Quantitation of acetol in common pharmaceutical excipients using LC-MS.

A method for the quantification of acetol at mug/L levels in propylene glycol and glycerol, two common pharmaceutical excipients, was developed and validated. This simple yet highly specific method makes use of derivatization by O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine (PFBHA) in aqueous solution at room temperature followed by analysis via LC-MS without sample pre-concentration, extraction, or cleanup. Kinetic studies indicated that the derivatization reaction was complete after 4.5h. Preliminary investigations demonstrate the applicability of this method to the separation and identification of other electrophilic impurities. This suggests the potential for a simple, quantitative assay at room temperature in aqueous solution for the determination of a variety of electrophilic impurities in pharmaceutical excipients, without the need for sample concentration or extraction.

Effect of incomplete removal of the tert-butoxycarbonyl protecting group during synthesis of a pharmaceutical drug substance on the residual solvent analysis.

During development of the residual solvent method using headspace-GC for a drug substance, an unexpected peak was observed in the chromatography. GC-MS analysis confirmed the unknown peak identity as isobutylene. An understanding of the source of the isobutylene was required in order to develop appropriate impurity and residual solvent control strategies for the drug substance. The experiments performed to determine the source of the isobutylene peak observed in the headspace-GC chromatography and how the tert-butoxycarbonyl (BOC) de-protection step used in the drug substance synthesis contributes to its observation are discussed.