Measurements of the abundances of naturally occurring stable isotopes in pharmaceutical materials can be used to quantitatively
characterize the sources of the products and the synthetic processes used to produce them (1, 2). Since 2001, industry has
had increased interest in the use of stable-isotopic analyses in industrial pharmacology. The results of reconnaissance studies
have led to detailed examinations of the mechanisms that determine the observed isotopic compositions. The initial, observational
work started with a field study to differentiate individual batches of drug products (3). This work led to an investigation
of stable isotopic analyses as monitors of process consistency during drug manufacturing. In that study, various batches of
two over-the-counter analgesic drugs were analyzed for isotopic consistency. Batch-to-batch variations in stable-isotopic
compositions indicated that either the sources of the starting materials or aspects of the manufacturing process had changed.
To follow up, blind isotopic studies were initiated by the Division of Pharmaceutical Analysis of the US Food and Drug Administration
(St. Louis, MO) to determine whether isotopic analyses of drugs could be used to identify the manufacturing source. In the
first of two studies, researchers demonstrated that stable-isotopic analyses could distinguish among individual manufacturers
and batches of four active pharmaceutical ingredients (APIs) produced by nine manufacturers (4). A second study examined the
ability of stable-isotopic analyses to differentiate manufacturer sources of an API as it was transported across national
borders. All six manufacturers of the API (naproxen) were recognized successfully (5).
The results demonstrate the utility of stable-isotopic analysis for monitoring and identifying pharmaceutical products and
manufacturers, thus providing a new tool for product security and drug authentication. It also can be used to monitor process
consistency (i.e., the changes or modifications that occur during the various synthetic steps in a pharmaceutical drug-manufacturing process).
Another area that is of interest for stable-isotopic analysis is its use as a forensic tool in cases of process patent protection.
Two sets of variables are pertinent: the stable-isotopic compositions of the starting materials and synthetic intermediates,
and the isotopic fractionations that occur during production. Understanding the extent of isotopic fractionation that occurs
at each step in a synthetic route can provide valuable insight into which process was used.
In this article, the authors focus on means of constraining the major variables (e.g., the precursors and synthetic pathways) that determine the isotopic compositions of pharmaceutical materials. Ideally, isotopic
compositions of pharmaceutical products will be predictable, and the synthetic processes used will be recognizable. In a broader
sense, these studies of process authentication bear on process-patent protection and on process analytical chemistry, including
To fully elucidate the isotopic fractionations that occur between reaction steps, it is ideal to have at least 0.1 mg of all
intermediates and products for each stable-isotope ratio being measured.