Process Patent Protection: Characterizing Synthetic Pathways by Stable-Isotopic Measurements

The authors describe the methods by which precise analyses of stable-isotopic abundances can be used in security and forensic applications for pharmaceutical materials. These methods include product and process authentication of raw materials, pharmaceutical intermediates, drug substances, formulated drug products, and synthetic pathways. Collectively, these methods can be used to investigate and mitigate patent infringement. In the future, more complete examples will be presented containing full isotopic..
Mar 02, 2007



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 process consistency.

Experiment

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.