Recent developments in combinatorial chemistry, high throughput screening, and robotics led to a large number of compounds with potential biological activity. The vast and ever increasing number of possible lead molecules requires to prioritize the most promising compounds. Physico-chemical properties of the drugs in solutions determine their pharmacodynamics and pharmacokinetcs and therefore are of key importance in the further development process.

We propose a multidisciplinary project that includes correlated experimental and theoretical efforts aimed at a better understanding of mechanisms of structural changes of biomolecules and thermodynamics of biomolecular solvation.

The aqueous solubility of bioactive compounds is one of the most important factors for biological activity. During the past years we have seen that the vast majority of the new drug candidates that show a high activity in receptor studies are practically insoluble in any biological fluids. Therefore, such compounds will not reach the site of action in vivo. This is a particular problem for the most preferred way of application, the oral route. Hence an insufficient aqueous solubility hampers bioavailability of the compounds.

A variety of techniques can be used to enhance the solubility of bioactive molecules. The use of pH control and cosolvents are two important examples of such techniques. A significant enhancement in the solubility has been achieved for a number of compounds employing these approaches. Another parameter which affects the solubility of a compound is the solid state form in which the compound is delivered. Polymorphism is the ability of stoichiometrically and chemically identical molecules to exist in a variety of solid forms. It means that different polymorphs possess different crystal structures, and they can exhibit different physical properties (Polymorph control: past, present and future., Drug discovery today, Vol 13, 5/6, 2008). Therefore, the determination of solubility, and the understanding and control of polymorphism, are strongly related issues that are extremely relevant to the design of new pharmaceuticals.

Our particular target is the study of polymorphism of drugs in the crystalline state and its dependence on hydrogen bonds network structures at ambient sub- and supercritical condition. The use of supercritical fluids technology may help to control solubility and polymorph distribution functions varying the parameters of state rather then changing of solvents and system pH. Coordination of physical experiments supplemented by computer simulations and theory will allow to address solubility and polymorphism at a new level of detail and deliver fundamental answers to the theory of liquids.