Mechanisms of adhesive mixing for drug particle inhalation (Numerical investigation of the interplay between formulation variables)

Doctoral thesis, 2020

Formulation of therapeutic dry powders for lung drug delivery via inhalation is done via adhesive mixing. In this process, micron-sized active pharmaceutical ingredient particles are blended with relatively coarse carrier particles until stable adhesive units of carrier and drug particles are formed. Inside the inhaler and upon its actuation, the turbulent kinetic energy of air stream is transferred to the bulk powder of adhesive units and consequently drug particles are dispersed into primary respirable particles. The formulation process-besides the inhaler design and the patient’s respiratory manoeuvre- is one of the three pillars that determine the overall performance of drug administration, and therefore, it needs to be genuinely understood. Despite all the recent advancements in the formulation of carrier-based dry powder inhaler, the in vitro efficiency of currently marketed inhalers is at best less than 50% of their nominal values(2017).
The goal of this research is to devise a methodology to comprehend the complex nature of the adhesive mixing process for inhalation, and to optimize this process. The small temporal and spatial scales of the adhesive mixing, on one hand, and the omnipresent interplay of process variables, on the other hand, require a modeling framework and several quality-assessment tools. The underlying principle of this framework is to treat the adhesive mixture as a particulate system, whose dynamic behaviour can be modelled by applying the Newton’s laws of motion to individual particles.
Several formulation variables are selected, in accordance with their significance in the process and with the capacity of the developed model, for parameter studying. These variables include the (i) adhesive properties of particles, (ii) the mixing intensity, (iii) the shape of carriers, (iv) the surface asperity of particles, and (v) the added fine particles (ternary blend). The process quality is inferred from mixing homogeneity indices, micro-scale structure of adhesive units, and the fragmentation analyses of drug agglomerates. In addition to the formulation process, simulated dispersion tests are performed in order to understand the role of the carrier surface roughness on the drug particle detachment during aerosolization. The combination of mixing energy and particle surface energies is used to map the mixing state. It is found that any imbalance between these two process variables results in poor adhesive mixtures. The non-sphericity of carrier particles is also shown to impose a noticeable difference in the breakage and adhesion pattern of drug agglomerates. In the context of formulation, the carrier surface roughness reduces the drug deposition, and in the context of dispersion, the drug detachment is found proportional to the roughness length scale. Lastly, different cases of ternary formulations are simulated and the relevance of the active site and the buffer theories are examined.