Automated DBS-online SPE-LC-MS/MS platform with dynamic solvent dilution: Robust quantification of antipsychotic drugs for decentralized therapeutic drug monitoring.

This study introduces a novel fully automated dried blood spot (DBS)-online solid-phase extraction (SPE)-LC-MS/MS system for the quantification of 19 antipsychotic drugs in dried blood spots, addressing critical challenges in therapeutic drug monitoring (TDM). By integrating dynamic online dilution technology, the system overcomes solvent incompatibility between DBS eluents (high organic content) and hydrophilic SPE sorbents, minimizing analyte loss during trapping. Moreover, the automated workflow eliminates manual intervention, achieving precision (CV ≤12 %), accuracy (RE ≤ ±10 %) and matrix-agnostic performance (ME%: -11.4 %-10.8 %, CV <10 %). When validated across serum and whole blood matrices, the method demonstrated exceptional linearity (R2 > 0.99) and sensitivity (LOD: 0.01-0.71 ng/mL). Stability studies confirmed DBS integrity at extreme temperatures (40 °C to 2-8 °C), enabling cost-effective sample transport via standard postal services. Comparative analysis with offline LC-MS-MS revealed strong agreement, underscoring the method's equivalence to gold-standard techniques. The platform's automation, minimal matrix dependency, and robustness position it as a transformative solution for decentralized TDM, particularly in resource-limited settings.