液晶分子印迹整体柱的制备及其分子识别热力学

液晶分子印迹聚合物(MIPs)因刚性液晶单体的加入而在超低交联度水平下也能印迹和识别模板分子,有效解决了传统MIPs因高交联度造成的位点包埋、结合容量低、传质慢等问题。尽管液晶MIPs具有如此独特的优势,但却面临着由于交联度的大幅度降低而导致印迹效果下降的问题。为了研究液晶MIPs的结合特性,制备具有良好印迹效果的低交联液晶MIPs,该文通过二次接枝聚合,制备了一系列不同交联度的液晶分子印迹整体柱,用高效液相色谱法研究了聚合参数与印迹整体柱亲和性的关系。实验中选用三羟甲基丙烷三甲基丙烯酸酯(TRIM)为交联剂,以甲苯和十二醇为致孔剂合成整体柱骨架,并在此基础上以(S)-萘普生为模板,加入液晶单体4-氰基苯基单环己基乙烯(CPCE)进行二次聚合接枝。实验中系统考察了流动相中乙腈比例及缓冲液pH值对色谱保留的影响,结果发现液晶单体的加入使得MIPs对萘普生保留控制机制由原来的氢键作用变为了疏水作用;通过动态吸附实验得到的突破曲线经前沿分析及对吸附等温线Langmuir、Freundlich和Scatchard分析拟合,发现交联度为15%时液晶MIPs印迹因子最大(3.78)、非均一性最强,且特异性吸附量高于非特异性吸附量。液晶MIPs的计量置换模型(SDM-R)分析表明,液晶印迹整体柱对模板分子的总亲和力(ln A=0.645)明显高于其类似物;而从空间匹配程度看,与液晶印迹整体柱空间匹配程度最高的是酮洛芬而非模板分子,但液晶印迹整体柱对酮洛芬的总亲和力(ln A=0.242)不及模板分子的一半,表明在本低交联液晶印迹系统中,空间效应不是决定印迹系统识别能力的主要因素。进一步的分离热力学研究发现,低交联液晶印迹柱的|ΔΔH|<T|ΔΔS|,而交联度为70%的非液晶MIPs柱的|ΔΔH|>T|ΔΔS|,表明液晶MIPs的分离过程是一个熵控制过程,而常规无液晶MIPs的分离过程是一个焓控制过程。上述结果表明,液晶单体的加入改变了MIPs的识别机制,适当的低交联度可显著提高液晶MIPs的识别性能,因此液晶MIPs这些特质有望使其成为新一代的MIPs。     

二维扩散排序核磁共振谱法研究β-环糊精/萘普生的相互作用

采用二维扩散排序(DOSY)核磁共振法研究了萘普生与β-环糊精的相互作用,考察了不同包合因素对主客体自扩散系数及平衡常数的影响,并对萘普生与β-环糊精包合反应进行了热力学分析,以揭示萘普生与β-环糊精的包合反应机理.实验结果表明,温度、水含量、溶液pH值、离子强度等对客体萘普生的自扩散系数影响较大,但对主体环糊精自扩散...     

Interaction of Naproxen with Crystalline and Amorphous Methylated β-Cyclodextrin in the Liquid and Solid State

Abstract

Interactions of naproxen (NAP) with amorphous, randomly methylated β-cyclodextrin at a degree of substitution per anhydroglucose unit of 1.8 (RAMEB) and with crystalline heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) were studied in aqueous solution and in the solid state using, respectively, phase-solubility analysis (at 25 °C, 37 °C and 47 °C) and differential scanning calorimetry (DSC) supported by X-ray powder diffractometry. RAMEB and DIMEB displayed similar solubilizing and complexing abilities towards NAP, suggesting analogous inclusion modes of the drug in the host cavity in aqueous solution. Differences were instead observed in interactions in the solid state, where the amorphizing capacity of RAMEB toward NAP (evaluated by DSC) was about twice that of DIMEB at each drug-to-carrier ratio. Assuming that inclusion complexation is also involved in solid-state interactions, molecular modelling accounted for the experimental results in terms of structural features of DIMEB, i.e. the particular inwards orientation of O-6-C-8 groups of three alternate glucoses on the primary hydroxyl side which hampers a deep penetration of NAP in the DIMEB cavity in the solid state. On the contrary, no obstruction of the cavity apparently occurs with RAMEB due its noncrystalline state. The aqueous dissolution rate of NAP from NAP-RAMEB and NAP-DIMEB blends containing 0.59, 0.73, 0.85, and 0.92 mass fraction of carrier linearly increased at decreasing drug-to-carrier ratios. The improvement was 5 to 20 times (from powders) and 50 to 200 times (from discs) the dissolution rate of NAP alone for both carrier. Therefore the choice of the amorphous RAMEB in pharmaceutical formulations can be recommended mainly for economic reasons, though the anhydrous and non-hygroscopic nature of crystalline DIMEB might be of particular advantage in case of moisture sensitive formulations.     

Optimisation of Supercritical Carbon Dioxide Systems for Complexation of Naproxen : Beta-Cyclodextrin

Supercritical carbon dioxide (scCO₂)offers several attractive scenarios for thepharmaceutical processing as an alternativeto aqueous and organic solvents. In thiswork naproxen, a widely used non steroidalanti-inflammatory drug with analgesic andanti-inflammatory properties, was chosenas a model drug. Its complexation with cyclodextrinsimproves the rate and extent of dissolutionof the drug, increase its rate of absorption and mayreduce the unpleasant side-effects of the drug.The interest in using this supercritical technologyled us to develop an experimental unit for the useof supercritical CO₂ as a processing medium forthe complexation of naproxen with beta cyclodextrin (CD).     

Synthesis of statistical glycidyl methacrylate‐n‐vinyl pyrrolidone copolymers and their reaction with naproxen

Free‐radical copolymerization of glycidyl methacrylate (GMA) with N‐vinylpyrrolidone (VPD) was carried out at 50 °C using 3.0 mol · L^?1 of N,N′‐dimethylformamide solution and 9.0 · 10^?3 mol · L^?1 of 2,2′‐azobisisobutyronitrile as an initiator. The modification reaction of GMA‐VPD copolymers with a model bioactive carboxylic acid, 6‐methoxy‐α‐methyl‐2‐naphthaleneacetic acid (naproxen), was studied in the homogeneous phase using basic catalysts. The influence of the type of catalyst and the GMA content was evaluated. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1192–1199, 2002     

CHIRALCEL OD手性柱直接拆分萘普生对映体

以CHIRALCELOD为固定相,建立了在正相条件下直接拆分萘普生对映体的HPLC方法。考察了流动相组成、流速、进样量和温度等因素对对映体分离的影响。优化后的色谱条件为:CHIRACELOD色谱柱(250mm×4.6mm,10μm);流动相:正己烷-异丙醇-冰醋酸(97∶3∶1,V/V);流速:1.0mL/min;紫外检测波长:254nm;柱温:35℃。在此条件下,萘普生对映体可得到基线分离。此方法可用于S-萘普生制备时酶膜反应器中萘普生甲酯动态拆分过程的跟踪分析。     

A Comparative Study of Naproxen – Beta Cyclodextrin Complexes Prepared by Conventional Methods and Using Supercritical Carbon Dioxide

Naproxen is a poorly soluble anti-inflammatorydrug, the solubility of which canbe enhanced by complexation withbeta-cyclodextrin. Besides that, the inclusioncomplex reduces the incidence of gastrointestinal side effects of the drug. The aim of this work was to compare the physicochemical characteristics of the solid complexes prepared by traditional methods (kneading, freeze-drying and spray-drying) and using a supercritical fluid technology. The unusual solvent properties of carbon dioxide above their critical temperature and pressure were exploited in order to prepare inclusion compounds. Complexes prepared using supercritical fluid technology showed similar properties to those of freeze-drying andspray-drying complexes as proved by DSC, FT-IRand UV.     

高效液相色谱法直接测定几种非甾体类解热镇痛药物中的对映体含量

用WHELK-O1手性色谱柱，在正相条件下测定了几种非甾体类解热镇痛药物萘普生、布洛芬、酮基布洛芬和苯氧布洛芬等中对映体的含量。结果表明：这种手性固定相色谱柱能够以正己烷和异丙醇为流动相，简便、快速、准确地测定非甾类药物中对映体的含量。     

Asymmetric Synthesis in the Presence of Cyclodextrins

Oxidative couplings of 2-naphthol, 6-bromo-2-naphthol and2-naphthylamine were achieved at room temperature in the presence of H₂O₂, horseradish peroxidase and a suitable cyclodextrin.2-Thionaphthol behaved differently, yielding the corresponding disulfide. Yields of binaphthyl derivatives were generally excellent, and a fairly good enantiomeric excess was observed. Under similar reaction conditions methyl 2-(6-methoxy-2-naphthyl) propanoate, when treated with esterase in the presence of cyclodextrin, yielded naproxen (a well-known anti-inflammatory drug) with a good enantiomeric excess. No reaction product was detected in the absence of cyclodextrin. Cyclodextrins do not act as simple transfer agents.