CN103992320A - 一种混悬结晶制备药物共晶的方法 - Google Patents
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Abstract
本发明涉及一种混悬结晶制备药物共晶的方法,其具体步骤为:先在不同溶剂中进行药物有效活性成分API和共晶形成物CCF的固体形态筛查,选用与API和CCF都不生成溶剂化物的溶剂配制CCF饱和溶液;在釜式搅拌器中投入配制好的CCF饱和溶液,按照一定的固体负载率投入固体API和CCF,并且API和CCF摩尔量的比值根据共晶化学计量学比决定;经过充分搅拌混合后,取样做XRD或DSC测试,证明是纯的共晶固体相后,所得固体经真空抽滤,CCF饱和溶液洗涤、干燥工序处理后得到的固体即为最终的共晶产品。相比其他方法来说,该法能耗低、使用溶剂少、成本低廉、工艺简单、易于放大、快速易得、且产品纯度高,适合工业上大批量合成药物共晶。
Description
技术领域
本发明属于医药技术领域,具体涉及一种混悬结晶制备药物共晶的方法。本发明提供一种工艺简单、易于放大、成本低廉、生产效率高、纯度达100%的药物共晶制备方法。
背景技术
1988年,法国科学家Lehn(Jean-Marie Lehn.SupramolecularChemistry—Scope and Perspectives Molecules,Supermolecules,and MolecularDevices(Nobel Lecture),Angewandte Chemie International Edition in English,1988,27:89-112)首次提出了超分子化学概念。超分子化学是基于分子间非共价键相互作用而形成的分子聚集体化学。物质的性质及功能除了依赖构成体系的分子的性质,还取决于分子的聚集形式及分子以上层次的高级结构。超分子化学主要研究分子之间通过非共价键(氢键、范德华力、π-π堆积、静电)及其之间的协同作用而形成的分子集聚体的结构与功能。
晶体工程学将超分子化学的原理应用于晶体的设计与生长,通过分子识别和自组装过程的共同作用,得到结构可调控且具有特定物化性质的新晶体。
超分子化学和晶体工程学在药物开发中的应用研究是国际学术界和工业界共同关注的一个热点。
常见固态药物有效成分根据其固体形态可分为:多晶型、无定型、溶剂化物、水合物、盐、和共晶。
药物有效活性成分(API)和共晶形成物(CCF)以固定的化学计量比通过非共价键,例如氢键结合形成的超分子化合物晶体mAPI·nCCF称为药物共晶,并且所用单体在常温下是固体。
作为一种新型药物固体形态,药物共晶可能会改善药物本身的物化性质(改变熔点、药物溶解度和溶出速率、以及生物利用度、稳定性、和可压缩性)。由于共晶形成物选择的多样性,药物共晶可以延长原有药物的专利保护期。
共晶的制备方法大体可以分为研磨法、溶液法和熔融法三类。鉴于熔融法工艺复杂、过程繁琐、能耗高等缺点,研磨法和溶液结晶法较常用。研磨法是将API和CCF混合于研钵或球磨机中研磨,借助机械力来制备共晶,此法取决于形成共晶的两种分子的结构互补性和移动性。人们对研磨法制备药物共晶的的过程机理认识不足,大批量制备中经常出现产品不纯的问题。溶液结晶法是将API和CCF按照一定的化学计量比加入到合适的溶剂中进行共结晶,API和CCF的相互作用要强于其它分子间的作用力,共晶才能生成。根据制备工艺的差异,溶液结晶包括反应结晶、溶剂挥发、和冷却结晶等方式。溶液结晶需要选择合适的溶剂、结晶方式及工艺条件、和组分之间的化学计量比,避免API或CCF单独析出(Andrew V.Trask,Jacco van de Streek,W.D.Samuel Motherwell,and WilliamJones.Achieving Polymorphic and Stoichiometric Diversity in Cocrystal Formation:Importance of Solid-State Grinding,Powder X-ray Structure Determination,andSeeding.Crystal Growth&Design,2005,5(6):2233–2241;Margaret C.Etter,SusanM.Reutzel.Hydrogen bond directed cocrystallization and molecular recognitionproperties of acyclic imides.Journal of American Chemical Society,1991,113(7):2586–2598)。通过研究API、CCF和共晶的溶解度关系(Bethune S.J.,Huang N.,Jayasankar A.,Rodriguez-Hornedo N.Understanding and predicting the effect ofcocrystal components and pH on cocrystal solubility.Crystal Growth&Design.,2009,9:3976-3988),构建三元相图,研究API、CCF、和共晶三者在三元相图中的稳定区间(Renato A.Chiarella,Roger J.Davey,and Matthew L.Peterson.MakingCo-Crystals-The Utility of Ternary Phase Diagrams.Crystal Growth&Design,2007,7(7):1223–1226),人们可以得出API、CCF以及共晶三者竞争导致API或CCF单独析出或者与共晶混合析出的原因。当API和CCF在溶液中的溶解度相差比较大的时候,溶液结晶很难制备得到纯的共晶,药物共晶甚至难以生成。鉴于药物共晶日益成为固体药物制剂的一个备选,工业界急需要一种能制备高纯度药物共晶的方法。
发明内容
本发明的目的是为了改进现有技术的不足而提供一种混悬结晶制备药物共晶的方法。本发明工艺简单、易于放大、成本低廉、生产效率高、纯度高。
本发明的技术方案为:借鉴晶体不同晶型转变过程中的溶剂介导相变理论,在混悬法的基础上加以改进,提供了一种工艺简单、易于放大、成本低廉、生产效率高、纯度达100%的药物共晶制备方法,其前提是该药物共晶是真实存在的,但由于制备条件未满足共晶的稳定条件导致共晶难以合成。
本发明的具体技术方案为:一种混悬结晶制备药物共晶的方法,其具体步骤如下:先在不同溶剂中进行API和CCF的固体形态筛查,选用与API和CCF都不生成溶剂化物的溶剂。用此溶剂来配制CCF的饱和溶液。在釜式搅拌器中先投入配制好的CCF饱和溶液,然后按照一定的固体负载率并且根据共晶的化学计量学比投入固体药物有效活性成分API和共晶形成物CCF,经过充分搅拌混合后,取样做XRD或DSC测试,证明是纯的共晶固体相后,所得固体经真空抽滤、CCF饱和溶液洗涤、干燥工序处理后得到药物共晶产品;其中配制共晶形成物CCF的饱和溶液所用溶剂为与API和CCF均不生成溶剂化物的溶剂。
该方法可用于由如下官能团而形成氢键的药物共晶:酰胺-羧酸、酰胺-酰胺、嘌呤-酰胺、羟基-酰胺或嘌呤-羧酸。该法已经成功制备了如下共晶:
●卡马西平-苯甲酸(摩尔比1:1),其氢键属于酰胺-羧酸类;
●卡马西平-4,4’-联吡啶(1:1),其氢键属于酰胺-酰胺类;
●咖啡因-乙二酸(2:1)、咖啡因-马来酸(2:1)、咖啡因-丙二酸(2:1),其氢键属于嘌呤-羧酸类;
●吲哚美辛-糖精(1:1),其氢键来自于羧酸-羧酸、酰胺-酰胺、N-H···O;
●茶碱-对乙酰氨基酚(1:1),其氢键属于嘌呤-酰胺和羟基-酰胺。
固体形态筛查的溶剂根据其极性强弱、形成氢键的供受体选择,可以是以下的一种或混合溶剂:水、甲醇、乙醇、环己烷、氯仿、丁酮、1,4-二氧六环、甲酰胺、硝基甲烷、乙酸异丙烯酯、正丙醇、乙腈、甲苯、乙酸乙酯、1,2-二氯乙烷、醋酸异丙酯、二氯甲烷、二甲基酰胺等。
本发明需要配制CCF在上述溶剂中的饱和溶液,投入CCF饱和溶液中的固体API和固体CCF通过溶剂介导相变的方式在悬浊液中生成共晶。
投入CCF饱和溶液中的固体是API和CCF,二者可以先后投入或一起投入,但API和CCF的物质的量的比值需根据共晶的化学计量学比决定;固体负载率(API和CCF固体混合物与CCF饱和溶液的比值)可控制在每升CCF饱和溶液中有30-100g混合固体。
在上述方法,反应温度控制在常温10-30℃之间,由于结晶过程对温度很敏感,在整个共晶制备过程中,温度要得到有效的控制。本发明在常温下制备共晶节省了大量能耗,但要保证操作在相同的温度条件下。CCF饱和溶液也是该温度下的饱和溶液。
有益效果:
1.API和CCF都经过严格的固体形态筛查,这样确保最终的产物是纯的药物共晶,排除了可能存在的溶剂化物。
2.反应温度可以在常温下进行,温度容易控制,无蒸发和冷却结晶过程中产生的能耗问题,降低了能耗。
3.混悬法不需要使用大量的溶剂,极大地节约了成本和减少了后续的溶剂回收利用。
4.与常规的混悬法相比,本发明采用CCF的饱和溶液,这样根据共晶计量学比投入反应器中的API和CCF按照摩尔比生成共晶,所得共晶纯度高。因为一般情况下API的溶解度小,配制好的CCF饱和溶液限制了CCF的继续溶解,保证了共晶中API和CCF的比例。
5.该法操作简单、快速易得、且产品纯度高,适合工业上大批量合成药物共晶。
附图说明
图1为实施例1茶碱-对乙酰氨基酚药物共晶和单体茶碱(THEO)及对乙酰氨基酚(APAP)的XRD图;
图2为实施例1茶碱-对乙酰氨基酚共晶的DSC-TG图;
图3为实施例2咖啡因-乙二酸共晶(2:1)和单体咖啡因及乙二酸的XRD图;
图4为实施例2咖啡因-马来酸共晶(2:1)和单体咖啡因及马来酸的XRD图;
图5为实施例2咖啡因-丙二酸共晶(2:1)和单体咖啡因及丙二酸的XRD图。
具体实施方式
下面结合实施例对本发明的技术方案做进一步说明,以下实施例不对本发明产生限制。
实施例1:
茶碱-对乙酰氨基酚(THEO-APAP)共晶在甲醇、乙醇、乙腈、丙酮、丁酮、硝基甲烷6种不同溶剂中的制备:
在这六种溶剂中,茶碱(THEO)作为API,对乙酰氨基酚(APAP)作为CCF,THEO和APAP在六种溶剂中均不存在溶剂化物,茶碱和对乙酰氨基酚能按照摩尔比1:1生成共晶茶碱-对乙酰氨基酚。先配制APAP对乙酰氨基酚的饱和溶液1000mL。在甲醇、乙醇、乙腈、丙酮、丁酮、硝基甲烷六种溶剂中,APAP对乙酰氨基酚的溶解度分别为216.3、139.9、22.2、73.6、48.0、3.9mg/mL,THEO茶碱的溶解度分别为6.1、3.4、1.6、2.3、1.6、1.5mg/mL。在APAP的饱和溶液中投入18.0g茶碱THEO(0.1mol)和15.1g对乙酰氨基酚APAP(0.1mol),这样投入CCF饱和溶液中的THEO和APAP各是0.1mol,固体负载率是33.1g/L。该悬浊液在15℃下充分混合搅拌10小时后,取固体做XRD或DSC测试,证明固体是纯的共晶相。所得固体经真空抽滤,CCF饱和溶液洗涤、干燥工序处理后得到的固体即为茶碱-对乙酰氨基酚,茶碱-对乙酰氨基酚药物共晶和单体茶碱(THEO)及对乙酰氨基酚(APAP)的XRD图如图1所示:单体对乙酰氨基酚(APAP,Form I)的特征峰位置在12°、14°、15.5°、18°、19°、21°、24.5°、27°;单体茶碱(THEO,Form I)的特征峰位置在7°、12.5°、14.5°、24°;制备得到的共晶(THEO-APAP)特征峰在11.5°、13°、26.5°。所有物质的XRD特征峰与晶体剑桥国际数据库(Cambridge Structural Database,CSD)中的XRD图特征峰位置一致。茶碱-对乙酰氨基酚共晶的DSC-TG图如图2所示:氩气氛围测试条件下,DSC曲线在173.7℃有一吸热峰,其焓变值是151.4J/g。该共晶受热后,质量在195℃开始减少,到359.3℃失重速率达到最大值,420℃以后质量基本上不发生明显变化,此分解对应DSC曲线里359.3℃处分解峰。
实施例2:
咖啡因与乙二酸、马来酸、丙二酸在乙腈中分别生成摩尔比为2:1的共晶
在乙腈中,咖啡因(CAF)作为API,乙二酸(OXA)、马来酸(MEI)、和丙二酸(MON)分别作为CCF,API和三种不同的CCF在乙腈中均不存在溶剂化物。
配制乙二酸OXA的饱和溶液1000mL。在饱和溶液中投入77.7g咖啡因(0.4mol)和18.0g乙二酸(0.2mol),这样投入CCF饱和溶液中的CAF和OXA摩尔比是2:1,固体负载率是95.7g/L。在25℃下充分混合搅拌6小时后,取固体做XRD测试,证明固体是纯的共晶相。所得固体经真空抽滤,CCF饱和溶液洗涤、干燥工序处理后得到的固体即为2CAF-OXA(图3)。所有物质的XRD特征峰与晶体剑桥国际数据库(Cambridge Structural Database,CSD)中的XRD图特征峰位置一致。
配制马来酸MEI的饱和溶液1000mL。在饱和溶液中投入58.3g咖啡因(0.3mol)和17.4g马来酸(0.15mol),这样投入CCF饱和溶液中CAF和MEI摩尔比是2:1,固体负载率是75.7g/L。在10℃下充分混合搅拌15小时后,取固体做XRD测试,证明固体是纯的共晶相。所得固体经真空抽滤,CCF饱和溶液洗涤、干燥工序处理后得到的固体即为2CAF-MEI(图4)。所有物质的XRD特征峰与晶体剑桥国际数据库(Cambridge Structural Database,CSD)中的XRD图特征峰位置一致。
配制丙二酸MON的饱和溶液500mL。在饱和溶液中投入38.8g咖啡因(0.2mol)和10.4g丙二酸(0.1mol),这样投入CCF饱和溶液中的CAF和MON摩尔比是2:1,固体负载率是49.2g/L。在25℃下充分混合搅拌6小时后,取固体做XRD测试,证明固体是纯的共晶相。所得固体经真空抽滤,CCF饱和溶液洗涤、干燥工序处理后得到的固体即为2CAF-MON(图5)。所有物质的XRD特征峰与晶体剑桥国际数据库(Cambridge Structural Database,CSD)中的XRD图特征峰位置一致。
Claims (5)
1.一种混悬结晶制备药物共晶的方法,其具体步骤如下:先在釜式搅拌器中投入配制好的共晶形成物CCF饱和溶液,然后按照一定的固体负载率并且根据共晶的化学计量学比投入固体药物有效活性成分API和共晶形成物CCF,经过充分搅拌混合后,取样做XRD或DSC测试,证明是纯的共晶固体相后,所得固体经真空抽滤、CCF饱和溶液洗涤、干燥工序处理后得到药物共晶产品;其中配制共晶形成物CCF的饱和溶液所用溶剂为与API和CCF均不生成溶剂化物的溶剂。
2.如权利要求1所述的方法,其特征在于所制备的药物共晶产品为咖啡因-乙二酸、咖啡因-马来酸、咖啡因-丙二酸、茶碱-对乙酰氨基酚、卡马西平-苯甲酸、卡马西平-4,4’-联吡啶或吲哚美辛-糖精。
3.如权利要求1所述的方法,其特征在于所述的固体负载率为30-100g/L。
4.如权利要求1所述的方法,其特征在于配制共晶形成物CCF的饱和溶液所用溶剂为水、甲醇、乙醇、环己烷、氯仿、丁酮、1,4-二氧六环、甲酰胺、硝基甲烷、乙酸异丙烯酯、正丙醇、乙腈、甲苯、乙酸乙酯、1,2-二氯乙烷、醋酸异丙酯、二氯甲烷或二甲基酰胺的一种或几种。
5.如权利要求1所述的方法,其特征在于整个制备过程的温度均控制在10-30℃之间。
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