Use of thermal desorption mass spectrometry for the detection of free acid impurities in pharmaceutical products

摘要

A method utilizing thermal desorption mass spectrometry (TDMS) for the detection and quantitation of free acid forms in pharmaceutical drug products formulated as salts is presented. Selective detection of neutral drug forms is possible because the volatility of a drug present in its free acid form is typically much higher than that of its corresponding salt forms, which have negligible volatility even at high temperatures. Tandem mass spectrometric detection allows selective quantitation of the desired free acid drug forms without significant interferences from formulation excipients. The application of the TDMS approach is demonstrated for a sodium salt of a representative, carboxylated drug molecule. Excellent sensitivity, specificity, and adequate linearity of detector signal as a function of micrograms of free acid added were demonstrated in the presence of the sodium salt of the drug and formulation excipients. The sensitivity of the method was demonstrated at free acid levels of 0.6% w/w ( 6 mu g absolute mass). Tablet samples were analyzed by thermal desorption EI-MS/MS with reference to external standards using a commercially available quadrupole ion trap mass spectrometer. The relative drug form stabilities in three different tablet formulations were differentiated using this method; the salt-to-free acid form conversion ranged between less than the limit of detection to near complete conversion during the stability study.