Evaluation of a high-throughput screening method for the detection of the excipient-mediated precipitation inhibition of poorly soluble drugs

摘要

The objective of the present study was to develop and evaluate a high-throughput (HT) precipitation inhibitor screening method that can be used for the identification of the excipient-mediated precipitation inhibition of poorly soluble drugs. The impact of incubation temperature, shaking intensity, phase separation, inter-and intraday variability, cosolvent, and plate selection on the HT screening method performance was investigated. Additionally, the pipetting quality of the automated workstation, the correlation with the classical laboratory approach, and the practical implementation of the developed HT screening method using two model compounds are disclosed. Investigation of the HT method resulted in optimized experimental conditions, which showed low inter-and intraday variability (relative standard deviation [RSD] 5.88%). Higher shaking intensity (7 Hz) and incubation temperature (37 C) resulted in a lower likelihood of obtaining false-negative results. The acceptable dimethyl sulfoxide concentration in the precipitation inhibitor screening assay was set to ??1% (v/v). All liquid dispensing steps resulted in an RSD of 3.4%, and an excellent correlation (R2=0.96, P0.01) with the classical laboratory method was obtained. The practical implementation of the developed HT method was demonstrated by investigating the impact of 23 diverse excipients on the precipitation inhibition of two poorly soluble drugs (fenofibrate and carbamazepine). The screen resulted in the identification of hit excipients, which were not identical for fenofibrate and carbamazepine. This outcome emphasized that the HT screening approach is a reasonable starting point for searching for effective precipitation inhibitors, especially because the excipient-mediated precipitation inhibition effect is case specific and cannot be predicted in a straightforward manner. ? 2013 Mary Ann Liebert, Inc.