(384h) Thermodynamics of Pharmaceutical Systems

Pharmaceuticals are complex compounds often exhibiting very low aqueous solubility. Because of this, they only slowly dissolve in the body when administered as crystalline solids, which leads to a low bioavailability. Several approaches to increase the bioavailability of pharmaceutical compounds have been presented in literature.

One of them is salt formation by ionization of functional groups which can be achieved by adding an acid or a base and therewith changing the pH in the solution. The observable increase in solubility depends on the acid and base constants of the pharmaceutical itself as well as on the amount and nature of the acid or base added.

Another possibility is to form a so-called solid solution in which the pharmaceutical compound is integrated into an amorphous hydrophilic polymer which acts as carrier matrix. In this matrix, the pharmaceutical is integrated in its amorphous state rather than in the crystalline state and therewith faster accessible upon dissolution of the polymer. However, if the solid solution is not thermodynamically stable, phase separation and even recrystallization of this solid solution might occur during storage. Therefore, thermodynamic phase behaviour of the solid solution has to be known and the appropriate polymer has to be chosen for a given pharmaceutical.

However, approaches as described above are so far usually found by trial and error procedures. A thermodynamic modeling which enables for the prediction of the phase behavior is the key step in choosing the appropriate formulation of a drug.

The talk gives an overview about the liquid-liquid as well as solid-liquid phase equilibria in systems containing pharmaceuticals. The influence of temperature, solvents, co-solvents, polymers as well as of pH will be discussed. Based on numerous examples, general conclusions will be drawn.

Moreover, it will be shown, that despite of the fact that pharmaceuticals are complex compounds, thermodynamic modelling allows for reliable correlations and even predictions of the phase behaviour of aqueous and organic solutions (in pure and mixed solvents) as well as for solid solutions.