In SituMoisture Determination of a Cytotoxic Compound During Process Optimization

A simple and safe prototype apparatus was designed and adapted for the in situdetermination of the moisture content of a cytotoxic compound (9‐fluorenylmethyl‐protected doxorubicin‐peptide conjugate, or Fm‐DPC) by near‐infrared absorbance spectroscopy during optimization of the chemical isolation procedure. The cytotoxic nature of the compound restricts one's ability to safely sample such drying processes for more traditional means of moisture determination for fear of hazardous solids dusting, hence in situsampling approaches are of great importance. These concerns also exist for the process development laboratory, where despite the smaller scale of operations, the volume of experiments (hence cytotoxic samples) required to define a chemical process is often more significant. In this application, partial least squares regression was used with Karl Fischer volumetric titration analysis to generate a calibration model. Although pronounced differences in cake density were observed as a function of the buffer selected for the isolation process, the model still achieved a standard error of calibration of 0.63% w/w and a standard error of prediction of 0.99% (w/w). These results demonstrated the versatility of the prototype apparatus/data processing approach to model Fm‐DPC drying under extremely variable conditions, as inherently expected during the investigational laboratory development of a chemical process.