CN101636223A - 制备晶体的方法 - Google Patents
制备晶体的方法 Download PDFInfo
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- CN101636223A CN101636223A CN200880008925A CN200880008925A CN101636223A CN 101636223 A CN101636223 A CN 101636223A CN 200880008925 A CN200880008925 A CN 200880008925A CN 200880008925 A CN200880008925 A CN 200880008925A CN 101636223 A CN101636223 A CN 101636223A
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Abstract
本发明公开了在存在超声波照射的条件下制备活性成分的晶体粒子的方法,该方法包括使在第一流动物流中的溶质在溶剂中的溶液接触在第二流动物流中的反溶剂,引发其混合,其中反溶剂∶溶剂的流速比高于20∶1,并收集产生的晶体。
Description
技术领域
本发明涉及制备小晶体的方法。特别地,本发明涉及制备具有最大约10微米的粒度的小晶体的方法。
背景技术
控制晶体和沉淀物的粒度在一些情况下非常重要,特别是在其中所关注的活性成分的最终产品形式为细粉形式的药物领域和农业化学领域中。活性成分在生物系统中发挥作用的方式根据许多因素的不同而异,所述因素尤其是粒度和晶形。小粒子可通过诸如研磨的方法来制备,但是这种方法可能对材料的性质具有不利影响,并且还可能产生显著比例的不适合所需应用的粒子,例如,这些粒子可能太小或者具有不恰当的形状。这些粒子可能经历形态学改变,发生不希望的表面多形态学转化,其又可导致形成无定形结构。所述粒子可能带大量电荷,这可促进流动速率的削弱。另外,意欲用在气雾剂中的粒子如果带大量电荷则可能受损。希望从溶液直接进行在所需粒度范围内的晶体的结晶。
多年来已知如下进行结晶:将包含待结晶活性成分的溶剂与反溶剂混合,从而使得在混合后所述溶液是过饱和的并发生结晶。所述混合可在存在超声波照射的条件下进行或者以不同方式(其中不使用超声波照射)如流体涡流混合方式进行。术语“反溶剂”是指促进从所关注的活性成分(或活性成分的前体)的溶剂中沉淀的流体。反溶剂可包括冷气体,或通过化学反应促进沉淀的液体,或者其降低所关注的活性成分在溶剂中的溶解度;其可能是与溶剂相同的、但处于不同温度下的液体,或者其可能是与溶剂不同的液体。
EP 1144065描述了一种系统,在该系统中,使用最高为10∶1的反溶剂∶溶剂的流速比,在存在超声波照射的条件下,在连续流动单元内,实现反溶剂与包含待结晶活性成分的溶剂的混合。其描述了将温热溶剂与冷的可混溶的反溶剂混合,尽管未公开冷的反溶剂的实际温度。
EP 1469938描述了一种系统,在该系统中,以最高为10∶1、通常为2∶1到最高5∶1的流速比,反溶剂与包含待结晶活性成分的溶剂的混合流速超过溶剂的流速。在存在超声辐射的条件下进行这一混合。
现有技术的方法能够采用通常低于20∶1的反溶剂∶溶剂的流速比(即,接近10∶1到低至1∶1的流速比)来制备晶体。
发明内容
根据本发明,提供了在存在超声波照射的条件下制备物质的晶体粒子的方法,该方法包括使在第一流动物流中的在溶剂中的至少一种溶质接触在第二流动物流中的反溶剂,其中反溶剂∶溶剂的流速比高于20∶1,并收集产生的晶体。
反溶剂物流典型地在例如连续式再循环流动物流中即在本文所述的第二流动物流中经历再循环。典型地,根据本发明提供了其中第二流动物流是还可包含被加入的在溶剂中的溶质的连续式再循环反溶剂物流的方法,其中所述第二流动物流(即反溶剂)∶溶剂的流速比高于20∶1。
在本发明的方法中,通过操控反溶剂∶溶剂的流速比,本发明人发现现在有可能提供所关注的活性成分的具有最大约10微米的所需粒度的晶体。能够使用本发明的方法所获得的粒子的平均粒径为500纳米到10微米,优选约600纳米到约5微米,和最优选650纳米到约2微米,例如为700纳米或1微米。
溶质可以是活性成分或其所需前体,诸如能够在本发明的方法中形成晶体的所关注的药物或农业化学品。在第一流动物流中可能存在超过一种的溶质,例如,是两种或更多种所关注的溶质的混合物,诸如两种或更多种所关注的活性成分,例如,两种或更多种药物,或两种或更多种农业化学品,根据所述溶质被提议的最终用途的不同而异。在本发明的方法条件下能够结晶的适合的溶质包括通过本发明的方法可形成晶体粒子的活性成分或药物,诸如皮质类固醇类,b2-激动剂,抗胆碱能药物,白细胞三烯拮抗剂,可吸入的蛋白质或肽,糠酸莫米松;二丙酸氯地米松;布地奈德;氟替卡松;地塞米松;氟尼缩松;曲安西龙;沙丁胺醇;舒喘宁;特布他林;沙美特罗;比托特罗;异丙托溴铵;氧托溴铵;色甘酸二钠;奈多罗米钠;扎鲁司特;普仑司特;福莫特罗;eformoterol;班布特罗;非诺特罗;克仑特罗;丙卡特罗;溴沙特罗;(22R)-6a,9a-二氟-11b,21-二羟基-16a,17a-丙基亚甲二氧基-4-孕甾烯-3,20-二酮;TA-2005;替泼尼旦;胰岛素;干扰素;降钙素;甲状旁腺激素;和粒细胞集落刺激因子。
可根据本发明被制备的其它粒子包括任何的可用于通过吸入被递送的药物或活性成分,例如,镇痛药,例如,可待因,双氢吗啡,麦角胺,芬太尼或吗啡;心绞痛制剂,例如地尔硫卓;抗过敏药,例如色甘酸盐,酮替芬或奈多罗米;抗感染药,例如头孢菌素类,青霉素类,链霉素类,磺酰胺类,四环素类或喷他脒;抗组胺药,例如美沙吡林;抗炎药,例如倍氯米松,氟尼缩松,布地奈德,替泼尼旦,曲安奈德或氟替卡松;镇咳药,例如那可丁;支气管扩张药,例如麻黄碱,肾上腺素,非诺特罗,福莫特罗,异丙肾上腺素,奥西那林,去氧肾上腺素,苯丙醇胺,吡布特罗,瑞普特罗,利米特罗,沙丁胺醇,沙美特罗,特布他林;新异丙肾上腺素,妥洛特罗,奥西那林或(-)-4-氨基-3,5-二氯-a[[[6-[2-(2-吡啶基)乙氧基]己基]氨基]甲基]苯甲醇;利尿药,例如阿米洛利;抗胆碱能药,例如异丙托铵,阿托品或氧托品;激素,例如可的松,氢化可的松或氢化泼尼松;黄嘌呤类,例如25氨基茶碱,胆茶碱,赖氨酸茶碱或茶碱;和治疗性蛋白质和肽,例如胰岛素或高血糖素。本领域技术人员可理解的是,如果适当的话,包含活性成分或药物的药剂可以盐(例如,作为碱金属盐或胺盐或作为酸加成盐)或酯(例如低级烷基酯)或溶剂合物(例如水合物)的形式被使用,从而使药剂的活性和/或稳定性最佳。
使用根据本发明方法获得的粒子进行制备的特别适合的药剂包括可用于通过吸入疗法治疗呼吸系统疾病诸如哮喘的抗过敏药、支气管扩张药和甾体抗炎药,例如色甘酸盐(例如作为钠盐),沙丁胺醇(例如作为游离碱或作为硫酸盐),沙美特罗(例如作为昔萘酸盐),特布他林(例如作为硫酸盐),瑞普特罗(例如作为盐酸盐),二丙酸氯地米松(例如作为一水合物),丙酸氟替卡松或(-)-4-氨基-3,5-二氯-α-[[[6-[2-(2-吡啶基)乙氧基]己基]氨基]甲基]苯甲醇及其生理学可接受的盐和溶剂合物。
本领域技术人员可理解的是,通过本发明方法制备的粒子可包含两种或更多种活性成分的组合。活性成分可选自上文所述的活性成分的适当组合。因此,支气管扩张药的适当组合包括麻黄碱+茶碱,非诺特罗+异丙托铵,和新异丙肾上腺素+去氧肾上腺素。
根据本发明的方法制备的活性成分的粒子的其它适当的组合包括皮质类固醇类(诸如布地奈德、二丙酸氯地米松和丙酸氟替卡松)与b2-激动剂(诸如沙丁胺醇、特布他林、沙美特罗和氟替卡松),沙美特罗和福莫特罗及其生理学可接受的衍生物(特别是包括硫酸盐在内的盐)的组合。
可通过本发明方法获得的粒子的其它实例可包括cromone,其可为色甘酸二钠,或奈多罗米,或可包括碳水化合物例如肝素。
通过本发明方法制备的粒子可包含适用于吸入的活性成分并且可为用于系统(systemic)使用的药理学活性剂。例如,这些活性粒子可包括肽或多肽或蛋白质,诸如去氧核糖核酸酶,白三烯(leukotine)或胰岛素(包括胰岛素原),环孢子菌素,白细胞介素,细胞因子,抗细胞因子和细胞因子受体,疫苗,生长激素,醋酸亮内瑞林(leuprolide)和有关类似物,干扰素,去氨加压素,免疫球蛋白,促红细胞生成素和降钙素。
作为替代,通过本发明方法制备的活性成分可适用于口服给药。用于口服给药的药物可为上述系统用药物之一。活性成分可为在消化道中表现出低溶解度的物质,例如三硅酸镁、碳酸钙和次硝酸铋。有机化合物可包括,例如,所有的组合化学产品,罗格列酮和其它有关的格列酮类药物,氢氯噻嗪,灰黄霉素,拉米夫定和其它核酸酶逆转录酶抑制剂,辛伐他汀和其它的他汀类药物,苯扎贝特和其它的贝特类药物以及氯雷他定,及其任何其它的生理学可接受的盐和衍生物。
适合被附加到根据本发明方法制备的粒子上的药物赋形剂包括例如碳水化合物,特别是单糖,诸如果糖、葡萄糖和半乳糖;非还原二糖,诸如蔗糖、乳糖和海藻糖;非还原低聚糖,诸如棉子糖和松三糖;非还原淀粉由来的多糖产品,诸如麦芽糖糊精、右旋糖酐和环糊精;和非还原醛糖醇,诸如甘露醇和木糖醇。
当通过本发明方法制备的一种或多种活性成分的粒子是农业化学活性剂时,所述活性成分可为,例如,植物生长调节剂,除草剂和/或杀虫剂,例如杀昆虫剂、杀真菌剂、杀螨剂、杀线虫剂、杀疥虫剂,灭鼠剂,杀细菌剂,杀螺剂或驱禽剂。
根据本发明方法制备的非水溶性的有机农业化学活性成分的实例包括杀昆虫剂,例如选自氨基甲酸酯类,诸如灭多虫、胺甲萘、克百威或涕灭威;有机硫代磷酸酯类,诸如EPN、异柳磷、异噁唑磷、毒死蜱或氯甲磷;有机磷酸酯类,诸如特丁磷、久效磷或四氯速灭磷;全氯化有机物诸如甲氧滴滴涕;合成除虫菊酯,诸如氰戊菊酯;杀线虫氨基甲酸酯类,诸如草氨酰除草剂,例如选自三嗪类诸如嗪草酮、环嗪酮或莠去津;磺酰脲类诸如2-氯-N-[(4-甲氧基-6-甲基-1,3,5-三嗪-2-基)氨基羰基]-苯磺酰胺;尿嘧啶类(嘧啶类),诸如环草定、除草定或特草定;尿素类,诸如利谷隆、敌草隆、环草隆或草不隆;乙酰苯胺类,诸如甲草胺或异丙甲草胺;硫代氨基甲酸酯类,诸如杀草丹(SATURN)、野麦畏;噁二唑酮类,诸如恶草酮;苯氧乙酸类诸如2,4-D;二苯醚类,诸如吡氟禾草灵、三氟羧草醚、甲羧除草醚或乙氧氟草醚;二硝基苯胺类,诸如氟乐灵;膦酸甘氨酸类,诸如草甘膦的盐和酯;二卤代苄腈类,诸如溴苯腈或碘苯腈;杀真菌剂,例如选自次硝基肟类,诸如霜脲氰(清菌脲);咪唑类,诸如苯菌灵、多菌灵或托布津-甲基;三唑类,诸如三唑酮;亚磺酰胺类,诸如克菌丹;二硫代氨基甲酸酯类,诸如代森锰、代森锰锌或秋兰姆;氯代芳烃类,诸如地茂散;二氯苯胺类,诸如异菌脲;杀蚜虫剂,例如选自氨基甲酸酯类,诸如抗蚜威;杀疥虫剂,例如选自丙炔基亚硫酸酯类,诸如克螨特;三氮杂戊二烯类,诸如阿米曲士;氯化芳烃类,诸如乙酯杀螨醇或四氯杀螨砜;和二硝基酚类,诸如乐杀螨。
非水溶性的有机农业化学活性成分可作为几种成分的混合物的形式被包含在根据本发明制备的粒子中。特别优选的非水溶性的有机农业化学活性成分是莠去津、霜脲氰、百菌清、环丙唑醇和戊唑醇。
包含溶质的溶剂(即“溶液”)的流动物流和反溶剂的流动物流可发生接触或混合在一起,从而使得两个物流沿着单一路径或轴线在相同方向流动,例如,在适合的递送工具的腔内流动,并进入适合的容器或室,诸如超声波连续流动单元。所述流动物流各自可以预定的流速从初始来源储器被泵送进入递送工具。适合的递送工具可包括管状工具诸如直管道或弯管道,例如,导管,并且两个物流可在其中发生同轴混合。作为替代,被泵送通过分离的递送工具,诸如两个分离的管状工具,例如两个导管,两个物流可被引入容器或室,诸如超声波连续流动单元内。
本发明的反溶剂∶溶剂的流速比(下文称为“流速比”)高于20∶1,并且可以根据使用本发明方法获得的晶体的设计和最终目的的不同而为任何流速比。在本发明方法中采用的流速比可基于以下考虑进行确定:所关注的物质,对于给定目的所要求的晶体的所需粒度,和如何以适合的药剂形式将晶体给予到受试者诸如哺乳动物(例如人;马;牛属动物;或羊)或如何以适合的农业化学品形式(例如杀虫剂,除草剂,杀真菌剂,杀细菌剂或杀病毒剂)将晶体给予到植物。用于本发明方法中的适合的流速比可为第二流动物流∶第一流动物流的流速比为最高1000∶1的任何流速比,例如,900∶1、800∶1、700∶1、600∶1、500∶1、400∶1、300∶1、200∶1、100∶1、50∶1、40∶1或30∶1,或者是其之间的任何流速比,诸如380∶1、330∶1、333∶1、165∶1、80∶1等等。所述流速比将根据对于给定的最终目的所要求的晶体尺寸以及要用于受试者有机体中的被提议的递送媒介物的不同而异。
典型地,对于使用本发明方法制备晶体粒子适用的反溶剂物流通过仪器的流速在若干升/小时(l/hr)[例如20L/hr]而非若干毫升/小时(ml/hr)的范围内,并且可为任何的适合正被讨论的最终目的的流速,只要反溶剂的流速以至少20∶1的比(并以本文所述的更高比)高于溶剂系统(即在溶剂中的溶质)的流速即可。例如,对于台式仪器而言,本发明的第一物流的流速可为20l/hr以及第二物流的流速为60ml/hr。当该方法在更大型仪器例如100升(1001)容器中被采用时,第一物流的通过流速可为2400l/hr以及第二物流的通过流速可为120l/hr。
自然地,本领域技术人员可理解的是,所述物流各自的流速可为任何所需流速,条件是两个物流的流速比是本发明所述的流速比。
在小型仪器中,诸如具有1升、5升或10升容量的仪器中,反溶剂的流速可为最高50l/hr,典型地为最高40l/hr,30l/hr,20l/hr,10l/hr或5l/hr,或者是之间的任何值,诸如4l/hr,8l/hr,15l/hr等等。该流速可由本领域技术人员根据对于特定的最终目的被选择的给药到所关注的部位的给药途径所要求的粒子大小来决定。相应地,要被加入的在溶剂中的溶质的溶液的流速将是其要接触的反溶剂的流速的最多1/20。本发明使用的流速比的实例(333∶1)在其中反溶剂流速为20l/hr和在溶剂中的溶质的流速为60ml/hr的实施例中可见。
可理解的是,反溶剂和溶剂应经过选择以适合特定的活性成分或其活性前体。反溶剂和溶剂对彼此可混溶。可混溶的反溶剂和溶剂对的实例包括水和2-丙醇;以及乙醇和水。作为替代,反溶剂和溶剂对可为处在不同温度下的相同液体。典型地,液体的温度可为-10℃到+120℃,但是在两个温度之间具有相当大的温度差。温度差可为50℃以上,例如,其中溶剂是热水(例如80℃)并且反溶剂是冷水(例如10℃)。适当的溶剂和反溶剂的选择必须根据待结晶物质来进行。
当在容器内部例如连续超声波流动单元内时,反溶剂和溶剂的合并的物流经历超声波照射以形成具有所需平均尺寸的晶体。超声能诱导在反溶剂中的溶质在超声波探针(如果使用超声波探针的话)的工作附近区域或在超声能换能器诸如环绕式超声能换能器(如果使用超声能换能器的话)的工作附近区域的成核和随后结晶。超声能可以连续或非连续的方式被施加,诸如通过脉冲施加。可使用任何适合的超声波照射来源。超声波探针可被例如插入到混合容器诸如连续超声波流动单元中,超声波发生器可被包含在混合容器中,或者可将混合容器放在超声波浴中,或者可在混合容器的外壁上固定超声换能器。超声波的振幅和频率影响成核速率和晶体生长。超声波的频率可为例如20kHz到1MHz,优选10-500kHz,更优选10-100kHz,诸如为10、20、40、60、80或100kHz,或者之间的任何频率,诸如20kHz或40kHz。
在适合形成具有用于预定应用的所需粒度的晶体的振幅下使用超声波照射。对于具有例如80平方厘米发射面的实验室探针系统而言,所选振幅可为约1-30微米,典型地为3-20微米,优选5-10微米,例如为5微米。具有8平方厘米的探针工作面积和5-80W功率需求的探针使用2-15微米的振幅提供0.6-12.5W/cm2的功率密度。在更大型的系统中,包括被结合到流动单元例如6升流动单元上的换能器在内,所用换能器的功率密度可为150-600W/l,优选250-600W/l,更优选300-600W/l,例如为250W/l或450W/l。
混合的组分在超声波流动单元内的停留时间可为10毫秒到最高约10秒。对于再循环系统,停留时间可根据设计的不同而更长。本领域技术人员可理解的是,对于被放入超声波流动单元内的每种流体量而言,在超声波流动单元内的停留时间根据设计的不同可为10毫秒到最高10秒左右。
该方法可被用在本领域所用的反应器中,诸如批进料反应器或连续流动反应器中,根据设计的不同而异。本领域技术人员对于这些反应器类型及其操作是充分获知的。通过使用本领域的传统方式从批料室中抽取,可以聚集或收获产生的晶体,诸如通过WO 03/092851中所述的方法。
现在将参考实施例和附图描述本发明。可理解的是,所述实施例和附图不被认为以任何方式限制本发明的范围。
发明详述
本发明的方法可采用附图中所示的常规设备进行,在附图中,
图1表示结晶设备的纵向剖视图,该仪器并入两个分离的进料物流递送工具,用于将溶剂和反溶剂引入其上布置有超声波探针的超声波连续流动单元内;
图2显示结晶设备的纵向剖视图,该仪器并入单一的进料物流递送工具,溶剂和反溶剂在该单一的进料物流递送工具中被同轴地引入、混合并以单一物流被驱入其上结合有超声波传感仪器的超声波连续流动单元内。
图3显示实施例1的结果。
图4显示实施例2的结果。
图5显示实施例3的结果。
图6显示实施例4的结果。
回到图1,闭合回路结晶设备10在第一进料室4(由热夹套3围绕)内包括转子5,轴向出口6(液体反溶剂经其流入递送工具7并经由泵8以第一流速被泵入超声波流动单元室12内)。同时,在溶剂中的液体溶质经由泵9以与反溶剂流速是不同的流速从第二室(未示出)被泵送通过递送工具10到达递送工具11以及进入超声波流动单元室12内,两种液体在12内被混合。超声波探针1使用超声能照射混合物,并且混合物流过出口2并进入第一进料室4,完成了连续闭合流动回路。流动循环重复进行直到获得具有所需大小的结晶粒子。因此,在使用仪器10时,饱和溶液与反溶剂彻底地和迅速地混合,室4的体积和流速为使得在超声波流动单元室12内的停留时间为例如10秒。来自探针1的超声能以足够的强度使室12的整个体积经受声波作用,以引起分散和成核,因为在微观水平下发生的局部空穴作用促进流体温度和压力的改变,这一改变诱导成核(还促进形成稳定的多晶型物)。通过调节超声的功率以及在室12内的停留时间,从而可控制成核程度。超声具有的额外益处是,在室12内的任何晶体沉积物倾向于从表面被除去。
本领域技术人员可理解的是,图1中的闭合回路结晶设备10可以不同方式被构建,例如,用单一递送工具代替递送工具11,在单一递送工具中,得自递送工具7和10的两种液体进料可在其中同轴接触,然后通过单一入口被进料到超声波流动单元室12中。
参见图2,闭合回路结晶设备20与图1具有类似的构造,不同之处在于室22具有位于室22外表面上的环绕式超声换能器23。环绕式超声换能器23以足够的强度使室22的整个体积经受声波作用以引发成核,并且因此可通过调节超声的功率和在室22内的停留时间来控制成核程度。超声具有的额外益处是,在室22内的任何晶体沉积物倾向于从表面被除去。
图2的构造与图1的构造的其它差异在于,得自递送工具7和10的两个液体进料在单一递送工具21内同轴接触并经由单一入口被进料到超声波室22内。
本领域技术人员还可理解的是,到达超声波流动室22的递送工具还可遵循图1中的递送工具的构造。
本领域技术人员可理解的是,热夹套被设计用来帮助保持反溶剂的温度处于所需温度,这根据设计的不同而异。
实施例1
将2-丙醇(0.7L)加入到1L的装备有热调节夹套的搅拌的结晶器(200rpm)中。将温度调节到16℃。使用隔膜泵(在20l/h工作)和装备有30mm直径的20kHz超声波探针的60ml热调节式玻璃超声波流动单元使2-丙醇围绕再循环回路被泵送。探针被保持在流动单元的最高位置上并以零振动点(结点)被密封/夹紧。流动单元在16℃进行热调节。施加在15W功率、5微米振幅的连续超声。将L-缬氨酸(1.5g)溶于水(35ml)中,然后使用在流动单元下侧的第二入口以60ml/h的速率被泵入超声波流动单元内。当完成L-缬氨酸溶液的添加时,通过微过滤或喷雾干燥分离微晶产品。
结果如图3所示。
实施例2
将2-丙醇(1L)加入到1L的装备有热调节夹套的搅拌的结晶器。将温度调节到16℃。使用隔膜泵(在20l/h工作)和装备有30mm直径的20kHz超声波探针的60ml热调节式玻璃超声波流动单元使2-丙醇围绕再循环回路被泵送。探针被保持在流动单元的最高位置上并以零振动点(结点)被密封/夹紧。流动单元在16℃进行热调节。施加在15W功率、5微米振幅的连续超声。将L-谷氨酸(4.5g)溶于水(100ml)中以形成饱和溶液,然后使用在流动单元下侧的第二入口以60ml/h的速率被泵入超声波流动单元内。当完成L-谷氨酸溶液的添加时,通过微过滤或喷雾干燥分离微晶产品。
结果如图4所示。
实施例3
将庚烷(0.75L)加入到1L的装备有热调节夹套的搅拌的结晶器(250rpm)中。将温度调节到5℃。使用隔膜泵(在20L/h工作)和装备有30mm直径的20kHz超声波探针的60ml的热调节式玻璃超声波流动单元使庚烷围绕再循环回路被泵送。探针被保持在流动单元的最高位置上并以零振动点(结点)被密封/夹紧。流动单元在5℃进行热调节。施加在15W功率、5微米振幅的连续超声。将布地奈德(1.5g)溶于甲醇(100ml)中,然后使用在流动单元下侧的第二入口以20ml/h的速率被泵入超声波流动单元内。当完成布地奈德溶液的添加时,将混合物保持在再循环下历时另外30分钟。通过超临界二氧化碳辅助干燥(以除去非极性溶剂)、微过滤或者喷雾干燥分离微晶产品。
结果如图5所示。
实施例4
将水(0.7L)加入到1L的装备有热调节夹套的搅拌的结晶器(200rpm)中。将温度调节到16℃。使用隔膜泵(在20l/h工作)和装备有30mm直径的20kHz超声波探针的60ml的热调节式玻璃超声波流动单元使水围绕再循环回路被泵送。探针被保持在流动单元的最高位置上并以零振动点(结点)被密封/夹紧。流动单元在16℃进行热调节。施加在15W功率、5微米振幅的连续超声。将奥美沙坦(2.1g)溶于丁酮(70ml)中,然后使用在流动单元下侧的第二入口以20ml/h的速率被泵入超声波流动单元内。当完成奥美沙坦溶液的添加时,通过微过滤或喷雾干燥分离微晶产品。
结果如图6所示。
Claims (16)
1.在存在超声波照射的条件下制备活性成分的晶体粒子的方法,该方法包括使在第一流动物流中的至少一种溶质在溶剂中的溶液接触在第二流动物流中的反溶剂,引发其混合,其中反溶剂∶溶剂的流速比高于20∶1,并收集产生的晶体。
2.权利要求1的方法,其中溶质包括至少一种活性成分或其前体。
3.权利要求1或2的方法,其中溶质包括至少一种活性成分。
4.权利要求1或2的方法,其中溶质包括两种活性成分的混合物。
5.权利要求3的方法,其中活性成分是丙酸氟替卡松。
6.权利要求3的方法,其中活性成分是沙丁胺醇。
7.权利要求1-6中任一项的方法,其中液体反溶剂与液体溶剂可混溶。
8.权利要求7的方法,其中液体反溶剂和溶剂是相同的并且反溶剂被保持在与溶剂温度不同的温度。
9.权利要求1-8中任一项的方法,其中液体反溶剂温度和溶剂温度为-10℃到+120℃并且溶剂温度和反溶剂温度的温度差为至少50℃。
10.权利要求1-9中任一项的方法,其中溶质是适用于吸入疗法的活性成分或载体物质。
11.权利要求1-10中任一项的方法,其中反溶剂∶溶剂的流速比为最高1000∶1。
12.权利要求11的方法,其中流速比为20∶1到900∶1。
13.权利要求12的方法,其中流速比为20∶1到500∶1。
14.权利要求13的方法,其中流速比为20∶1到400∶1。
15.权利要求14的方法,其中流速比为20∶1到380∶1。
16.权利要求15的方法,其中流速比为约333∶1。
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EP (1) | EP2134457B1 (zh) |
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CN (1) | CN101636223B (zh) |
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CA (1) | CA2680105C (zh) |
ES (1) | ES2701728T3 (zh) |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102872612A (zh) * | 2012-10-15 | 2013-01-16 | 中国工程物理研究院化工材料研究所 | 超声结晶器 |
CN102872612B (zh) * | 2012-10-15 | 2013-11-27 | 中国工程物理研究院化工材料研究所 | 超声结晶器 |
CN104955449A (zh) * | 2013-01-31 | 2015-09-30 | 普罗索尼克斯有限公司 | 用于吸入治疗的多组分结晶颗粒 |
CN103172476A (zh) * | 2013-04-08 | 2013-06-26 | 中国工程物理研究院化工材料研究所 | 一种亚微米颗粒1-氧-二氨基-3,5-二硝基吡嗪炸药的制备方法 |
CN105037253A (zh) * | 2015-05-27 | 2015-11-11 | 上海应用技术学院 | 一种超声逼晶法提纯化合物的方法 |
CN110773079A (zh) * | 2019-11-18 | 2020-02-11 | 江苏博迁新材料股份有限公司 | 一种超声喷雾法制备超细粉球的方法 |
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EP2134457B1 (en) | 2018-09-12 |
JP2014094965A (ja) | 2014-05-22 |
CA2680105C (en) | 2016-05-17 |
EP2134457A1 (en) | 2009-12-23 |
ES2701728T3 (es) | 2019-02-25 |
RU2009138325A (ru) | 2011-04-27 |
WO2008114052A1 (en) | 2008-09-25 |
GB2447761B (en) | 2012-02-29 |
US20100018853A1 (en) | 2010-01-28 |
BRPI0809275A2 (pt) | 2014-10-14 |
CA2680105A1 (en) | 2008-09-25 |
IL200802A (en) | 2013-04-30 |
US10143991B2 (en) | 2018-12-04 |
GB0804995D0 (en) | 2008-04-16 |
GB0705159D0 (en) | 2007-04-25 |
GB2447761A (en) | 2008-09-24 |
US9162160B2 (en) | 2015-10-20 |
CN101636223B (zh) | 2015-09-16 |
JP2010522154A (ja) | 2010-07-01 |
US20160001252A1 (en) | 2016-01-07 |
IL200802A0 (en) | 2010-05-17 |
RU2456066C2 (ru) | 2012-07-20 |
JP5808830B2 (ja) | 2015-11-10 |
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