Powder mechanics and dispersion properties of adhesive mixtures for dry powder inhalers : Conceptualized as a blend state model

Abstract: Inhaled medicines is a therapy that dates back several thousands of years. Nowadays, using various types of inhaler devices to deliver active pharmaceutical ingredients (APIs) to treat respiratory diseases has become common practice. One such device is the dry powder inhaler (DPI) which often contains an adhesive powder mixture consisting of micron-sized API particles and larger inert particles (carriers). The general goal of a DPI formulation is to reach as high inhalable dose (dispersibility) as possible while maintaining a low dose variability. In addition, the formulation has to be stable during manufacturing and handling to avoid segregation. In this thesis, critical properties of adhesive mixtures for DPIs have been identified and summarized in a blend state model that describes the spatial distribution of API- and carrier particles in a mixture. The model consists of four distinct states, which are identified using a combination of powder mechanical analysis and imaging techniques. In the first state, denoted S1, the drug deposits at the open pores of the carriers resulting in a denser powder packing but a low dispersibility. At the second state, S2a, the drug will adhere to the outer carrier surfaces, which results in a more porous powder packing and increased dispersibility. Following further increases in drug load, reaching the S2b state, the adhering drug layer grows in complexity resulting in further reductions in powder density but with additional increases in dispersibility. At the final state, S3, the mixture is oversaturated with fines, which results in segregation and large self-agglomerates that are poorly dispersed during an inhalation experiment. The evolution of the blend state was found to be dependent on the carrier and API properties such as size and shape. Irregular carriers could handle higher drug loads before segregation occurred, while irregular API particles formed more porous adhesion layers resulting in lower drug loads. In terms of dispersibility, it was found that porous adhesion layers were more easily dispersed than coherent adhesion layers. When varying the pressure drop (airflow rate), the dispersibility of the S1 state increased linearly with higher pressure drops. However, S2a-S3 were more or less insensitive to increased pressure drops above a certain critical pressure drop. With the blend state model and the mapping of the evolution in blend state with increased drugs loads, the formulation work can ideally be improved leading to more effective treatments for patients.