Surface mediated polymorphic structures of drug molecules

New active pharmaceutical ingredients (APIs) often exhibit unfavorable low solubility and/or hindered dissolution behavior within an application relevant aqueous environment. As a result the therapeutic activity is diminished due to insufficient adsorption and bioavailability in-vivo which may even cause a rejection of highly potential APIs. The aim of this project is the solution based preparation and identification of surface mediated polymorphic crystal structures of APIs within thin solid films at substrate surfaces. Such polymorphs are distinct from other polymorphs which form in bulk solutions. They occur due to interactions with the surface on account of altered boundary conditions; variations in Coulomb, Van der Waal or H-bonding interactions results in surface mediated structures during crystallization. In addition, the kinetic of the crystallization is of importance as a fast crystallization favors the assembling into surface mediated polymorphs. In general, the solubility of materials strongly depends on the polymorphic structure, as different crystal facets provide altered surface energies. The introduction of surface mediated structures is expected to alter the solubility and the dissolution properties significantly providing new routes for pharmaceutical formulations. Within the project fundamental interactions of API molecules with surfaces will be identified. Adsorption studies of various API molecules at liquid solid interfaces will be performed by in-situ quartz crystal microbalance measurements. Variations of solvents and surfaces will highlight correlations of the surface access/kinetic of the adsorption or desorption process and the boundary conditions. Solution based deposition techniques like spin coating and drop casting will be applied to obtain thin and solvent free API layers on various surfaces which will be investigated by state of the art microscopy or X-ray based techniques. Changes in the process conditions (rotation speed, concentration, evaporation time of the solvent, ) will provide sufficient variability to identify important parameters for the formation of surface mediated polymorphic structures. Standardized dissolution testing with USP apparatuses will provide information on altered dissolution properties with respect of standard preparation routes. The knowledge on the formation of surface mediated structures will be used to prepare defined thin layers of API on nanoparticle surfaces which are usable within pharmaceutical relevant formulations.

Medications ready to be used by patients required the solid state structure of the drug molecules to be defined so that a reproducible therapeutic action is guaranteed. In industry there are many different approaches established to achieve this goals but these are limited in many respects. Especially in optimizing drug formulation for better or more controlled drug release standard techniques often fail. In this project, the effect of solid supports or substrates had been investigated for their capability to induce new solid state forms of drugs. To achieve different forms or polymorphs the project team employed various thin film preparation techniques, which are uncommon for the fabrication of medication but are state of the art in other fields like semiconductor industries. This involved spin coating, drop casting, dip coating or vacuum deposition. The drugs under investigation included caffeine and derivatives, aspirin, paracetamol, phenytoin, nabumetone, ibuprofen or carbamazepine. The results of the project shows that the usage of thin film techniques enables distinct crystal growth for these substances, whereby different morphologies, different textures and even new polymorphs had been identified. The new polymorph of phenytoin even demonstrates to be of much higher effectiveness in terms of drug release compared to the forms typically found in the commercial products. It can be concluded that additional control on the final crystal form is achievable. This suggests that applying such approaches on other drug molecules might assist in improving also their therapeutic action; many drug molecules suffer from poor solubility which using thin films might be strongly improved. As lower drug amounts are capable of providing the same therapeutic action, this reduce side effects in the patients. Further, this also means that the amount of material wasted reduces which minimizes the impact on the environment but also the cost for therapy might be less so that an economic improvement for the individual might be obtained.