Rapid and accurate prediction of degradant formation rates in pharmaceutical formulations using high-performance liquid chromatography-mass spectrometry

• Published in: Journal of pharmaceutical sciences Vol. 93; no. 4; pp. 838 - 846
• Main Authors: Darrington, Richard T., Jiao, Jim
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.04.2004; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Algorithms; Arrhenius extrapolation; Biological and medical sciences; Calibration; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; degradation kinetics; Drug Stability; Drug Storage; formulation; General pharmacology; Hexoses - chemistry; initial rate method; Linear Models; liquid chromatography/mass spectrometry; Macrolides - chemistry; Mass Spectrometry; Medical sciences; Nonlinear Dynamics; nonlinear regression; Pharmaceutical Preparations - analysis; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Predictive Value of Tests; Spectrophotometry, Ultraviolet; stability prediction; Temperature; nonlinear regression; stability prediction; liquid chromatography/mass spectrometry; degradation kinetics; formulation; Arrhenius extrapolation; initial rate method; Spectrometry; Prediction; HPLC chromatography; Dosage form
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20006

Rapid and accurate stability prediction is essential to pharmaceutical formulation development. Commonly used stability prediction methods include monitoring parent drug loss at intended storage conditions or initial rate determination of degradants under accelerated conditions. Monitoring parent drug loss at the intended storage condition does not provide a rapid and accurate stability assessment because often <0.5% drug loss is all that can be observed in a realistic time frame, while the accelerated initial rate method in conjunction with extrapolation of rate constants using the Arrhenius or Eyring equations often introduces large errors in shelf-life prediction. In this study, the shelf life prediction of a model pharmaceutical preparation utilizing sensitive high-performance liquid chromatography–mass spectrometry (LC/MS) to directly quantitate degradant formation rates at the intended storage condition is proposed. This method was compared to traditional shelf life prediction approaches in terms of time required to predict shelf life and associated error in shelf life estimation. Results demonstrated that the proposed LC/MS method using initial rates analysis provided significantly improved confidence intervals for the predicted shelf life and required less overall time and effort to obtain the stability estimation compared to the other methods evaluated.