Development Of High-speed Capillary Electrophoresis Based On-line Continuous Monitoring System And Its Application In Drug Dissolution Test And Biomass Catalytic Conversion

Dissolution testing is used to evaluate the rate and extent of the dissolution of active ingredients from pharmaceutical formulations objectively and reasonably.The accurate dissolution information of all active ingredients from the beginning to the end of the dissolution process is of great significance to the understanding of the dissolution kinetics of drugs.It plays many important roles throughout the pharmaceutical industry,including drug product research and development,assessing the quality and efficacy consistency of generic drugs.However,it is a challenging task to achieve both high-efficient separation and high-temporal resolution drug dissolution detection to obtain accurate dissolution curves.In addition,the research and development of biomass catalytic conversion reaction in fine chemistry are also of great importance.While numerous studies have been performed to search for functional materials to catalyze biomass conversions,a robust and high-throughput analytical method is rather limited,which may hamper further integration and automation of the reactions.Therefore,how to achieve the high-efficient separation and high-temporal resolution detection of the analytes in the pharmaceutical formulations and biomass conversion reaction is the focus of this thesis.This thesis focuses on the research and application of continuous on-line monitoring system based on high-speed capillary electrophoresis technology,and carries out the following research work:1.An automatic on-line monitoring method with high-temporal resolution for drug dissolution based on high-speed capillary electrophoresis technology is proposed.It has been successfully applied in the dissolution determination of immediate-release drugs and fixed-combination drugs.High-speed capillary electrophoresis(HSCE)technology realizes the high-temporal resolution and high-efficient separation monitoring of drugs.Through the flow-gating injection(FGI)technology,the high precision and high accuracy automatic micro-injection of samples is achieved.In this work,taking the immediate-release drug paracetamol dispersible tablets and the fixed-combination drug chlorzoxazone tablets as examples,we systematically analyze the properties of the proposed method.Compared with the traditional off-line drug dissolution method,this method can automatically monitor the drug dissolution process with high reproducibility and accuracy.Our study show that the proposed method is capable to achieve simultaneous dissolution testing of multiple ingredients,and the matrix interferences can be avoided.Therefore,it is of potential valuable applications in various fields of pharmaceutical research and drug regulation.2.Development and application of an automatic in vitro dissolution analyzer with high-temporal resolution for oral solid formulations.An automatic drug dissolution analyzer integrating a dynamic simulation of body fluid circulation flow-through cell technology,an automatic sequence injection technology and high-speed capillary electrophoresis separation and detection technology is developed.The dissolution analyzer solves several key technologies,such as high-temporal resolution automatic on-line monitoring of the whole process,high-efficient separation,and analysis of dissolution of different dosage forms,as well as the correlation between in vitro dissolution and in vivo absorption.Taking the immediate-release drug amoxicillin tablets and the fixed-combination drug amoxicillin clavulanate potassium tablets as examples,high-temporal resolution automatic on-line monitoring of the entire dissolution process of pharmaceutical formulations is realized,and the in vitro and in vivo correlation models are further established to improve the correlation between in vitro dissolution test and in vivo absorption.The analyzer is controlled by the Lab VIEW program,is easy to operate,and has a high degree of integration and automation.It provides an effective tool for scientifically and effectively evaluating the quality of pharmaceutical formulations and exploring the process optimization and quality control methods of different dosage forms of pharmaceutical formulations.3.Study on dissolution testing of multiple drugs loaded electrospun nanofibers.We perform the first on-line automated analysis of the dissolution of electrospun nanofibers loaded with multiple drugs.Using single needle electrospinning technology,hydrophilic polyvinylpyrrolidone(PVP)and hydrophobic polycaprolactone(PCL)as carriers to load three poorly water-soluble non-steroidal anti-inflammatory drugs(paracetamol,nimesulide and ibuprofen).The drugs loading in PVP/PCL nanofibers are characterized by scanning electron microscopy(SEM),X-ray diffraction(XRD),Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC).The in vitro dissolution of drugs in nanofibers is studied using the developed high-temporal resolution automatic dissolution analyzer.The analyzer can be used for simultaneous on-line determination of multiple drugs released from nanofibers.The results show a wide linear detection range and the limit of detection(LOD)can reach ?g/m L.Throughout the entire dissolution process,the dissolution curves of the three components in the nanofibers can be monitored every 30 s from the beginning to the end with only one HSCE run.Under various dissolution media,drug loading content and PVP/PCL ratios,the dissolution kinetics,including the dissolution curves,characteristic dissolution time and dissolution efficiency are obtained and evaluated.Our study provides a novel method for rapid and accurate determination of drug dissolution of nanofiber-based drugs and will expand the applications of separation technology in drug analysis.4.Study on high-throughput monitoring of biomass catalytic conversion reaction based on automatic time-resolved analysis.In this study,by combining a catalytic conversion reactor,sequential sample injection and HSCE-indirect UV detection method,we can monitor the catalytic conversion of glucose to 5-hydroxymethylfurfural(5-HMF)from the beginning toward the end.All the compounds(fructose,5-HMF,formic acid,levulinic acid and the remaining substrate glucose)involved in the process of glucose conversion reaction are effectively separated and sensitively detected,with a temporal resolution of only 1 minute.This method has a high-resolution separation and a wide linear range with limit-of-detection down to ?g/m L-level.The results demonstrate that the proposed method is of great value in the analysis of complicated biomass conversion and could be potentially applied in various catalytic chemical reactions.