溶剂之后可以得到无定型形态的雷芬那辛。当溶剂与雷芬那辛比例为3~10:1时,无定型状态最佳。
本发明优点:
本发明涉及一种无定型形态的雷芬那辛及其制备方法,该无定型形雷芬那辛稳定性良好、溶剂残留低,制得的制剂产品展示出较好的适用性。该生产方法步骤简单,易于生产操作,收率高,适合于工业化大规模生产。
附图说明
图1无定型雷芬那辛的X-射线粉末衍射图谱。
图2无定型雷芬那辛的差式扫描热量法(DSC)曲线。
图3无定型雷芬那辛的红外图谱。
图4无定型雷芬那辛稳定性考察后样品的X-射线粉末衍射图谱。
图5无定型雷芬那辛稳定性考察后样品的差式扫描热量法(DSC)曲线。
具体实施方式
下面结合具体实施方式和范例性实施例对本发明作进行详细说明,但这些说明并不能理解为对本发明的任何限制。本领域技术人员理解,在不偏离本发明精神和范围的情况下,可以对本发明技术方案及其实施方式进行多种等价替换,修饰或改进,这些均落入本发明的范围内。本发明的保护范围以所附权利要求为准。具体实施例阐述如下:
雷芬那辛游离碱的制备(参照中国专利CN101163677A)
向三颈2L烧瓶中添加异哌啶甲酰胺(5.99g,40.0mmol)、乙酸(2.57mL)、硫酸钠(6.44g)和异丙醇(400mL)。用冰浴将反应混合物冷却到0~10℃并且缓慢地添加联苯-2-基氨基甲酸1-{2-[(4-甲酰基苯甲酰基)甲氨基]乙基}哌啶-4-基酯(11g,22.7mmol)在异丙醇(300mL)中的溶液。在室温搅拌反应混合物2小时,然后冷却到0~10℃。分次添加三乙酰氧基硼氢化钠(15.16g,68.5mmol)并且在室温搅拌该混合物16小时。然后在碱压下浓缩反应混合物至体积为约50mL并且用1N HCl(200mL)酸化该混合物pH至3。在室温搅拌得到的混合物1小时,然后用二氯甲烷(3×250mL)萃取。然后用冰浴将水相冷却至0~5℃并且添加50%NaOH水溶液,以将混合物的pH调节至10。然后用乙酸异丙酯(3×300mL)萃取该混合物并且用水(100mL)、盐水(2×50mL)洗涤合并的有机层,用无水硫酸钠干燥,过滤并且浓缩得到雷芬那辛游离碱。
实施例1反应溶剂筛选
向200mL圆底烧瓶中加入5.0g雷芬那辛游离碱,随后加入如表1所示用量的不同反应溶剂。开启搅拌,升温溶解,溶清后趁热过滤。减压蒸除上述有机溶剂滤液制得各组雷芬那辛。进行X-射线粉末衍射分析,实验结果见表1。
表1反应溶剂筛选实验表
雷芬那辛PXRD、DSC、IR检测方法如下:
X-射线粉末衍射(PXRD):型号Empyrean,步宽0.026°,步长时间50s。
差式扫描热分析仪(DSC):型号DSC214Polyma气吹扫气40ml/min,保护气60ml/min。升温速率10K/min。温度范围25~200℃。
红外光谱测定试验(IR),型号:Nicolet iS5红外分光光度计,并使用KBr压片检测。
按照实施例1方法制备的雷芬那辛晶型,经X-射线粉末衍射和DSC测定,确定乙酸乙酯、丙酮、无水乙醇组为雷芬那辛无定型晶型,该无定型具有特定的红外特征,X-射线粉末衍射图谱如图1所示,差式扫描热量法(DSC)曲线如图2所示,红外图谱如图3所示。
实验结果表明,选用乙酸异丙酯、甲苯、甲醇、四氢呋喃和二氯甲烷等作溶剂均无法制得无定型雷芬那辛。选用乙酸乙酯、丙酮、乙醇可制得无定型雷芬那辛。
实施例2本发明无定型雷芬那辛与雷芬那辛晶型III的溶解性比较研究
分别取实施例1制得的雷芬那辛无定型晶型,参照中国专利文献CN102470130A制备得到雷芬那辛游离碱晶型III。将其分别加入到相应介质中,在37℃条件下振荡24小时,0.45μm水相滤膜过滤,收集滤液,采用高效液相进行饱和溶液浓度测定。其中,pH4.0、pH5.0和pH5.8为醋酸缓冲溶液,pH7.0、pH7.4和pH8.0为磷酸缓冲溶液。
缓冲溶液配置方法:
醋酸缓冲溶液:2mol/L醋酸溶液:取120.0g(114mL)冰醋酸用水稀释至1000mL,即得。取下表中规定物质的取样量,加水溶解并稀释至1000mL,摇匀,即得。
pH值 | 4.0 | 5.0 | 5.8 |
醋酸钠取样量(g) | 1.22 | 4.50 | 6.23 |
2mol/L醋酸溶液取样量(ml) | 20.5 | 8.5 | 2.1 |
磷酸盐缓冲液:0.2mol/L磷酸二氢钾溶液:取27.22g磷酸二氢钾,用水溶解并稀释至1000mL。
0.2mol/L氢氧化钠溶液:取8.00g氢氧化钠,用水溶解并稀释至1000mL。取250mL0.2mol/L磷酸二氢钾溶液与下表中规定量的0.2mol/L氢氧化钠溶液混合后,再加水稀释至1000mL,摇匀,即得。
pH值 | 7.0 | 7.4 | 8.0 |
0.2mol/L氢氧化钠溶液取样量(ml) | 145.5 | 195.5 | 230.5 |
无定型雷芬那辛有关物质检验方法如下:
方法依据:液相色谱法(中国药典2020年版二部附录ⅤD)。
色谱条件:
高效液相色谱仪(HPLC):型号Waterse2695,流动相A:0.01mol/L磷酸二氢铵溶液(磷酸调至pH2.95),抽滤超声即得。流动相B:乙腈,柱温:40℃,检测波长:230nm,色谱柱:YMC Triart C18柱(4.6mm×150mm,3μm)。
溶液制备:
(1)稀释剂:乙腈:流动相A=20:80。
(2)供试品溶液:取本品10mg,精密称定,置20ml量瓶中,加入适量稀释剂使其完全溶解,用稀释剂稀释至刻度,摇匀,作为供试品溶液。
梯度洗脱:
时间(min) | 流动相A% | 流动相B% |
0 | 85 | 15 |
3 | 85 | 15 |
30 | 35 | 65 |
35 | 35 | 65 |
37 | 85 | 15 |
45 | 85 | 15 |
表2无定型雷芬那辛与雷芬那辛晶型III的溶解性比较
实验结果见表2,显示本发明制得的雷芬那辛无定型晶型与原研制制剂使用的晶型III相比在各种缓冲溶液中均有更高的饱和溶液浓度。尤其是在碱性缓冲液中,无定型晶型相比晶型III饱和溶液浓度提升明显。使得该晶型能更好的运用在制剂制备中,具有更高的药用开发价值和工业生产价值。
实施例3本发明无定型雷芬那辛与雷芬那辛晶型III的稳定性考察
影响因素考察条件包括:
1、热降解:取雷芬那辛约200mg,置于60℃干燥箱中放置;
2、光降解:取雷芬那辛约200mg,置于照度为5000±500lux的条件下放置,总照度不低于1.2×106lux·h,近紫外灯能量不低于200W·h/m2;
3、高湿降解:取雷芬那辛约200mg,置于放有KNO3饱和溶液的干燥器中,25℃放置。雷芬那辛有关物质检验方法见实施例2。
表3雷芬那辛无定型晶型与晶型III的影响因素考察影响因素考察
*:忽略限度为0.05%。
稳定性考察条件包括:
加速稳定性:温度40℃±2℃、相对湿度75%±5%的条件下放置6个月;
长期稳定性:温度25℃±2℃,相对湿度60%±5%的条件下放置12个月。
表4雷芬那辛无定型晶型与晶型III的长期及加速稳定性考察
由表3可知,在影响因素考察实验中,无定型雷芬那辛与晶型III相比稳定性基本一致。无定型雷芬那辛稳定性更好,杂质种类无明显增加,且纯度无明显降低。
由表4可知,相较晶型III,无定型雷芬那辛在加速稳定性试验和长期稳定性试验中表现良好。同时将通过稳定性测试的样品复检PXRD、DSC,均无异常(表征见图4、图5),以上实验表明雷芬那辛无定型晶型具有较好稳定性。
实施例4本发明无定型雷芬那辛与雷芬那辛晶型III的残留溶剂考察
仪器条件:
色谱柱:6%氰丙基苯基-94%二甲基聚硅氧烷(或极性相似)为固定液的毛细管柱为色谱柱(推荐使用Agilent DB-624,0.53mm×30m,3μm或效能相当的色谱柱);
升温程序:起始温度为40℃,维持11分钟,以每分钟20℃的速率升温至180℃,维持5分钟;
进样口温度:200℃;
检测器:氢火焰离子化检测器(FID),检测器温度为250℃;
柱流量:每分钟2ml;
分流比:15:1;
顶空瓶平衡温度:95℃;平衡时间:30min。
表5雷芬那辛无定型晶型与晶型III的残留溶剂考察
雷芬那辛残留溶剂高是其制备的一大难点,该晶型的制备均采用三类溶剂为制备溶剂。在该制备工艺下,实施例1各组无定型雷芬那辛的残留溶剂均远低于限度,说明本发明所述无定型雷芬那辛溶剂残留非常低,有利于该无定型作为药物活性成分用于制备药物。
实施例5本发明无定型雷芬那辛与雷芬那辛晶型III的制剂稳定性比较研究
1)称取0.054g硬脂酸镁和1.0200g无定型雷芬那辛(或雷芬那辛晶型III)原料搅拌混合10min后,转移至气流粉碎机中以5bar粉碎压力共微粉,制备雷芬那辛复合物。
2)称取剩余处方量的硬脂酸镁1.646g和全部处方量的乳糖337.280g置TRV高剪切混合设备,以500.0r/min的混合速度混合6min,出料,获得乳糖预混物。
3)依次向TRV混合设备中平铺加入约1/2乳糖预混物、全部的雷芬那辛复合物和剩余约1/2乳糖预混物,设定混合速度1150r/min,混合3min,出料,获得雷芬那辛总混物。
4)取雷芬那辛总混物粉末,按25mg±1mg的填充量装填胶囊,制备可通过干粉吸入装置递送至肺部给药的雷芬那辛吸入粉雾剂胶囊。
5)将上述载药胶囊进行双铝包装,然后置40℃,RH75%环境内,每隔一段时间测定产品微细粒子剂量、含量和有关物质等的变化,结果如表7所示。
表6稳定性考察条件
考察条件 | 具体条件 |
加速 | 温度:40℃±2℃,相对湿度75%±5% |
表7稳定性考察结果
无定型雷芬那辛制备的吸入粉雾剂,其微细粒子剂量和微细粒子分数均显著高于雷芬那辛晶型III制备的吸入粉雾剂。稳定性考察试验中,无定型雷芬那辛吸入粉雾剂在加速3个月内的微细粒子剂量和微细粒子分数保持稳定,雷芬那辛晶型III吸入粉雾剂在加速3个月内的微细粒子剂量和微细粒子分数呈下降趋势。无定型雷芬那辛吸入粉雾剂在加速3个月内的有关物质增长缓慢,雷芬那辛晶型III吸入粉雾剂在加速3个月内的有关物质增速略快。
实施例6动物组织分布试验
制剂选择:实施例5制得的无定型雷芬那辛吸入粉雾剂和晶型III雷芬那辛吸入粉雾剂给药频率:单次给药
给药途径:经口鼻吸入
试验动物:SD大鼠
分组:共72只SD大鼠,分为无定型雷芬那辛吸入粉雾剂300μg/kg剂量组和晶型III雷芬那辛吸入粉雾剂300μg/kg剂量组,每组36只。分别于给药后0.5h采集动物肺泡灌洗液、肺组织、主气管及支气管、膀胱、心脏、肝脏和肾脏的药物浓度。
表8大鼠吸入两制剂0.5h后雷芬那辛在体内主要器官和组织的分布情况
雷芬那辛是长效抗胆碱能药物,它与肌氨酸受体M1-M5的亚型具有相似的亲和力。在气道中,它通过抑制平滑肌M3受体引起支气管扩张而表现出药理作用。平滑肌M3受体主要位于气管及支气管部位,是雷芬那辛的主要药效部位。由上述动物组织分布试验可知,吸入给药0.5h后,无定型雷芬那辛吸入粉雾剂在药效部位肺组织、主气管及支气管的浓度显著高于晶型III雷芬那辛吸入粉雾剂,而在可能产生临床副作用(如尿潴留)的膀胱、心脏等处,无定型雷芬那辛吸入粉雾剂的浓度显著低于晶型III雷芬那辛吸入粉雾剂,提示无定型雷芬那辛吸入粉雾剂具有优于晶型III雷芬那辛吸入粉雾剂支气管扩张作用以及较低的临床副作用。
Claims (5)
1.雷芬那辛无定型晶型,其特征在于所述雷芬那辛无定型晶型结构式如下:
所述晶型的X-射线粉末衍射图谱如图1所示。
2.根据权利要求1所述的雷芬那辛无定型晶型,其特征在于:具有如图2所示的DSC图谱。
3.根据权利要求1所述的雷芬那辛无定型晶型,其特征在于:所述晶型的红外图谱在3195±3cm-1、3057±3cm-1、1206±3cm-1、1009±3cm-1处有红外吸收。
4.根据权利要求3所述的雷芬那辛无定型晶型,其特征在于:所述晶型的红外图谱在3419±3cm-1、2943±3cm-1、2806±3cm-1、1918±3cm-1、1731±3cm-1、1673±3cm-1、1615±3cm-1、1518±3cm-1、1493±3cm-1、1488±3cm-1、1401±3cm-1、1339±3cm-1、1141±3cm-1、1044±3cm-1、934±3cm-1、858±3cm-1、749±3cm-1、702±3cm-1、556±3cm-1处有红外吸收。
5.根据权利要求1~4任一项所述雷芬那辛无定型晶型的制备方法,其特征在于,包括如下步骤:
a)将雷芬那辛游离碱加入有机溶剂中,所述有机溶剂选自乙酸乙酯、丙酮、无水乙醇中的一种或几种;
b)搅拌、升温溶解、过滤;
c)减压蒸除上述有机溶剂滤液制得无定型雷芬那辛。
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