Analytical validation of accelerator mass spectrometry for pharmaceutical development
Bradly D Keck1, Ted Ognibene, John S Vogel
1Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason OH 45040, USA.
Bioanalysis
|November 19, 2010
Summary
Accelerator mass spectrometry (AMS) offers a precise method for measuring carbon-14 (14C) to carbon (C) ratios in pharmaceutical analysis. This technique provides sensitive, accurate, and stable quantification of drug compounds in biological samples.
Area of Science:
- Analytical Chemistry
- Radiochemistry
- Pharmaceutical Analysis
Background:
- Accurate quantification of drug compounds in biological matrices is crucial for pharmaceutical development.
- Traditional methods for measuring radiolabeled compounds can be complex and time-consuming, often requiring chemical separation.
- Accelerator Mass Spectrometry (AMS) offers a potential alternative for direct isotope ratio measurement.
Purpose of the Study:
- To validate the performance of Accelerator Mass Spectrometry (AMS) for measuring the carbon-14 (14C) to carbon (C) ratio in pharmaceutical analyses.
- To assess the key validation parameters of AMS, including specificity, stability, linearity, accuracy, precision, and sensitivity.
- To evaluate AMS as a method for quantifying drug compounds in biological matrices without chemical separation.
Main Methods:
- Measurement of the 14C/C isotope ratio using AMS, independent of chemical separation procedures.
- Evaluation of specificity, sample storage stability (up to 1 year), and linearity over four orders of magnitude.
- Determination of analytical range (0.1 to >2000 Modern), accuracy (1-3%), precision (1-6% CV), and sensitivity (LOD/LLOQ).
Main Results:
- The AMS measurement of the 14C/C ratio demonstrated specificity due to the 14C label.
- Measurements remained stable across sample storage conditions for at least 1 year.
- The method showed excellent linearity over four orders of magnitude, with high accuracy (1-3%) and good precision (1-6% CV).
- Sensitivity was high, with a limit of detection (LOD) of 1 attomole and a limit of quantitation (LLOQ) of 10 attomoles of 14C.
- For a typical small molecule labeled at 10% with 14C, this corresponds to 30 fg equivalents.
Conclusions:
- Accelerator Mass Spectrometry (AMS) is a validated, sensitive, accurate, and precise method for measuring the 14C/C ratio in pharmaceutical analyses.
- AMS enables direct quantification of drug compounds in biological matrices without the need for chemical separation procedures.
- The method's stability, linearity, and high sensitivity make it suitable for various pharmaceutical applications, including pharmacokinetic studies.
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