In this work, various sugar-based (drug) delivery systems and corresponding drug-loaded formulations were developed and extensively characterized to correlate and rationalize the various properties observed with the underlying (supra)molecular structures. In Chapter A, the two drugs atorvastatin calcium and efavirenz were characterized first, from which corresponding formulations were to be produced later. The drugs were investigated using NMR spectroscopy in solution and in the solid state, as well as X-ray powder diffraction and quantum chemical calculations. This provided a sound knowledge of the drugs, which serves as a basis and reference for the subsequent investigation of the drugs in the formulations. Since atorvastatin calcium can also form the corresponding acid, atorvastatin, and atorvastatin lactone under acidic conditions, these two forms of atorvastatin calcium were also characterized by NMR spectroscopy in case they should form in the later formulations. Since the formulations of the two drugs were to be produced at high temperatures (>100 °C) under microwave conditions, the stability of the drugs under these conditions was also investigated. While atorvastatin calcium remained stable in both acidic and basic aqueous solutions even at 120 °C, efavirenz showed partial decomposition under the same conditions in a basic environment. For this reason, milder conditions of only 80 °C and only brief heating to 110 °C were used for the subsequent formulations of efavirenz. In addition, the solubility of the two drugs was determined by NMR spectroscopy as a function of pH; for efavirenz, the solubility was below the detection limit in all cases, so literature values were used for efavirenz. In Chapter B, the so-called boron-containing sugar surfactants were investigated, which were obtained by the reaction of a glucose- or mannose-based sugar amide with borax (Na2B4O7∙10 H2O) in water under microwave conditions. In addition to the sugar scaffold, the length of the hydrophobic chain and the molar ratio of sugar amide to borax were varied as further parameters. Through a combination of NMR spectroscopic investigations in solution and in the solid state, as well as quantum chemical investigations, various boron-containing building blocks were identified: boric acid, tetrahydroxyborate, cross-linking borate complexes, monoborate complexes, and bis(polyol)borate complexes. For simplicity, the last three building blocks were also referred to as “cross-linking building blocks,” “non-bridging five-membered rings,” and “spiro compounds.” Depending on the borax content, the individual building blocks are present in different relative proportions and also form a wide variety of subspecies, which determined the properties of the corresponding surfactants. In this context, the concept of the “glucose-mannose switch” was used to show why the glucose derivatives have better solubility and stability compared to the mannose derivatives, thereby establishing helpful structure-property relationships. At room temperature and the concentrations investigated, the decyl and dodecyl derivatives with a glucose-based scaffold proved to be stable and soluble systems. Comprehensive NMR spectroscopic investigations in solution and cryo-TEM measurements showed that the systems (depending on borax content and chain length) can form both anisotropic micelles and long worm-like micelles, which can also be cross-linked with each other due to the cross-linking building blocks. The boron-containing sugar surfactants thus represent structurally versatile systems that can be controlled by carefully selecting the components and quantities used in their preparation. The data presented makes it possible to carry out these adjustments in the future on a rational basis. Of the glucose derivatives, the decyl and dodecyl derivatives were successfully used to produce formulations with the drugs atorvastatin calcium and efavirenz, and the formulations were investigated as a function of the loading. By investigating the spatial proximity, the preferred orientation of efavirenz in the formulation could be determined. In addition to an initial contact model, first structure-property relationships for the formulations were also developed. The structure-property relationships obtained were confirmed and expanded by formulating derivatives of the drugs and additional test molecules. In summary, spectroscopic and physicochemical data for both the pure surfactants and the formulations could be correlated and rationalized with the structures at the atomic, molecular, and supramolecular levels. Chapter C looked at the cationic surfactants, which are obtained by stoichiometric reaction of a sugar amine with the organic diacid adipic acid under microwave conditions, resulting in a cationic surfactant consisting of two sugar ammonium cations and an adipate anion. In these surfactants, both the sugar scaffold (glucose-, mannose-, and galactose-based) and the length of the hydrophobic chain were varied. It was found that the glucose derivatives were superior to the other two sugar derivatives at the concentrations investigated, and that only hydrophobic chains with 10, 12, or 14 carbon atoms from the glucose derivatives resulted in stable systems under the conditions investigated. Through a combination of extensive NMR spectroscopic investigations in solution and cryo-TEM measurements, it was shown that, depending on the chain length, either free surfactants (C10) or micelles (C14) are present as extreme cases, or there is an equilibrium between free surfactants and micelles (C12). The position of the equilibrium significantly determines the properties of the pure surfactants, such as hygroscopicity and handling properties. For the dodecyl and tetradecyl glucose derivatives, formulations with atorvastatin calcium and efavirenz were successfully produced, whereby the equilibrium described is then extended by the formation of (different) vesicles. The formulations exhibit extremely complex behavior that is primarily determined by the chain length and not by the drug used (atorvastatin calcium or efavirenz). In line with this complexity, it was demonstrated that the adipate anion plays an important role in the storage of the drugs and, in particular for efavirenz, is spatially close to the drug and is not only present separately as a single counterion. The investigation of the spatial proximity of the drug and the surfactant revealed a preferred orientation of efavirenz in the formulation and initial possibilities for the arrangement of individual atorvastatin anions in the formulations. Furthermore, in the case of efavirenz, initial model structures could be postulated and modeled through the interplay of experimental and quantum chemical data. The cationic surfactants and their formulations represented highly reproducible systems in solution, but it could not be fully clarified whether the structure remained unchanged during freeze-drying. In any case, the optical appearance changed significantly under MAS conditions, so that no meaningful investigations in the solid state were possible. Nevertheless, the freeze-dried samples could be easily dissolved again by rehydration and formed stable systems in solution once more. Overall, information at the atomic, molecular, and supramolecular levels was obtained for the pure surfactants and formulations, and the spectroscopic and physicochemical data obtained were rationalized and converted into structure-property relationships. In Chapter D, the boron-containing sugar surfactants and cationic surfactants were compared in terms of various (physicochemical) properties, but also in terms of their synthesis and aspects of Green Chemistry. The comparison revealed that there is no clear in terms of practical aspects: While the cationic surfactants perform better in terms of potential safety, the boron-containing sugar surfactants are significantly easier to handle and prepare. Future studies should therefore attempt to make one of the two surfactant classes superior in both aspects by making various adjustments, such as sugar scaffold or chain lengths. Furthermore, future studies must also investigate other aspects, such as the bioavailability of the drugs in the developed formulations or the release of the drugs, as these also have a significant influence on the applicability of the surfactants or formulations. The studies presented here therefore provide an important basis for the further development of (drug) delivery systems based on the cationic surfactants or the boron-containing sugar surfactants, which can be supplemented and completed by future studies. In Chapter E, emulsions of the cationic surfactants with orange oil and cinnamon oil were produced, which could also be loaded with efavirenz as alternative drug delivery systems. Both coarse emulsions and nanoemulsion-like, clear systems were obtained. By using the oils as solvents for the drug in the emulsion formulations, a significant increase in drug loading was achieved compared to normal cationic surfactants. In particular, the cinnamon oil-based nanoemulsion-like systems proved to be promising candidates for drug delivery, as they could also be produced by simple mechanical shaking of the sample. Furthermore, it was shown that these systems can be well investigated using NMR spectroscopic methods despite their complex heterogeneous microscopic structure, which will enable the development of targeted approaches for further development of the emulsions in the future. Thus, the emulsions can be further developed by varying the individual components and the resulting properties can be rationalized by NMR spectroscopic investigations and complementary methods, which should enable targeted optimization of the systems. Finally, in Chapter F, a software program was presented that enables the heterogeneous data sets obtained in this work to be stored in a database, arc
Sebastian Scheidel (Thu,) studied this question.