Abstract
Process patent protection via the analysis of natural-abundance stable isotopes has been demonstrated as an approach to extend the effective life of bio/pharmaceutical patents. The high specificity of isotope ratio analysis compared to other approaches (for example, concentrations of organic impurities or trace metals) allows the isotopic analysis to differentiate processes that were not previously resolvable by less precise analytical methods. Here we summarize the rationale for, and some selected case studies of, this emerging field. We review: (i) the systematics of stable isotope chemistry, (ii) approaches to instrumental analysis of stable isotopes, (iii) the biogeochemical origin of stable isotopic fingerprints, (iv) equilibrium versus kinetic isotope effects on those fingerprints, (v) categories of application of process patent protection, and (vi) case histories of application. The three reviewed cases include one of nutraceutical false advertising, one of a small molecule antibiotic drug product ...
Highlights
Applications from our own work largely focused on batch manufacturing, in which we established that batches of pharmaceutical materials have distinctive ratios of the stable isotopes of each element present in the final product.[5,6]
In 2005, in a blind study commissioned by the US Food and Drug Administration (FDA), Wokovich et al.[7] characterized the ratios of carbon (13C/12C) and oxygen (18O/16O) isotopes in 26 batches of the pain reliever, naproxen
There remains significant untapped potential for these approaches: Stable isotopic technologies can identify more than just the uniqueness of product batches[7] or the sources of natural or manufacturing materials[1,2] the examples we present here show how these technologies can be used to protect the processes used during manufacture
Summary
Equilibrium isotope effects can influence exchangeable moieties on organic molecules, in functional positions that are prone to acid- and base-catalyzed substitution reactions, or any other reversible process, e.g., keto−enol tautomerism Most commonly this affects signatures of oxygen and hydrogen moieties in isotopic process analysis, and it may Article. In the case of a continuous process system in which new A is continuously supplied, that is, the inlet is open, the reaction fractionates the isotopes between A and B by εA/B but always relative to the initial isotopic composition of A, which remains stable (i.e., eqs 13−15; Figure 3a). In complex systems of reactions, both kinetic and/or equilibrium isotope fractionation may apply along many steps of the reaction This may result in isotopic distributions in final reaction products that have been affected by more than one of the processes outlined in sections 1.2.4 and 1.2.5. If a product, E, is composed of a mixture of a component B that has equilibrated with an excess of A (a common example would be equilibration with water), plus two other components C and D that each have unique biogeochemical sources (section 1.2.3) but experienced no additional isotope fractionation, the total isotope balance of E will be[41]
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