AbstractsEngineering

The efficient delivery of active pharmaceutical ingredients (APIs) to the lung by inhalation products depends on several parameters which include the formulation, the inhaler device, and the patient’s inhalation technique. APIs which exhibit larger sized particles (> 5 µm) might impact in upper airways and thus boost side effects. In general, the common active pharmaceutical ingredients (APIs) are synthesized as crystalline solids and subsequently processed by standard pharmaceutical operations such as milling, blending and even sieving. These processing steps can lead to structural changes, crystal defects and amorphous regions which may have an enormous potential to change during handling and storage and should be limited to a minimum. The conditions and kinetics of such process-induced disorders and changes during storage may affect product stability. In terms of the determination and control of the amorphous content, there is still lack in reliable methods that accurately assess the amorphous content in pharmaceutical powders down to a minimal level (< 1%). Therefore, this thesis focuses on the impact of amorphous parts of inhalation APIs, the improvement of their production techniques and detection methods for quantifying minimal amorphous amounts as well as the understanding of their influence on inhalation powder formulations. In a first step the preparation techniques of semi-crystalline/fully amorphous samples were investigated by using different technologies and process conditions. The focus was set on ball-milling, spray-drying, freeze-drying and quench cooling for the establishment of purely amorphous material. On the contrary, jet-milling and intensive blending (simulation with glass beads) led to the generation of partially amorphous APIs (up to 17%) mainly localized on the surface of the particles. Furthermore, the influence of these process-induced disorders on the stability and shelf-life was investigated (humidity/temperature/time). The accurate assessment of the amorphous content down to a level < 0.5% in pharmaceutical powders was demonstrated by a developed one-step DVS method which is based on ‘equilibrium moisture uptake’. The applicability was tested for various hydrophilic and hydrophobic powders and their induced amorphous amounts. This highly accurate DVS study demonstrates how amorphous regions are specifically detectable as “reactive spots” to polar or nonpolar vapors. A high affinity of the API to the solvent was targeted to receive a high sensitivity of the method, a higher slope of the calibration curve and to detect minimal differences between powder samples. The development was divided into six main sections (water moisture sorption isotherms, organic solvent screening, optimization of the p/p0 values, temperature robustness, influence of particle size/surface and validation). Finally, a schematic model for the explanation of the adsorption and absorption theory was illustrated. This approach may facilitate the specifications for in-process controls in the pharmaceutical industry.…