Solid State and Diffusion NMR Spectroscopy as Applied to Characterization of Complex Formulated Products and Biological Materials

S. Ulvenlund, D. Topgaard, S. Gustavsson, E. Sparr
CR Competence AB,

Keywords: NMR, formulated products, skin, stratum corneum, phase diagram


Solid and semisolid formulations in pharmaceutics, cosmetics and foods normally comprise complex structures on the molecular and colloidal length scales. Proper understanding of the functionality of a formulated product, as well as rational optimization of its physical and chemical stability, requires detailed understanding not only of the structure itself, but also of dynamics. Solid state NMR is a versatile tool for studies of complex colloidal systems. Over the last couple of years, we have systematically investigated the applicability of the method in the fields of formulated products and biological materials. The suite of pulse sequences that we utilize is based on polarization transfer, and combines features from high-resolution NMR and solid state NMR. It allows for study of both structure (in terms of the orientational order parameter) and dynamics (in terms of re-orientational correlation times) of solid and semisolid materials in a way that makes it directly applicable to formulation design, prediction of product stability and understanding of interactions with biological tissue. The talk will describe the basis of polarization transfer solid state NMR, and how it can be applied in formulation science and technology. Examples will primarily be extracted from our work on lipid- and carbohydrate-based systems. These examples will be used to show that the characteristics of higher-order phase transitions (e.g. glass transitions) can be pinpointed in molecular detail. More specifically, NMR can be used to pinpoint the order by which a given molecule or molecular fragment “melts” (i.e. become mobile, as defined by the correlation time) when the material is heated over the glass transition temperature range or subjected to other physical changes. This, in turn, allows the formulation scientist to understand the nature and practical implications of these phase transitions in more detail than do conventional techniques (for instance, calorimetry). The examples will also be used to demonstrate that NMR provides an extremely valuable tool for characterization of complex materials under “almost dry” conditions. In this context “almost dry” refers to systems in which the water content if below 5%. Here, NMR affords a tool for structural studies that supplement conventional X-ray techniques, and allows for extraction of phase diagrams that describe how formulated systems behave at low water activity. This is directly relevant for prediction of stability of solid pharmaceutical dosage forms, freeze-dried formulations and manifold other products. When applied to biological materials, the same methodology can be used to assess structure and dynamics (“fluidity”) of structured lipid and lipid-protein systems. We will demonstrate this by describing the results from studies of the outermost layer of the skin (stratum corneum). Here, we have used NMR to build understanding of the molecular mechanisms by which small polar molecules in natural moisturizing factor and formulated products act to protect the skin from drying. Finally, we will briefly discuss how solid state NMR relates to diffusion NMR, and how a combination of these two techniques can be used to elucidate how low-molecular weight components (i.e. water) diffuse (or not) in complex biological and non-biological matrices.