Determining the Structure of Hexametaphosphate by Titration and 31P-NMR Spectroscopy

Hexametaphosphate (HMP) is an inorganic condensed phosphate, which has been used in a wide variety of industries for nearly a century, originally patented to deflocculate clay and soften hard water. Today, HMP is still used in the minerals processing industry as a dispersant to improve separation. It is also used in the food industry, as additive E452i, to improve the stability of whey protein drinks, prevent efflorescence in fermented sausages, and as an emulsifying salt in processed cheese. HMP is used in some toothpastes, to prevent caries and reduce the amount of fluorine required. HMP is particularly useful in these applications due to its ability to bind to surfaces to provide steric and electrostatic repulsion, and to form strong soluble complexes with multivalent cations. Indeed, studies have identified HMP as the most potent of the condensed phosphates for cation binding, however, the exact reason for this is somewhat unclear because of confusion about the structure of HMP. While important for all of these industries, understanding the structure of HMP is of particular importance for its emerging biomedical applications. These include biomaterial formulations such as cements, materials for controlled antibiotic release and nanoparticulate drug delivery vehicles, but also using HMP as the active therapeutic to combat pathological calcifications, such as heterotopic ossification and kidney stones. It is particularly important to know the precise structure of HMP for clinical applications in order to reliably and reproducibly predict efficacy and ADME (absorption, distribution, metabolism and excretion) properties, to overcome regulatory hurdles. There are currently two popular ideas for the structure of HMP. Some studies state that HMP is a 12 membered ring (Figure 1A), while others claim HMP is a linear polyphosphate (Figure 1B). It has also been suggested that both linear and cyclic products are available, but are both referred to as HMP commercially. This confusion has prevented some attempts to compare between studies, because it is not clear whether the HMP used in each is the