Natural complex substances: From molecules to the molecular complexes. Analytical and technological advances for their definition and differentiation from the corresponding synthetic substances.

Natural complex substances (NCSs) are a heterogeneous family of substances that are notably used as ingredients in several products classified as food supplements, medical devices, cosmetics and traditional medicines, according to the correspondent regulatory framework. The compositions of NCSs vary widely and hundreds to thousands of compounds can be present at the same time. A key concept is that NCSs are much more than the simple sum of the compounds that constitute them, in fact some emerging phenomena are the result of the supramolecular interaction of the constituents of the system. Therefore, close attention should be paid to produce and characterize these systems. Today many natural compounds are produced by chemical synthesis and are intentionally added to NCSs, or to formulated natural products, to enhance their properties, lowering their production costs. Market analysis shows a tendency of people to use products made with NCSs and, currently, products made with ingredients of natural origin only are not conveniently distinguishable from those containing compounds of synthetic origin. Furthermore, the uncertainty of the current European regulatory framework does not allow consumers to correctly differentiate and identify products containing only ingredients of natural origin. The high demand for specific and effective NCSs and their high-cost offer on the market, create the conditions to economically motivated sophistications, characterized by the addition of a cheap material to a more expensive one, just to increase profit. This type of practice can concern both the addition of less valuable natural materials and the addition of pure artificial compounds with the same structure as those naturally present. In this scenario, it becomes essential for producers of natural products to have advanced analytical techniques to evaluate the effective naturalness of NCSs. In fact, synthetically obtained compounds are not identical to their naturally occurring counterparts, due to the isotopic composition or chirality, as well as the presence of different trace metabolites (since pure substances in nature do not exist). For this reason, in this review, the main analytical tests that can be performed to differentiate natural compounds from their synthetic counterparts will be highlighted and the main analytical technologies will be described. At the same time, the main fingerprint techniques useful for characterizing the complexity of the NCSs, also allowing their identification and quali-quantitative evaluation, will be described. Furthermore, NCSs can be produced through different manufacturing processes, not all of which are on the same level of quality. In this review the most suitable technologies for green processes that operate according to physical extraction principles will be presented, as according to the authors they are the ones that come closest to creating more life-cycle compatible NCSs and that are well suited to the European green deal, a strategy with the aim of transforming the EU into a sustainable and resource-efficient society by 2050.