Preparation Of Novel Hypercrosslinked Polymers And Application In Pharmacokinetic Study Of Albendazole

Albendazole?ABZ?,a benzimidazole drug,is widely applied to veterinary and husbandry,which has a broad spectrum anthelmintic effect and has remarkable activity against roundworm,tapeworm,pinworm,whipworm and nematode,et al.Potential anti-tumor property of ABZ has gained wide concern in recent years,which can inhibit the proliferation of cancer cells both in vivo and in vitro.The low solubility of ABZ in water and most solvents limits its absorption in the gastrointestinal tract.Some studies indicate that a quarter of the population absorbs less than 30%after oral administration of ABZ.In addition,ABZ is rapidly metabolized to albendazole sulfoxide?ABZSO?after oral administration due to first-pass effect in the liver,leading to the very low level in plasma.ABZSO is considered as the main active component of anthelmintic effect.It is present in plasma with concentration level of ng mL^?1,which is dependent on the type of food and pH of the stomach.Therefore,it is of great significance to establish an efficient and sensitive analytical method to study the pharmacokinetic properties of ABZ.Considering low concentrations of ABZ and its metabolites and complex plasma matrix,the direct detection remains a great challenge.For this reason,an effective separation and enrichment method for sample pretreatment to eliminate interference and improve sensitivity is often required before quantitative analysis.Solid phase extraction?SPE?is a widely used method for sample pretreatment at present,which is characterized by fast extraction rate,less use of organic solvent,simple operation and strong designability.The analyte is separated from sample matrix based on different forces between solid adsorbents with the target and the interference.As the core of SPE technology,adsorbents play a decisive role in recovery,reproducibility and accuracy of analysis results.Hypercrosslinked polymers?HCPs?,featuring easy preparation,high surface area,adjustable pore size and excellent chemical stability,have been extensively applied to SPE.The preparation of HCPs based on Friedel-Crafts chemistry creates a highly crosslinked network with predominant porosity.In the past years,three synthetic strategies have been employed including post-crosslinking,one-step polycondensation of functionalized small molecules and external crosslinking strategy.Among them,external crosslinking strategy can realize the diversity and tunability of pore structure by using crosslinkers of different lengths and monomers of different types.Thus,choosing appropriate crosslinker and monomer to prepare HCPs is of great significance in external crosslinking strategy.Several crosslinkers have been recently attempted to construct HCPs,such as formaldehyde dimethyl acetal?FDA?,dichloroxylene?DCX?,and 4,4'-bis?chloromethyl?-1,1'-biphenyl?BCMBP?.Reported HCP monomers in external crosslinking strategy are mainly aromatic compounds including benzene,biphenyl,methylbenzene,chlorobenzene,and phenol,et al.It is a novel idea to use chemically modified supramolecular macrocyclic compounds as the monomers of HCPs at present.The prepared materials have broad application prospects in the field of adsorption and separation,which can be a result of not only the high specific surface area and porous structure of hypercrosslinked network,but also the inherent cavitation of macrocyclic compounds.In this thesis,two HCPs based on macrocyclic compounds were successfully prepared and the adsorption capacity of two materials for ABZ was investigated.An analytical method for simultaneous detection of ABZ and ABZSO in rat plasma was established by using HCPs as SPE adsorbent and combining with high performance liquid chromatography?HPLC?detection.The method was successfully applied to pharmacokinetic study of ABZ in rats.The main contents of this thesis are as follows:In chapter 1,we summarized the development of ABZ,SPE and HCPs.Pharmaceutical properties and analysis methods of ABZ,novel solid phase extraction adsorbents,preparation and application of HCPs were emphatically introduced.In chapter 2,a novel type of well-constructed HCPs?BnO-CB[6]-HCP?was designed in which cucurbit[6]uril?CB[6]?was employed as the monomer.CB[6],a supramolecular macrocyclic compound,was used in the area of the HCPs for the first time.The structure and property of prepared material were verified by Fourier transform infrared spectroscopy?FT-IR?,hydrogen nuclear magnetic resonance?¹H NMR?,elemental analysis,thermogravimetric analysis?TGA?,power X-ray diffraction?PXRD?,scanning electron microscope?SEM?,and N₂adsorption-desorption measurements.The specific surface area of BnO-CB[6]-HCP was as high as 787 m² g^?1,which was the highest among porous materials based on CB[6].The adsorption performance of BnO-CB[6]-HCP for ABZ was preliminarily investigated through adsorption kinetics,isotherms and thermodynamics experiments.Futhermore,the adsorption mechanism,desorption and recycling capacity were also discussed.In chapter 3,another macrocyclic compound?-cyclodextrin??-CD?was applied to prepare HCPs?Bn-CD-HCP?using BCMBP as the crosslinker.The structure and property of prepared material were proved by FT-IR,X-ray photoelectron spectroscopy?XPS?,TGA,PXRD,SEM and N₂ adsorption-desorption isotherms.Bn-CD-HCP showed high surface area and favorable thermal stability.The adsorption capacity of Bn-CD-HCP for ABZ was investigated.The adsorption process agreed with pseudo-second-order model and Langmuir isotherm model.A high adsorption capacity of 181.82 mg g^–1 was achieved,which was the highest among current porous materials for ABZ adsorption.We discussed the adsorption mechanism and the reason of high adsorption ability for ABZ compared with BnO-CB[6]-HCP prepared in chapter 2.In addition,Bn-CD-HCP could be reused for multiple cycles without significant losing its adsorption amount.In chapter 4,a method for simultaneous determination of ABZ and ABZSO concentrations in rat plasma was established by means of solid phase extraction coupled with high performance liquid chromatography?HPLC?in which mebendazole?MBZ?was employed as internal standard.HCPs were used as solid phase extraction adsorbents for sample pretreatment.The conditions of solid phase extraction were optimized to simplify sample processing process and improve extraction recovery.Under the optimized conditions,the recoveries of ABZ and ABZSO were determined to be in the range of 93.76-99.33%and 96.32-101.36%,respectively.The limit of quantitation?LOQ?was calculated to be 5 ng mL^-1.The experimental results showed that this method was efficient and sensitive.HCPs were suitable for solid phase extraction to enrich ABZ and ABZSO in plasma.The method was applied to detect the blood concentrations of rats after oral administration of ABZ.The results show that this method could meet analytic requirement of pharmacokinetic research.