CN101448815A - 度洛西汀hci多晶型物 - Google Patents
度洛西汀hci多晶型物 Download PDFInfo
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- CN101448815A CN101448815A CNA2007800187266A CN200780018726A CN101448815A CN 101448815 A CN101448815 A CN 101448815A CN A2007800187266 A CNA2007800187266 A CN A2007800187266A CN 200780018726 A CN200780018726 A CN 200780018726A CN 101448815 A CN101448815 A CN 101448815A
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- duloxetine
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Abstract
提供粒料度洛西汀盐酸盐的晶形,度洛西汀盐酸盐的晶形的药物组合物,以及制备度洛西汀盐酸盐的晶形的方法。
Description
相关申请的交叉引用
本申请要求了2006年5月23日提交的下列美国临时专利申请No:60/808,094的权益,它的内容被引入这里供参考。
本发明的领域
本发明涉及度洛西汀HCl的固态和它们的制备方法。
本发明的背景
度洛西汀是神经传递质血清素和去甲肾上腺素的双再摄取抑制剂,并且已经发现可用于应激性尿失禁(SUI),抑郁症,和疼痛发作的医治。
同质多晶型现象,不同晶形的存在,是一些分子和分子配合物的性能。单种分子,象度洛西汀HCl,可以导致得到具有不同的晶体结构和物理性能如熔点、X射线衍射图、红外吸收指印图和固态NMR谱的各种晶形。一种晶形可以导致与另一个晶形的热行为不同的热行为。热行为能够通过诸如已经用于鉴别多晶型物的毛细管法熔点,热重分析(“TGA”),和差示扫描量热法(“DSC”)的技术在实验室中测量。
不同晶形的物理性能上的差异是从本体固体中相邻分子或配合物的取向和分子间相互作用产生的。因此,多晶型物是有共同的分子式但具有不同的有利物理性能(与相同化合物或配合物的其它晶形相比)的不同固体。
药物化合物的最重要的物理性能中的一种是它们在水溶液中的溶解度,尤其它们在患者的胃液中的溶解度。例如,当经由胃肠道途径的吸收是缓慢的时,常常希望对于患者的胃部或肠中的各种条件表现不稳定的药物慢慢地溶解,以使得它在有害的环境中不聚集。相同药物化合物的不同晶形或多晶型物能够和据报道具有不同的水溶液溶解度。
US2006/0270859,通常方式转让的申请,重复了US专利No.5,362,886的方法并报道说该产物是度洛西汀HCl的无水多晶型物,表示为A晶型。这一晶型据报道通过在约9.6°,13.9°,18.1°,18.9°,20.9°和23.4°2θ±0.2°2θ处的X射线粉末衍射峰来表征。A晶型的XRD(X射线衍射)图在本申请的图1(湿)和2(干)中举例说明。
US2006/0270859进一步公开度洛西汀HCl的两种形式,其中包括指定为B晶型的晶形和无定形。该晶形据报道可通过从具有度洛西汀HCl的溶液中蒸发甲醇来获得。该晶形据说通过在约11.1,12.1,14.9,21.6和24.2±0.2°2θ处的峰来表征。
药物学上有用化合物的新多晶型物的发现为改进药物产品的性能特征提供了新机会。它扩大了材料的全部用途,配方科学家能够设计具有目标释放曲线或其它所需特性的药物的药物剂型。在现有技术中仍然需要度洛西汀HCl的多晶型物。
本发明的概述
在一个实施方案中,本发明提供度洛西汀HCl溶剂化物。优选,该度洛西汀HCl溶剂化物是丙酮溶剂化物。
在另一个实施方案中,本发明提供结晶性度洛西汀HCl,它通过在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的X射线粉末衍射峰来表征。
在另一个实施方案中,本发明提供了制备以上度洛西汀HCl晶形的方法,包括掺混度洛西汀,丙酮和HCl以获得度洛西汀HCl晶形,后者通过在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的X射线粉末衍射峰来表征。另外地,该起始原料可以是度洛西汀的盐。
在另一个实施方案中,本发明提供了制备以在约9.6°,13.9°,18.1°,18.9°,20.9°和23.4°2θ±0.2°2θ处的X射线粉末衍射峰为特征的度洛西汀HCl晶形的方法,该方法包括干燥度洛西汀HCl晶形,后者以在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的X射线粉末衍射峰为特征。
在另一个实施方案中,本发明提供包含度洛西汀HCl晶形的药物组合物,该晶形以在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的X射线粉末衍射峰为特征。
附图的简述
图1说明湿的度洛西汀HCl(由公开在US 5,362,886中的程序获得)的粉末X射线衍射图。
图2说明干燥的度洛西汀HCl(由公开在US 5,362,886中的程序获得)的粉末X射线衍射图。
图3说明度洛西汀HCl晶型C的粉末X射线衍射图。
图4说明通过干燥晶型C获得的度洛西汀HCl晶型A的粉末X射线衍射图。
本发明的详细说明
在这里使用的术语“无水”指含有不超过0.5wt%水/溶剂的度洛西汀HCl。
在这里使用的“溶剂化物”在含义上包括以大于约1wt%的水平引入溶剂的任何晶形。
在一个实施方案中,本发明提供度洛西汀HCl溶剂化物。
优选,本发明的度洛西汀HCl是丙酮溶剂化物。
在另一个实施方案中,本发明提供这里被定义为C晶型的结晶度洛西汀HCl,它通过在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的X射线粉末衍射峰来表征。
该晶形可以进一步通过X射线粉末衍射图案来表征,具有在约5.5°,13.3°,和154°2θ±0.2°2θ处的峰,基本上如图3中所述。
晶型C具有约9wt%的重量损失,由TGA测量。这对应于度洛西汀HCl的丙酮溶剂化物。
本发明进一步提供制备度洛西汀HCl晶形C的方法,该方法包括掺混度洛西汀,丙酮和HCl而获得度洛西汀HCl。
该度洛西汀起始原料能够作为碱或以其HCl盐形式被引入反应中。当该起始原料是度洛西汀HCl时,HCl的添加不是必需的。
在一个实施方案中,度洛西汀在丙酮中的溶液与HCl掺混而获得固体物,随后回收度洛西汀HCl晶形C。
优选,溶液在搅拌的同时维持在大约室温。
任选地,在将溶液与HCl掺混之前,溶液用度洛西汀HCl接种。优选,度洛西汀HCl种子是A晶型或C晶型,最优选A晶型。
优选,在接种后,溶液进一步维持约5分钟-约1小时。
优选,掺混的HCl是气态的。
优选,HCl被鼓泡通入溶液中,直到获得约3-约5的pH为止。
优选,在将该溶液与HCl掺混之后,混合物进一步维持约5分钟-约30分钟。
度洛西汀HCl晶形C可以通过现有技术中已知的任何方法如过滤来回收。回收的晶体能够进一步洗涤。
在另一个实施方案中,本发明提供制备度洛西汀HCl晶形A的方法,包括干燥晶型C。
本领域中的技术人员将会认识到,为了获得度洛西汀HCl晶形A所需要的时间将根据,在众多因素中,所要干燥的湿度洛西汀HCl晶型C的量和干燥温度来变化,并且通过拍取周期的XRD图来测定。优选地,晶型C在约室温-约70℃下,在低于约1大气压的压力下,更优选低于约100毫米汞柱的压力下干燥。干燥所需要的时间优选是至少5分钟,更优选约6小时。
在另一个实施方案中,本发明提供包含度洛西汀HCl晶形C的药物组合物。
药物组合物可以制备为口服,胃肠外,直肠,透皮,面颊或鼻内途径给药的药物。口服的合适形式包括药片,压缩或包衣药丸,糖衣丸,小药袋,硬胶囊或明胶胶囊,舌下含服的药片,糖浆剂,和悬浮液。肠胃外投药的合适晶型包括水溶液或非水溶液或乳液,而对于直肠给药,合适的给药形式包括具有亲水性或疏水性赋形剂的栓剂。对于局部给药,本发明提供在现有技术中已知的合适透皮输送体系,和,对于鼻内输送,提供在现有技术中已知的合适的气溶胶输送体系。
除活性成分之外,本发明的药物组合物可以含有一种或多种赋形剂或助剂。赋形剂的选择和用量容易由配方设计科学家根据经验和在本领域中的标准程序和参考资料的考虑来确定。
稀释剂增大固体药物组合物的体积,并且使得含有该组合物的药物剂型让患者和医护人员更容易处置。固体组合物的稀释剂包括,例如微晶纤维素(例如),微细纤维素,乳糖,淀粉,预胶凝淀粉,碳酸钙,硫酸钙,糖,葡萄糖结合剂,糊精,右旋糖,二元磷酸钙二水合物,三元磷酸钙,高岭土,碳酸镁,氧化镁,麦芽糖糊精,甘露糖醇,聚甲基丙烯酸酯(例如),氯化钾,粉末纤维素,氯化钠,山梨糖醇,和滑石。
被压缩成剂型如药片的固体药物组合物可以包括赋形剂,它的作用包括有助于在压缩之后将活性成分和其它赋形剂粘结在一起。固体药物组合物的粘结剂包括***树胶,藻酸,丙烯酸聚合物(例如carbopol),羧甲基纤维素钠,糊精,乙基纤维素,明胶,胍尔豆胶,氢化植物油,羟乙基纤维素,羟基丙基纤维素(例如),羟丙基甲基纤维素(例如),液状葡萄糖,硅酸镁铝,麦芽糖糊精,甲基纤维素,聚甲基丙烯酸酯,聚乙烯基吡咯烷酮(例如 ),预胶凝淀粉,海藻酸钠,和淀粉。
压缩的固体药物组合物在患者胃部内的溶解速率可通过向组合物中添加崩解剂来提高。崩解剂包括藻酸,羧甲基纤维素钙,羧甲基纤维素钠(例如),胶体二氧化硅,交联羧甲基纤维素钠(croscarmellose sodium),聚乙烯聚吡咯烷酮(例如),胍尔豆胶,硅酸镁铝,甲基纤维素,微晶纤维素,离子交换树脂钾,粉末纤维素,预胶凝淀粉,海藻酸钠,淀粉羟基乙酸钠(例如),和淀粉。
助流剂能够被添加来改进未压缩固体组合物的流动性和改进按剂量给药的精确度。用作助流剂的赋形剂包括胶体二氧化硅,三硅酸镁,粉末纤维素,淀粉,滑石,和三元磷酸钙。
当剂型如药片通过粉末组合物的压缩来制备时,该组合物承受来自冲孔器和模头的压力。一些赋形剂和活性成分倾向粘附于冲孔器和模头的表面,这能够引起该产物具有麻点和其它表面不规则性。润滑剂能够被添加到组合物中以减少粘附和有利于产物从模头松脱。润滑剂包括硬脂酸镁,硬脂酸钙,单硬脂酸甘油酯,棕榈酸硬脂酸甘油基酯,氢化蓖麻油,氢化植物油,矿物油,聚乙二醇,苯甲酸钠,十二烷基硫酸钠,硬脂基富马酸钠,硬脂酸,滑石,和硬脂酸锌。
固体和液体组合物也可以使用任何药物学上可接受的着色剂来改进它们的外观和/或有利于产品和单元剂量水平的病人识别。
在本发明的液体药物组合物中,该活性成分和任何其它固体赋形剂悬浮于液体载体如水,植物油,醇,聚乙二醇,丙二醇,或甘油中。
液体药物组合物可含有乳化剂,以便在组合物中均匀地分散了不溶于液体载体中的活性成分或其它赋形剂。可用于本发明的液体组合物中的乳化剂包括,例如明胶,蛋黄,酪蛋白,胆固醇,***树胶,黄芪胶,角叉菜胶,果胶,甲基纤维素,丙烯酸聚合物,十六烷基十八烷基醇,和十六烷醇。
本发明的液体药物组合物还可含有粘度增强剂以改进产品的口感和/或涂覆胃肠道的内层。此类试剂包括***树胶,藻酸膨润土,丙烯酸聚合物,羧甲基纤维素钙或钠,十六烷基十八烷基醇,甲基纤维素,乙基纤维素,明胶胍尔豆胶,羟乙基纤维素,羟基丙基纤维素,羟丙基甲基纤维素,麦芽糖糊精,聚乙烯醇,聚乙烯基吡咯烷酮,碳酸亚丙基酯,海藻酸丙二醇酯,海藻酸钠,淀粉羟基乙酸钠,淀粉黄芪胶,和黄原酸胶。
甜味剂如山梨糖醇,糖精,糖精钠,蔗糖,阿斯巴特,果糖,甘露糖醇,和转化糖可以被添加来改善味道。
防腐剂和螯合剂如醇,苯甲酸钠,丁基化羟基甲苯,丁基羟基苯甲醚,和乙二胺四乙酸能够以摄入安全的水平添加以改进贮存稳定性。
根据本发明,液体组合物还可含有缓冲剂如葡糖酸,乳酸,柠檬酸或乙酸,葡糖酸钠,乳酸钠,柠檬酸钠,或乙酸钠。
赋形剂的选择和用量容易由配方设计科学家根据经验和在本领域中的标准程序和参考资料的考虑来确定。
本发明的固体组合物包括粉末,颗粒物,聚集物,和压缩的组合物。剂量包括适合于口服,面颊,直肠,胃肠外(包括皮下,肌内,和静脉内),吸入,和眼部给药的剂量。虽然在任何给定的情况下最合适的给药将取决于所要医治的病症的性质和严重性,但是本发明的最优选的给药途径是口服。该剂量适宜以单元剂型存在并且通过在药物领域中众所周知的那些方法中的任何一种来制备。
剂型包括固体剂型如药片,粉末,胶囊剂,栓剂,小药袋,锭剂,和losenges,以及液体糖浆剂,悬浮液,和酏剂。
本发明的剂型可以是在硬或软壳内含有组合物(优选本发明的粉末状或粒化的固体组合物)的胶囊剂。该壳可以从明胶制备,和任选地含有增塑剂如甘油和山梨糖醇,和不透明剂或着色剂。
该活性成分和赋形剂可以根据现有技术中已知的方法被配制到组合物和剂型中。
压片或胶囊填充用的组合物可以通过湿法成粒来制备。在湿法成粒中,粉末形式的活性成分和赋形剂的一些或全部被掺混,然后在液体(典型地水)存在下混合,该液体引入粉末结块形成颗粒物。颗粒物进行筛选和/或研磨,干燥,和然后筛选和/或研磨到所需颗粒尺寸。颗粒物然后被压片或其它赋形剂在压片之前添加,如助流剂和/或润滑剂。
制片剂用的组合物可以通常由干混合法来制备。例如,活性物和赋形剂的共混组合物可以被压缩成块或片,然后磨碎成压缩的微粒。压缩的颗粒物随后被压缩成药片。
作为干法成粒的替代,共混的组合物可通过使用直接压缩技术被直接压缩成压缩的剂型。直接压缩产生没有颗粒物的更均匀的药片。特别适合于直接压缩压片的赋形剂包括微晶纤维素,喷雾干燥乳糖,二水磷酸二钙,和胶态氧化硅。这些和其它赋形剂在直接压缩制片剂中的合适使用是在直接压缩制片剂的特殊配方设计挑战中有经验和技术的那些本领域技术人员所已知的。
本发明的胶囊填充可包括参考制片剂所描述的上述掺混物和微粒中的任何一种,然而,这些不进行最终的制片剂步骤。
实施例
尽管本发明已参考具体的实施例和优选实施方案进行了描述,但是可以理解的是本发明不局限于这些实施例和实施方案。因此本发明包括这里所述的具体实施例和优选实施方案的变化形式,这对于本领域中的技术人员是显而易见的。
用于分析和鉴定度洛西汀HCl的晶形的X射线衍射分析仪是Scintag X射线粉末衍射仪型号X’TRA,Cu-管固态检测器。样品夹持器是具有有粗糙度零背景石英片的标准圆形铝制样品夹持器,它具有25mm的腔直径和0.5mm的深度。扫描参数是:
范围:2°至40°2θ;
扫描方式:连续扫描;
步长:0.05°;和
速率:5°/分钟。
为了由热解重量分析(TGA)测定重量损失,样品以约10℃/分钟的速率从约25℃加热到约200℃,同时用40ml/min的流速的氮气吹扫。
实施例1-度洛西汀HCl晶型C的制备
在装有机械搅拌器、温度计和冷凝器的100L玻璃反应器中添加49.7kg的由度洛西汀在甲苯中形成的溶液(87%)。溶液在20-30毫米汞柱的真空下蒸馏,直到干燥为止。在冷却到室温之后,添加63.65升的丙酮,溶液在25℃下搅拌45分钟,然后添加10g的度洛西汀盐酸盐。在1小时搅拌后,HCl被鼓泡通入到溶液中,直至混合物达到pH3,然后该溶液在同一温度下搅拌半小时。所得固体被滤出,用丙酮(9.5升)洗涤,由X射线衍射法(XRD)分析,并且在样品中鉴定C晶型。
实施例2-度洛西汀HCl晶型C的制备
在装有机械搅拌器、温度计和冷凝器的100L玻璃反应器中添加由度洛西汀在丙酮中形成的溶液(11.5%)。溶液在15分钟的时间中在30℃下进行搅拌,将HCl鼓泡通入到溶液中,直至混合物达到pH3和冷却到0℃。所得固体被滤出,用丙酮(30ml×3)洗涤,然后由X射线衍射法(XRD)分析。
实施例3-度洛西汀HCl晶型A的制备
度洛西汀HCl晶型C在真空中箱(27-34毫米汞柱)中在47℃-54℃下干燥6小时。干燥样品由X射线衍射法分析,然后在样品中鉴定晶型A(图4)。
Claims (26)
1.晶体度洛西汀HCl溶剂化物。
2.权利要求1的晶体度洛西汀HCl,其中该溶剂化物是丙酮溶剂化物。
3.通过具有在约10.5°,16.7°,23.9°,24.8°,和27.7°2θ±0.2°2θ处的峰的X射线粉末衍射图案来表征的度洛西汀HCl的晶形。
4.权利要求3的晶形,进一步通过具有在约5.5°,13.3°,和15.4°2θ±0.2°2θ处的峰的X射线粉末衍射图案来表征。
5.权利要求3或4的晶型,通过在图3中描绘的X射线粉末衍射图案来表征。
6.权利要求3,4或5的晶形,具有约9wt%的由TGA测量的重量损失。
7.权利要求3的晶形,它是丙酮溶剂化物。
8.制备权利要求2-7中任何一项的度洛西汀HCl晶体的方法,该方法包括掺混度洛西汀或度洛西汀盐,丙酮和HCl,获得度洛西汀HCl晶体。
9.权利要求8的方法,其中度洛西汀盐是度洛西汀HCl。
10.权利要求8或9的方法,其中度洛西汀在丙酮中的溶液与HCl掺混以沉淀出度洛西汀HCl。
11.权利要求8,9,10或11的方法,进一步包括在HCl的添加之前或之后接种。
12.权利要求11的方法,其中接种是在HCl的添加之前进行。
13.权利要求8-12中任何一项的方法,其中HCl是气态的。
14.权利要求8-13中任何一项的方法,其中在HCl的添加之后获得约3-约5的pH。
15.权利要求8-14中任何一项的方法,其中回收通过过滤来进行。
16.制备通过具有在约9.6°,13.9°,18.1°,18.9°,20.9°和23.4°2θ±0.2°2θ处的峰的X射线粉末衍射图来表征的度洛西汀HCl晶形的方法,该方法包括干燥权利要求3的度洛西汀HCl的晶形。
17.权利要求16的晶形,其中干燥是在大约室温-约70℃下和在低于约1大气压的压力下进行的。
18.权利要求17的方法,其中干燥是在低于约100毫米汞柱的压力下进行的。
19.药物组合物,它包括权利要求3的度洛西汀HCl的晶形和至少一种药物学上可接受的赋形剂。
20.抑制哺乳动物体内血清素和去甲肾上腺素的再摄取的方法,该方法包括对哺乳动物施用权利要求20的药物组合物。
21.制备权利要求1-7中任何一项的度洛西汀HCl晶体的方法,该方法包括将度洛西汀HCl与丙酮掺混,然后回收该晶形。
22.权利要求21的方法,进一步包括在HCl的添加之前或之后接种。
23.权利要求21的方法,其中接种是在HCl的添加之前进行。
24.权利要求21-23中任何一项的方法,其中HCl是气态的。
25.权利要求21-24中任何一项的方法,其中在HCl的添加之后获得约3-约5的pH。
26.权利要求21-25中任何一项的方法,其中回收通过过滤来进行。
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CA2599478A1 (en) * | 2005-03-14 | 2006-09-21 | Teva Pharmaceutical Industries Ltd. | Process for the purification of duloxetine hydrochloride |
US20060165776A1 (en) * | 2005-08-31 | 2006-07-27 | Ramesh Sesha | Antidepressant oral pharmaceutical compositions |
ITMI20051970A1 (it) * | 2005-10-18 | 2007-04-19 | Solmag S P A | Processo per la preparazione di eteri misti derivanti dall'inaftolo e intermedi di forme cristalline definite di + e - duloxetina |
US7759500B2 (en) * | 2005-12-05 | 2010-07-20 | Teva Pharmaceutical Industries Ltd. | 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, an impurity of duloxetine hydrochloride |
EP1820800A1 (en) * | 2006-02-17 | 2007-08-22 | KRKA, tovarna zdravil, d.d., Novo mesto | Crystalline forms of duloxetine hydrochloride and processes for their preparation |
-
2007
- 2007-05-23 MX MX2008001079A patent/MX2008001079A/es unknown
- 2007-05-23 WO PCT/US2007/012591 patent/WO2007139984A2/en active Application Filing
- 2007-05-23 US US11/805,625 patent/US20080027128A1/en not_active Abandoned
- 2007-05-23 CN CNA2007800187266A patent/CN101448815A/zh active Pending
- 2007-05-23 EP EP07795403A patent/EP1934197A2/en not_active Withdrawn
-
2008
- 2008-11-02 IL IL195058A patent/IL195058A0/en unknown
Also Published As
Publication number | Publication date |
---|---|
MX2008001079A (es) | 2008-03-19 |
US20080027128A1 (en) | 2008-01-31 |
WO2007139984A3 (en) | 2008-03-27 |
IL195058A0 (en) | 2009-08-03 |
EP1934197A2 (en) | 2008-06-25 |
WO2007139984A2 (en) | 2007-12-06 |
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