【作者】 张晓明；

【导师】 朱广山；

【作者基本信息】 吉林大学 ， 无机化学， 2016， 博士

【摘要】 药物共晶因其能够潜在调节药物活性成分(API)的理化性能及生物学性质而备受行业关注。药物共晶的设计与合成是基于氢键、范德华力或者π···π堆积等相互作用力来完成的,我们可以根据目标分子设计构筑各种组织框架结构以调节所需药物的理化性质。而晶体工程学可以通过一种灵活的方法引入另一个分子作为配体进入晶格中,这样使API与公认安全的药学上可接受的共晶形成物(CCF)彼此之间建立关联,形成共结晶。这也是晶体工程学研究的主要内容之一。由于同一化合物的不同固体形态具有不同的物理和化学性质,此外,一个API分子中可能含有一个或多个超分子合成子,不同API的分子结构决定了其各自不同的自组装方式,而不同结构CCF的引入则对API的理化性质及药学性质有不同程度的改善。因此,通过引入CCF形成药物共晶能够安全的调节和改善API的熔点、溶解度、稳定性和生物利用度等。本论文从API和CCF的结构角度出发,着眼于不同API的自组装官能团和CCF的筛选技术,以超分子化学和晶体工程学为基本原理,选择了四种极具代表性的不同分子结构和性能的API进行药物共晶的设计,分别选用反应结晶法、回流挥发结晶法、研磨法和超声辅助结晶四种方法合成了12种药物共晶,系统的验证了苯甲酸、羧酸类及吡啶类前驱体作为CCF在芳环、外围携带杂原子芳环及杂环分子中的作用并对其结构进行研究,讨论了API与CCF的合成条件及其与新的异项合成子性质变化识别的交互作用。分别通过单晶x-射线衍射分析(SXRD)、粉末x-射线衍射分析(PXRD)、差热分析(DTA)、热失重分析(TGA)、红外光谱分析(FT-IR)、元素分析(EA)等技术对合成的共晶进行表征和结构解析。通过液质联用/质谱技术(HPLC-MS/MS)在p H=1.2的模拟人体胃液中对药物共晶进行体外溶解研究,同时对药物共晶的化学稳定性及吸湿性进行了测试。具体研究结果如下:1、以乙型肝炎治疗药物阿德福韦(adefovir)作为API,选择对氨基苯甲酸(PABA),3,5’-二羟基苯甲酸(3,5’-DHBA)和吡啶2,6’-二羧酸(2,6’-PDA)三种苯甲酸及羧酸类化合物作为CCF,通过反应结晶法合成了cocrystal 1-3三种新型的药物共晶。其中,cocrystal 1-2为adefovir与苯甲酸类CCFs通过氢键作用形成的共晶水合物,cocrystal 2-3的超分子结构均是通过adefovir与CCFs之间的π···π堆积作用及氢键形成的。他们的体外溶出速率是cocrystal 3>cocrystal 1>API>cocrystal 2。Cocrystal 3在4 h内全部溶解,cocrystal 1、API和cocrystal 2在4 h时释放百分率分别达到96.8%,94.1%和92.5%。Cocrystal 1和cocrystal 3的溶出度较API有明显的提高,通过形成共晶使adefovir较差的溶解性得到了改善,这一结果将能够改善其在肠胃中的吸收利用从而提高药效,减少药物副作用。2、以第一个口服铁螯合剂去铁酮(deferiprone)为API,选择了对羟基苯甲酸(PHBA)、2,5’-二羟基苯甲酸(2,5’-DHBA)和顺丁烯二酸(Maleic acid)三种苯甲酸及羧酸类化合物为CCFs,分别通过反应结晶法和回流挥发结晶法合成了cocrystal 4-6三种新型的药物共晶。其中cocrystal 4-5是API与两种苯甲酸类CCFs以1:1的摩尔比形成的超分子化合物,通过deferiprone的吡啶环与苯甲酸类CCF的芳香环平面之间π···π堆积作用及氢键结合形成的网状结构。Cocrystal 6是API与羧酸类CCF通过氢键以1:1摩尔比结合形成的超分子化合物。Cocrystal 4-6在模拟人体胃液中的体外溶出度均有显著的下降,他们的溶出速率顺序为:cocrystal 5<cocrystal 6<cocrystal 4<API。共晶cocrystal 4-6克服了deferiprone在胃液中溶解速率过快的问题,这一研究结果将对去铁酮药物在临床上由于溶解度高导致的频繁给药及由此带来的肠胃副作用有明显改善。3、以常用的解热镇痛药扑热息痛(Paracetamol)为API,选择4,4’-联吡啶(4,4’-Bipyridine)为CCF,通过反应结晶法、回流挥发结晶法、研磨法和超声辅助结晶四种方法合成了Paracetamol-4,4’-Bipyridine药物共晶cocrystal 7。以该药物共晶为模板对共晶的合成方法进行了筛选,讨论不同方法对共晶的影响。四种方法合成物均为同一种共晶cocrystal 7,其中反应结晶和回流挥发结晶法合成的晶体形貌较完整,可用于单晶衍射的测定。他们通过氢键以及Paracetamol的芳香环与4,4’-Bipyridine的吡啶环通过π···π堆积作用结合形成超分子网状结构。此外,共晶cocrystal 7的体外溶出度较Paracetamol有明显的提高。4、以抑菌药Tavaborole为API,选择了对羟基苯甲酸(PHBA)、邻羟基苯甲酸(salicylic acid)、间羟基苯甲酸(MHBA)和2,3’-二羟基苯甲酸(2,3’-DHBA)和吡啶2,6’-二羧酸(2,6’-PDA)五种CCF,通过研磨法合成了5种新型药物共晶cocrystal8-12。对合成的药物共晶进行了稳定性测试,结果表明cocrystal 8-12热分解温度均有所提高,化学性质稳定,测试期内均未发生化学分解。Cocrystal 8-12吸湿稳定性也较Tavaborole有显著提高。克服了Tavaborole吸湿性强的问题。以上研究使我们在药物共晶的设计与合成方面不断的积累经验,为今后合成出更多结构和性能优异的药物共晶提供参考依据,并为及进一步的生物利用度及临床研究提供基础。更多还原

【Abstract】 Pharmaceutical cocrystals have received attention in pharmaceutical industry due to their potential for their readily tuned physicochemical and biological properties of free active pharmaceutical ingredient(API). Cocrystals are usually designed and synthesized in the form of stable solid-state structures based on π···π stacking interaction or hydrogen bond interactions. The construction of a variety of organized frameworks, often with potentially demanded chemical and physical properties, is one of the aims of crystal engineering. Crystal engineering could be achieved by a flexible approach of introducing another molecular component into the crystal lattice, making it possible to establish the linkage between the compounds that mainly refers to API and cocrystal former(CCF). The CCFs were included in the pharmaceutically acceptable formers list, a classification known as Generally Recognized As Safe(GRAS). The different solid forms of the same compound have different chemical and physical properties. API are inherently predisposed for self-assembly since their utility is normally the result of the presence of one or more functional supramolecular synthons. The CCF of different structure into the crystal lattice, makes it possible to improve the physicochemical properties of API. The pharmaceutical cocrystal would be safe to use in pharmaceutical formulations and regulate and modify the solubility and bioavailability of different drugs.Based on the above reasons, this paper from the perspective of the structure of the API and CCF, focusing on the self-assembly functional groups of different API and high-throughput screening technology of CCF in supramolecular chemistry and crystal engineering as the basic principle, Based on supramolecular chemistry and crystal engineering, This article chose the four representative drug active ingredient, they each have different molecular structure, self-assembly functional groups and efficacy, The cocrystal(1-12) of APIs with the corresponding CCFs were obtained using the solution crystallization and evaporation crystallization method, the grinding method and ultrasonic method. Systematic introduction of acid groups in an aromatic periphery with a heteroatom was carried out to observe the changes in original structure. Identification of new heterosynthons changes in properties upon interacting with the ratio of the API and coformers. Their structures were characterized by single crystal X-ray diffraction, powder X-ray diffraction(PXRD) analysis, thermogravimetric analyses(TGA), differential thermal analysis(DTA),elemental analysis(EA) and infrared spectral analysis(IR). Dissolution and stability study of API and cocrystals were also measured and discussed, and their dissolution in vitro and chemical stability, moisture absorption were evaluated. Detailed the research results are as follows:1. Three novel cocrystals(1-3) were synthesized, which are composed of adefovir for hepatitis B treatment drug as the API with p-aminobenzoic acid(PABA), 3,5’-dihydroxybenzoic acid(3,5’-DHBA) and 2,6’-pyridinedicarboxylic acid(2,6’-PDA) three carboxylic acid compounds as CCFs, respectively, Pharmaceutical cocrystals(1-3) were synthesized by backflow volatile crystallization method. Among them, the cocrystal 2-3 linked were through hydrogen bonding and π···π interactions of adefovir with CCFs. The average dissolution rates of cocrystal 1, 2, 3 and original API were in following order: cocrystal 3 > cocrystal 1 > API > cocrystal 2. Overall dissolution behavior demonstrate that a complete release of cocrystal 3 from gelatincapsules in 4 h, comparing 96.8 %, 92.5 %, 94.1 % of cocrystal 1, 2 and API respectively. The initial dissolution rate in 0.5 h of cocrystal 1 is the rapidest, which reaches 77%. This profile is significant because it shows that a greater concentration of API can be achieved depending upon the cocrystal 1 and 3. The observation suggested that cocrystal 1 and 3 with an enhanced dissolution rate would potentially favorably absorption the gastrointestinal(GI) absorption and onset action of adefovir.2. Three novel cocrystals(4-6) were synthesized based on deferiprone which is the first oral medicine as iron chelator. Solitary deferiprone possesses some known problems due to its good solubility and frequent dosing side effects. For these three novel co crystals, deferiprone is the active pharmaceutical ingredient(API), p-hydroxybenzoic acid(PHBA), 2,5’-dihydroxybenzoic acid(2,5’-DHBA) and maleic acid are used as CCFs, respectively. Among them, the cocrystal 4-5 linked were through hydrogen bonding and π···π interactions of adefovir with CCFs. The average dissolution rates of cocrystal 1, 2, 3 and original API were following the order of cocrystal 5 < cocrystal 6 < cocrystal 4 < API. This profile is significant because it shows that extended release of deferiprone can be achieved via the synthesis of cocrystal(4-6). The observation suggested that the cocrystal(4-6) exhibited good extended release tendency, comparing with original deferiprone.3. The cocrystals 7 were synthesized using the reaction crystallization method and backflow volatile crystallization method, the grinding method and ultrasonic method. Cocrystals 7 are composed of Paracetamol for antipyretic analgesic as the API with 4,4’-Bipyridine. In the cocrystal 7 as a template for synthesis of the pharmaceutical cocrystal were screened, we discussed the effects of different methods of pharmaceutical cocrystals. Four methods are the same cocrystal composition cocrystal 7, The used cooling crystallization method and evaporation crystallization method synthesized more complete, can be used to determine the SXRD. The average dissolution rates of cocrystals 7 than Paracetamol has increased significantly.4. The novel cocrystals(8-12) were synthesized using the grinding method, which are composed of tavaborole for antibacterials as the API with p-aminobenzoic acid(PABA), m-aminobenzoic acid(MHBA) 2,3’-dihydroxybenzoic acid(2,3’-DHBA), salicylic acid and 2,6’-pyridinedicarboxylic acid(2,6’-PDA). The stability of API and cocrystals(8-12) were also measured and discussed, respectively. The results suggest that ermal stability and chemically stable of cocrystal(8-12) improved, no degradation occurred during the test. cocrystals(8-12) hygroscopic stability than the API improved significantly.We continue to accumulate experience for the future create more pharmaceutical cocrystals of excellent properties provide basis.更多还原