Strong acidic drugs are a class of chemical compounds that normally have high hydrophilicity and large negative charges, such as organophosphatic compounds and organosulphonic compounds. This review focuses on sample preparation and separation methods for this group of compounds in biological matrices in recent years. A wide range of separation techniques, especially chromatographic method, are presented and critically discussed, which include liquid chromatography (e.g., ion-pair and ion-exchange chromatography), capillary electrophoresis (CE), and other types. Due to the extremely low concentration level of target analytes as well as the complexity of biological matrices, sample pretreatment methods, such as dilute and shoot methods, protein precipitation (PP), liquid-liquid extraction (LLE), solid-phase extraction (SPE), degradation, and derivatization strategy, also play important roles for the development of successful analytical methods and thus are also discussed. 1. Introduction The main members of strong acidic drugs include organophosphatic compounds and organosulphonic compounds, which have emerged as promising candidates for treating a wide range of diseases such as AIDS [1], cancer [2], osteoarthritis [3], Alzheimer’s disease, and cardiovascular disorders [4]. For example, nucleoside reverse transcriptase inhibitors (NRTI), the first safe and effective agents for the treatment of patients infected with HIV, must be selectively phosphorylated to their active triphosphate moieties (NRTI-TP) within human peripheral blood mononuclear cells [1]. Taurine, a major metabolite of sulfur-containing amino acid in mammals, plays a very important role in several essential biological processes, and recently existence of taurine in urine was found to be an indicator of bladder cancer [5]. Chondroitin sulfate (CS) and dermatan sulfate (DS) show important functions in central nervous system development, wound repair, infection, growth factor signaling, morphogenes and cell division, differentiation, and migration in addition to osteoarthritis and their conventional structural roles. Furthermore, CS is used and recommended by the European League against Rheumatism (EULAR) as a SYSADOA (symptomatic slow-acting drug for osteoarthritis) drug in Europe in the treatment of knee and hand osteoarthritis [3]. Due to the high hydrophilicity, there are numbers of difficulties and challenges for analyzing these strong acidic drugs. (a) These compounds contain one or more strong acidic groups, and they are hard to be retained on common HPLC chromatographic columns like
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