Research On Quantitative Analysis Of Drugs In Complex Matrices With Second-order Calibration Method

The multi-way calibration method can achieve simultaneous quantitative analysis of various components of interest in complex matrices,even in the presence of unknown interferences or non-trilinear factors by utilizing “mathematical separation” to replace or enhance the traditional physical or chemical separation.And this unique property,namely second-order advantage.As a green and efficient analysis method,second-order calibration method combined with high-order analytical instruments has been widely used in the fields of life sciences,food,environment,and cosmetics.Recently,with the improvement of healthcare and continuous advancement of pharmaceutical reform,the progress of research and clinical trials for new drugs and generic drugs are constantly accelerating.Thus,the importance of developing new methods and technologies for drug analysis in complex matrices has become increasingly prominent.The authors adopt the above analysis strategy for the quantitative analysis of anti-tumor and cardiovascular drugs that seriously affect human health,and the main content are as the following:In Chapter 2: Warfarin(WAR)plus low-dose aspirin(ASA)not only might have an additive effect,but also calls for less intensive anticoagulation therapy.However,the risk of bleeding was greatly increased and excessive bleeding events often occur clinically when the doses of both are inappropriate or are not adjusted in time.In this work,a practical method that combines excitation-emission matrix fluorescence with a second-order calibration method based on an alternating trilinear decomposition(ATLD)algorithm was developed in order to simultaneously and directly determine the contents of warfarin and aspirin in human plasma and urine samples,even in the presence of overlapped fluorescence spectra and unknown interferences.With the pre-estimated component number of 4,the obtained average spiked recoveries were 105.4±7.8% and 104.2±8.3% for WAR,96.5±2.8% and 91.2±2.3% for ASA in human plasma and urine samples,respectively.Furthermore,the figures of merits were calculated and inter-and intra-day experiments were also performed that proved the proposed method is of great significance to the monitoring of clinical administration and also being simple sample pre-treatment and low-cost.In Chapter 3: A new compound drug(Sacubitril(SAC)plus valsatan(VAL)),as the first dual inhibitor of angiotensin receptor blocker and neprilysin,was approved by the FDA in 2015.It can not only reduce the mortality rate of patients with heart failure by 20%,but also can significantly improve the efficacy of other indicators compared with enalapril that widely used in clinic,which may make it become the preferred drug for anti-heart failure treatment.In this work,a simple method that combines ?-cyclodextrin-enhanced excitation-emission matrix fluorescence with second-order calibration method based on an alternating normalization-weighted error(ANWE)algorithm was developed to simultaneously and directly determine the contents of sacubitril and valsatan in biological fluids,even in the presence of unknown interferences.Without any complex sample pre-treatment steps,the obtained average spiked recoveries were 94.0±9.1% and 95.2±2.6% for SAC,97.6±5.3% and 92.7±7.2% for VAL in human plasma and urine samples,respectively.Moreover,the figures of merit and statistical parameters such as root-mean-square error of prediction(RMSEP),sensitivity(SEN),selectivity(SEL)and limit of detection(LOD)were calculated,which also proved that the proposed method can be developed into a universal method for the analysis of new drugs and provides a strategy for the determination of weak fluorescent substances in complex systems.In Chapter 4: Lenvatinib,pazopanib,axitinib,cabozantinib,and sorafenib that target vascular endothelial growth factor receptor(VEGFR)are particularly suitable for the treatment of patients with advanced kidney cancer.In order to compare their therapeutic efficacy,safety,and tolerability,optimize the dosing regimens,as well as reduce toxicity and side effects,it is of great significance to develop a simple and universal method for the determination of new anti-cancer drugs in plasma.In this chapter,a second-order calibration method based on the alternating trilinear decomposition(ATLD)algorithm combined with high performance liquid chromatography with diode array detector(HPLC-DAD)were proposed for the simultaneous quantitative analysis of five anti-cancer drugs in human plasma sample.Even in the presence of baseline drift,overlapped chromatographic peaks and unknown background interferences and other issues,the spiked recoveries of five target analytes were still between 98.4% and 109.7%,and the results for figures of merit and inter-and intra-day experiments were also satisfactory.Due to the "mathematical separation" capability of the ATLD method,the proposed method effectively reduces the consumption of analysis time and organic solvents.Moreover,it can be developed into a universal method for the simultaneous determination of multiple anti-cancer drugs in complex biological matrices.In Chapter 5: Rhizoma Chuanxiong is a commonly used traditional Chinese medicine for blood circulation and headache treatment.It can also be used for the treatment of cancers and cardiovascular diseases.The content of active ingredients in Rhizoma Chuanxiong is dependent on many factors,such as climate,place of origin,and processing conditions.In this chapter,a chemometrics-assisted high performance liquid chromatography-diode array detection(HPLC-DAD)strategy was applied to the determination of six active ingredients in two Chinese medicine of Chuanxiong.After a simple gradient elution procedure,all six analytes eluted out within 8 minutes.Owing to the second-order advantage of alternating trilinear decomposition(ATLD)method,several problems,such as,baseline drift,unknown background interferences,and chromatographic co-elution were successfully solved.Satisfactory quantitative results were obtained with average spike recoveries between 98.9% and 110%.Furthermore,the results of inter-and intra-day experiments also verified the repeatability and reproducibility of this method.The method is simple,efficient,and universal,which has certain practical value for the quality supervision and ensuring the stability of its medicinal properties.