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

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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..


Pharmaceutical Technology


Understanding isotopic process parameters can be useful in process-patent protection applications. With a full description of a given pharmaceutical synthetic pathway, the isotopic differences between any precursor and another precursor or a precursor and the final product can be predicted or at least provisionally understood in principle. This provides valuable insight into which synthesis process was used. Consistencies in expected isotopic matrix values can provide important information about process counterfeiting.

Summary

Stable-isotopic fractionations resulting from isotope effects are usually large compared with the precision of isotopic measurements. These fractionations significantly modulate the isotopic compositions that would be observed if isotopic compositions of starting materials were the only controlling factor. The fractionations depend not only on the magnitudes of isotope effects associated with the synthetic reactions used, but also on reaction conditions, specifically those affecting the extent to which reactants are converted to products. Because of these phenomena, the final isotopic composition of a manufactured product is directly related to the synthetic scheme used. Subsequently, process analytical chemistry using stable-isotopic analysis can be useful not only for product authentication, but also for process monitoring or reconstructing the processes by which the product was synthesized.

Acknowledgments

The concepts of both stable-isotopic product and process authenticity are covered under either existing or pending patents in either the United States or in G7 countries and Australia owned by Molecular Isotope Technologies LLC. This paper is dedicated to medical-surgical team at UCSD's Thornton Medical Center.

John P. Jasper, PhD,* is the chief scientific officer of Nature's Fingerprint Authentication, a Division of Molecular Isotope Technologies LLC, 8 Old Oak Lane, Niantic, CT 06357,
, tel. 860.739.1926, fax 860.739.3250. Larry E. Weaner, PhD, is a senior research fellow with Johnson & Johnson Pharmaceutical Research and Development (Spring House, PA). John M. Hayes, PhD, is a scientist emeritus with Woods Hole Oceanographic Institution (Woods Hole, MA).

*To whom all correspondence should be addressed.

Submitted: Nov. 3, 2006. Accepted: Dec. 27, 2006.

Key words: isotope fractionation, process analytical chemistry, PAC, process patent protection, stable isotopes, synthesis.

References

1. J.P. Jasper, "Pharmaceutical Security: Using Stable Isotopes to Authenticate Pharmaceutical Materials," Tablets and Capsules 2 (3), 37–42 (2004).

2. J.P. Jasper, R.C. Lyon, and L.E. Weaner, "Stable Isotopes Provide a New PAT [Process Analytical Technology] Tool," Pharm. Mfg. 4 (5), 28–33 (2005).

3. J.P. Jasper et al., "Stable Isotopic Characterization of Analgesic Drugs," Pharm. Technol. 28 (8), 60–67 (2004).

4. J.P. Jasper et al., "Stable Isotopic Characterization of Active Pharmaceutical Ingredients," J. Pharm. Biomed. Anal. 35, 21–30 (2004).

5. A.M. Wokovich et al., "Stable Isotopic Composition of the Active Pharmaceutical Ingredient (API) Naproxen," Pharm. Biomed. Anal. 38, 781–784 (2005).

6. A. Schimmelman, M.D. Lewan, and R.P. Wintsch, "D/H Isotope Ratios of Kerogen, Bitumen, Oil, and Water in Hydrous Pyrolysis of Source Rocks Containing Type-I, -II, -IIS, and -III kerogen," Geochim. Comsochim. Acta 63 (22), 3751–3766 (1999).

7. L.I. Wassenaar and K.A. Hobson, "Improved Method for Determining the Stable-Hydrogen Isotopic Composition (δD) of Complex Organic Materials of Environmental Interest," Environ. Sci. Technol. 34, 2354–2360 (2000).


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