BIOSOL · Solvent effects on physico-chemical properties of bioactive compounds: combination of theory with experiments

Solvent effects on physico-chemical properties of bioactive compounds: combination of theory with experiments.

Recent technological advancements in combinatorial chemistry, high throughput screening, and robotics led to an increasing number of biologically active compounds. However, a vast majority of the compounds, showing a high activity in receptor binding studies, rendered insoluble in any biological fluids. Thus such compounds will not reach the site of action in vivo. This is a particular problem for the most preferred way of application of drugs - the oral route. The aqueous solubility is one of the most important factor and therefore of key importance in the further development process of potential drug candidates. Therefore physico-chemical properties became a major concern in pharmaceutical research since they strongly influence pharmacodynamics and pharmacokinetcs of biologically active compounds. Solubility is also highly relevant for determination of the distribution of bioactive molecules in the environment since it determines where the compounds will agglomerate. Physico-chemical properties in particular water solubility also plays a decisive role in safety assessment of chemicals. A particular target of the BioSol project has been the study of polymorphism of drugs in the crystalline state and its dependence on hydrogen bonds network structures at ambient sub- and supercritical condition. Polymorphism is the ability of stoichiometrically and chemically identical molecules to exist in a variety of solid forms. This means that different polymorphs possess different crystal structures, and can exhibit different physical properties Supercritical fluids technology was used to control the polymorph distribution of the drug molecules within supercritical carbon dioxide. Varying temperature and pressure of the supercritical carbon dioxide, different polymorphs could be prepared. Upon rapid expansion the solvated drug molecules formed crystals with high content of the respective polymorphic form. Thus crystals containing a specific polymorph could created. Apart from supercritical carbon dioxide other approaches to enhance solubility have been pursued. Crystalisation of the drug molecules with an additional molecular species at a specified ratio forming co-crystals has been performed. The bioactivity and solubility of the drug molecules was strongly enhanced compared to the pure drug. Theoretical approaches supplemented by computer simulations were used to develop models of solvation of bioactive compounds. A first computational model based on integral equations has been created, which was able to predict hydration free energy of a large set of bioactive molecules. Correlated experimental and theoretical efforts allowed to extend the model to macromolecules and describe their behaviour in various solvents in the presence of dissolved molecular species. The model could be used in design of pharmaceutical drug carrier systems describing the concentration of drug molecules within the macromolecules in various conditions. Encapsulation of drug molecules by large macromolecules and later release in tissue has been actively investigated mainly by experimental methods. The developed model could help to rationally select the most perspective candidates based on their molecular interactions.

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