Innate Tracers of Pharmaceuticals: Stable Isotopes

Counterfeiting of pharmaceuticals threatens consumer confidence and product efficacy, as well as the economic well being of pharmaceutical companies. A recent study of the natural stable isotopic "fingerprints" of pharmaceuticals points to a new and highly specific method for product monitoring that will allow product identification and suppress counterfeiting.

A novel study presenting analytical results of four over-the-counter analgesic drugs shows that individual batches of each drug can be identified on the basis on their bulk isotopic "fingerprints" (Jasper et al., 49th Ann. Conf. On Mass Spectrometry and Allied Topics, Chicago IL, May 26-June 1, 2001). The ability to isotopically trace pharmaceuticals by the batch represents a significant advance in the area of pharmaceutical forensics. Stable isotopes are non-radioactive and exist naturally in pharmaceuticals — and in virtually all other materials. Nothing needs to be added to existing pharmaceutical lines to generate this batch-specific tracer of drug substances or drug products. The specificity of the technique is in one in the millions-to-billions scale, analogous to DNA identification (cf. Jasper et al. (2002) Fire Arson Investig. 51(2):30-34).

The background needed to understand this technique comes from introductory chemistry. Stable isotopes are simple mass variants of the chemical elements whose masses are determined by the number of protons and neutrons in a given element’s nucleus. As an example, carbon-12 (12C) is composed of 6 neutrons and 6 protons (12C composes ~ 98.89% of all natural C); 13C is composed of 7 neutrons and 6 protons (and composes ~1.11% of all C). Other common stable isotopic pairs include 14N and 15N, 16O and 18O, etc. Elements sometimes have radioactive isotopes as well, but these are only practically measurable in a few elements — for example, radioactive 14C represents only ~1 part per trillion of natural carbon.

MIT LLC offers two main areas of isotopic services: Product Authentication andProcess Authentication. Product Authentication is simply "isotopic fingerprinting" of existing Active Pharmaceutical Ingredients (APIs) and drug products at an analytical cost of ~1-3 cents per 100-tablet bottle lot of product at production scale. Natural Labeling is the use of pre-analyzed raw materials to produce pharmaceutical products with particular ranges of isotopic values. Process Authentication is the isotopic fingerprinting of synthetic pathways (Isotopic Pedigree® Authentication) to identify a firm's synthetic pathways.

Combination Lock Analogy: The specificity of Product Authenticity can be understood in analogy with a combination lock. A lock with 4 tumblers and 10 digits on each tumbler has 104 —or, 10,000–combinations. By analogy, the isotopic "combination lock" is composed of 4 isotopes (C, H, N, O), each with a dynamic range of 100 ("digits") has 1004 — or, 100 million — combinations. It is broadly accepted by pharmaceutical-isotope chemists that it would cost more to accurately counterfeit a given isotopic combination than it would to legally purchase the product, thus undermining the incentive for counterfeiting, countertrading, and vicarious liability.

Isotope Product Authenticity is presently accepted in scientific quarters. The technique is gaining in acceptance by quality officials, and is being explored for manufacturing scale by pharmaceutical companies. M.I.T. LLC is currently pursuing field studies of pharmaceutical countertrading and is exploring industrial applications or stable isotope technologies at the manufacturing and distribution levels.