【作者】 韩洋；

【导师】 郭放；

【作者基本信息】 辽宁大学 ， 有机化学， 2019， 硕士

【摘要】 临床中多数药物活性成分（API）属于BCS II和IV类药物,它们的溶解度都比较差。近年来,晶体工程被广泛的应用于医药领域,通过药物共晶或者药物盐作为可替代的API固体形式,从而有效改善药物溶解性。其中,含磺酰基药物分子中的磺酰基可以增加极性从而降低hERG毒性,和该官能团在超分子共晶或成盐的作用,得到了药物化学家的关注。本论文根据晶体工程中的acid???amine超分子合成子,以含有磺酰基的呋塞米（FS）和樟脑磺酸（Cam）为研究对象,选用含有氨基的化合物作为共晶形成剂（CCF）,遵循“绿色化学”的理念设计合成一系列药物共晶或者药物盐。此外,以异烟肼为原料合成了异烟肼衍生物。主要的研究内容如下:1.通过固态研磨快速筛选了API分子呋塞米（FS）和几种共晶形成剂,如六次甲基四胺（HTEM）、金刚烷胺（Amd）和异烟肼（INZ）的共晶和成盐。进一步通过溶液挥发法,得到了两种药物盐（FS）₁（HTEM）₁、（FS）₁（Amd）₁和一种药物共晶（FS）₁（INZ）₁的结晶,通过X-射线粉末衍射、单晶X-射线衍射和红外光谱对结构进行了表征。桨化实验、差示扫描量热法和热重实验研究了三种新型晶体的溶剂稳定性和热稳定性。动态蒸汽吸附实验说明（FS）₁（HTEM）₁是非吸湿性的,而另两种晶体是吸湿性的。研究在不同pH值下共晶或药物盐的溶解度,结果表明水为溶媒时,（FS）₁（HTEM）₁和（FS）₁（INZ）₁相比于原料FS,溶解度有显著的提升,并且在pH=6.8时,所有的晶体都具有最大的溶解度。进一步研究了此pH下的溶出速率,在60 min内的溶出过程中,（FS）₁（Amd）₁相比于原料药FS具有更快的溶出速率。此工作显示FS通过成盐和形成共晶,提高了药物本身的理化性质,为改善其生物利用度提供了良好的理论基础和数据基础。2.以樟脑磺酸和异烟肼为原料,通过脱水缩合一步得到了异烟肼衍生物B,通过溶剂（乙醇和水的混合溶剂）挥发获得单晶,通过X-射线粉末衍射、单晶X-射线衍射、紫外光谱、红外光谱和核磁共振（氢谱）对结构进行了表征。通过差热实验和热重实验研究其热稳定性,并研究其荧光性质和对恶性细胞的毒性。此工作中通过将两种药物分子作为前驱体,在无催化剂条件下,羰基和氨基发生脱水缩合反应制备新型化合物有望降低异烟肼的毒副作用,体现异烟肼酰腙化合物的应用价值,并且以绿色化学的方法解决酮羰基反应活性弱的问题。更多还原

【Abstract】 Recently,crystal engineering is widely used in medicine.Most of the active ingredients（API）belong to BCS II and IV drugs,which owning poor solubility in clinical.In order to improve the physical properties,the pharmaceutical cocrystal is introduced as alternative API solid form.Cocrystals can improve the physicochemical properties of drugs without compromising their therapeutic benefit.Sulfonyl group can offer two hydrogen-bond receptors,attracting extensive attention from scientists.Based on acid???amine supramolecular synthons widely used in crystal engineering,different kinds of pharmaceutical cocrystal/salts were designed and synthesized by mechanochemistry and traditional solution methods with furosemide as API.Isonicotinic acid hydrazide derivatives were synthesized with camphorsulfonic acid.The main content as following:1.Two salts（FS）₁（HTEM）₁、（FS）₁（Amd）₁ and a cocrystal（FS）₁（INZ）₁ were formed by grinding and solvents method,using Furosemide（FS）as API,and their structure were characterized by PXRD and SC-XRD.The thermal stability,solvent stability and hygroscopic stability studies revealed excellent results by pulping experiment,dynamic vapor adsorption experiment,differential scanning calorimetry and thermogravimetry.Solubility experiments showed that the solubility of（FS）₁（HTEM）₁ and（FS）₁（INZ）₁ were higher than that of the pure material FS.At pH=6.8,cocrystal/salts and pure drug both own the highest solubility.Besause of favourable property,the（FS）₁（Amd）₁ salt shows a faster dissolution rate than pure FS and other cocrystal/salt over the entire time span（60 min）in pH 6.8.2.A isonicotinic acid hydrazide derivative was synthesized by condensation reaction of camphorsulfonic acid with isonicotinic acid hydrazide,and the reaction process was non-catalytic.The single crystal structure was obtained in the mixed solvent（ethyl alcohol and water）,and the structure was characterized by PXRD,SC-XRD,UV,FT-IR and ¹H-NMR.Thermal stability was studied by differential scanning calorimetry and thermogravimetry.In this work,a novel compound prepared by dehydration condensation reaction of a carbonyl group and an amino group under a catalyst-free condition by using two drug molecules as a precursor is expected to reduce the side effects of isoniazid and develop the application value of isoniazid hydrazide compound.And the problem of weak ketone carbonyl reactivity is solved by a green chemical method.更多还原