Abstract by Nele Hempel

In situ amorphization describes the solid-state transformation from a crystalline state of the drug into the amorphous form inside the final dosage form, e.g. the formation of an amorphous solid dispersion (ASD) in a tablet. The approach of in situ amorphization can potentially circumvent downstream process challenges of ASDs, as well as stability issues during the shelf-life of ASDs.

It has been hypothesized that microwave-induced in situ amorphization follows a dissolution process of the drug into a mobile polymer network at temperatures above the glass transition temperature (T_g) of the polymer. This work aimed to show that radiation-induced in situ amorphization (here: using microwave and laser radiation) follows a dissolution process of the drug into a mobile polymer. For this, the Noyes-Whitney equation describing the dissolution rate of a solute (drug) into a solvent (polymer) was consulted and the effect of several parameters from the Noyes-Whitney equation (and Stoke-Einstein equation for the diffusion coefficient) - namely the surface area, the temperature, the viscosity, the drug in polymer solubility and the radius of the drug molecule - on radiation-induced in situ amorphization were investigated. Furthermore, a thermal analysis method based on DSC measurements of drug-polymer mixtures was investigated to determine the on- and endset temperatures of the underlying dissolution process of radiation-induced in situ amorphization.

Additionally, several process and formulation parameters were analyzed for their impact on radiation-induced in situ amorphization, such as compaction pressure and the choice and amount of radiation-absorbing excipient, i.e. the heating source. Lastly, the dissolution performance of amorphized powderized compacts obtained after exposure to microwave radiation and laser radiation was investigated and compared to physical mixtures.

The studies conducted for this thesis confirmed that radiation-induced in situ amorphization follows a dissolution process. Furthermore, the use of glycerol and polyethylene glycol as absorbing excipients for microwave-induced and the use of plasmonic nanoparticles for laser-induced in situ amorphization were successfully introduced. Additionally, a correlation between exposure time, temperature and rate of in situ amorphization was established, i.e. with increasing exposure time, the temperature and hence the rate of amorphization was increased. Powderized in situ amorphized compacts showed a higher drug release compared to the crystalline drug.  

In summary, this work systematically investigated radiation-induced in situ amorphization and showed the underlying mechanistic principles. Thereby, this work provides the basis for further investigation and aids to find suitable excipients and process parameters for successful radiation-induced in situ amorphization.