Accuracy Profile Theory for the Validation of an LC-MS-MS Method for the Determination of Risperidone and 9-Hydroxyrisperidone in Human Plasma

A sensitive and specific LC-MS-MS method is described for the simultaneous quantification of risperidone and 9-hydroxyrisperidone in human plasma. After extraction with tert-butyl methyl ether, plasma samples were separated on an Atlantis HILIC Silica C18 column (4.6 x 150 mm, 5 mu m)with a mobile phase of ammonium formate buffer (10 mM, pH 4.0)/acetonitrile (40/60, v/v). Detection was by MS-MS. The method was fully validated according to the accuracy profile theory. It is based on beta-expectation tolerance interval for the total measurement error which includes trueness and intermediate precision. The measurement uncertainty derived from beta-expectation tolerance interval was estimated at each of the validation standards. The linearity fitted well over the range of 0.11-26.75 ng mL(-1) for risperidone with an LLOQ of 0.11 ng mL(-1), and for 9-hydroxyrisperidone, at a range of 0.15-37.8 ng mL(-1) with an LLOQ of 0.15 ng mL(-1). The intra- and inter-batch precision of risperidone were < 5.71 and 8.22%, respectively. For 9-hydroxyrisperidone, the data were 5.78 and 6.48%. The recoveries were 88.78% (risperidone) and 70.35% (9-hydroxyrisperidone). The developed method was applied to a pharmacokinetic study of risperidone.