A new, simplified solid phase extraction procedure for the determination of risperidone and 9-hydroxyrisperidone in human plasma has been developed. This method involves the use of an optimized extraction protocol developed in Waters OASIS ® HLB 30mg 1cc extraction columns using 1 mL of human serum. Separation was performed by HPLC using a Waters XTerra RP-18 (5 µm, 150x4,6 mm) column with a mobile phase consisting in acetonitrile -potassium dihydrogen phosphate 50 mM pH 3.4 (27/73). UV detection at 278 nm was used to quantify analytes, encountering good linearity (r 2 > 0.999) in the 2-100 ng/mL concentration range. The mean recovery was 92.4 % and 92.8 % for risperidone and 9-hydroxyrisperidone respectively, with an intraday -interday precision below 7%, and accuracy below 115 %. The method has been successfully applied in pharmacokinetic studies that require a large sample number.Keywords: Risperidone, 9-hydroxyrisperidone, solid phase extraction. 1.-INTRODUCTIONRisperidone (RSP, figure 1) is a benzoisoxazole derivative that is clinically used as an atypical antipsychotic. Since its introduction in the 1990s, it has been considered to be a first-rate choice in the treatment of schizophrenia and other mental disorders because of its pharmacodynamics 1 (selective blocking of 5-HT2 and D2 receptors in brain), providing effective management of positive, negative and cognitive symptoms of schizophrenia with a low profile of extrapyramidal and autonomic side effects 2 .Several methods have been proposed for therapeutic and toxicological monitoring of RSP and 9-hydroxyrisperidone (9-OH RSP, figure 1). These are more-or-less sensitive depending on the detection mode used. UV detection offers simplicity but higher limit of quantitation (LOQ=2 ng/ml) and presence of interferents if the extraction procedure is not selective 3.4.5 . Electrochemical detection offers lower LOQ (< 0.5 ng/mL) but lacks selectivity and sample and standard preparation require high purity reagents 6,7 . Ultimately, mass spectrometry detection offers high sensitivity and selectivity, but the cost is not accessible for most laboratories, especially in Latin America 8-11 . e-mail: cvonples@udec.cl; corresponding authorFigure 1: Chemical structures of Risperidone, 9-OH hydroxyrisperidone and Clozapine.The extraction procedures described to isolate RSP and 9-OH RSP from biological matrices are predominantly based on liquid-liquid extraction [3][4][5]8,9,11 . These are very effective and offer high recoveries (> 85 %) with good precision and accuracy, but sample handling requires the use of toxic solvents or multiple extraction steps in order to obtain clean extracts, and this factor is a drawback when the analysis demands to work with a large sample number. On the other hand, solid phase extraction (SPE) procedures offer an easier sample handling but the results are reliable only if the analyst avoids sorbent drying 7,10,[12][13][14][15] . In our laboratory, we tested the properties of the sorbent included in Waters OASIS ® HLB cartridges be...