【作者】 王林；

【导师】 杨平； 张海禄；

【作者基本信息】 苏州大学 ， 化学， 2015， 硕士

【摘要】 超过80%的药物活性组份(原料药)及其药物产品是以固态形式开发的。同一种药物化合物可能具有不同的固态形式,例如,多晶型、无定形、水合物、溶剂化合物、共晶以及盐等。不同的固态形式具有不同的物理化学性质,进而影响药物的生物利用度和有效性。因此研究活性药物的固态形式至关重要。此外,药物的固态形式提供了一种简单的改善原料药物物理化学性质的方法。其中药物的多晶型、共晶和盐这三种固态形式是制药工业和晶体工程研究的热点。本文首先研究了非洛地平药物的多晶型现象,之后又分别以5-氟胞嘧啶和茶碱为原料药物制备了药物的盐和共晶的固态形式。使用多种表征方法对所制备的固态形式进行了表征,并对其物理化学性质进行了研究。(1)使用溶液结晶法制备得到了非洛地平晶型IV,使用了X射线单晶衍射确认为晶型IV。掌握了稳定制备晶型IV的方法,研究了其物理化学性质。晶型IV相比市售产品采用的晶型I而言具有稍高的溶解度和熔点,晶型IV和晶型I之间存在热力学互变异构关系,在室温条件下晶型I较稳定,而在高温条件下晶型IV较稳定,其互变转化温度约为87.6oC。(2)使用溶液结晶法和冻干法分别制备了两种不同比例的5-氟胞嘧啶和安赛蜜盐(FCAH11和FCAH21)。ss NMR和X射线单晶衍射证明了5-氟胞嘧啶和安赛蜜形成了纯的盐。且通过X射线单晶衍射,获得了结构信息,形成盐之后分子间形成了大量氢键。热分析和动态水吸附(DVS)测试证明了所制备的盐与原料药物相比具有优异的稳定性和耐引湿性。(3)采用溶剂助研磨的方法和溶液结晶法分别制备了两种不同比例的茶碱与安赛蜜的共晶(THPAH12和THPAH11)。使用ss NMR分别证实了得到的两种产物都是茶碱与安赛蜜形成的共晶。通过形成共晶,原料药物的溶解度、本征溶出度以及水合稳定性都明显改善了,此外热分析表明两种共晶的热稳定性也很好。另外还构建了茶碱、安赛蜜在甲苯中的三元相图。更多还原

【Abstract】 To study and improve physicochemical properties of pharmaceutical materials, we prepared novel solid forms(polymorphism, cocrystal or salt) of three raw medicines. The products were analyzed by XRD, DSC, ss NMR et al. The novel solid forms show different physicochemical properties.(1) Felodipine form IV was obtained by using solvent evaporation method and characterized by single crystal X-ray diffraction. Comparing with form I, the crystal form used in the marketed products, form IV has higher melting temperature but lower melting enthalpy. Hence, according to the heat of fusion rule, polymorphs I and IV should be in an enantiotropic relationship. Form I is thermodynamically more stable than form IV at room temperature. Their theoretical polymorphic transformation temperature was estimated at 87.6 oC, which was also con?rmed by the solvent mediated polymorphic transformation experiments.(2) Two novel crystalline salts of 5-Fluorocytosine(FC) were obtained with an artificial sweetener, Acesulfame(AH), in molar ratios of 2:1(FCAH21) and 1:1(FCAH11), respectively. The result products were characterized by a variety of analytical methods, including single crystal and powder X-ray diffractions(XRD), differential scanning calorimetry(DSC), nuclear magnetic resonance(NMR), as well as dynamic vapor sorption(DVS). 13 C and 15 N solid state NMR spectra provide solid evidences on the salt formation. The new salts are nonhygroscopic/slightly hygroscopic, and resistant to FC hydrate formation at high RH condition(> 80%). FCAH21 has higher FC content and presents more favorable thermal stability than those of FCAH11, which make it more attractive for further pharmaceutical application.(3) Two cocrystal of Theophylline(THP) were prepared with Acesulfame(AH), in molar ratios of 1:2(THPAH12) and 1:1(THPAH11), respectively. 13 C and 15 N solid state NMR spectra provide solid evidences on the cocrystal formation. Both of the cocrystal show improved solubility as well as enhanced hydration stability. The ternary phase diagram for the two components was constructed in toluene.更多还原