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

Discrete Element Method

Carrier Particle

Dispersion

Agglomerate

Adhesive mixing

DPI-formulation

Pater Noster
Opponent: Prof. Agba Salman, The university of Sheffield, UK.

Författare

Mohammadreza Tamadondar

Chalmers, Kemi och kemiteknik, Kemiteknik, Kemisk apparatteknik

Agglomerate breakage and adhesion upon impact with complex-shaped particles

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The influence of particle interfacial energies and mixing energy on the mixture quality of the dry-coating process

Powder Technology,; Vol. 338(2018)p. 313-324

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Numerical modeling of adhesive particle mixing

AICHE Journal,; Vol. 63(2017)p. 2599-2609

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The role of fine excipient particles in adhesive mixtures for inhalation

Over 200 million people across the world suffer from chronic respiratory diseases, in particular asthma. While such diseases cannot be entirely cured, treatments can significantly reduce symptoms, prevent escalation and improve quality of life. The appropriate management of asthma is done via small devices that lie in any asthmatic patient’s pocket called inhaler. The inhaler delivers controlled dosage of active pharmaceutical particles into airways. Daily, long-term drug inhalation is required for people with persistent symptoms since it can control the progression of the disease and lowers the number of lives it claims yearly.
The performance of these inhalers needs further improvement, as the efficiency of currently marketed inhalers are reported to be around 50% of their nominal values (2017). My doctoral research project was directed towards understanding the preparation of the drug particle assemblies that go into the inhalers and the coupling to inhaler performance. The underlying principle of the research was to treat the therapeutic powder as a particulate system, whose dynamic behavior can be governed based on physical laws and chemical properties of particles. Over the past five years, what pushed me forward at any moment of frustration in my research, was the delightful feeling that this work may -even in the slightest- alleviate the suffering of asthmatic patients.

Ämneskategorier

Kemiska processer

Kemiteknik

ISBN

978-91-7905-314-7

Doktorsavhandlingar vid Chalmers tekniska högskola. Ny serie: 4781

Utgivare

Chalmers tekniska högskola

Pater Noster

Opponent: Prof. Agba Salman, The university of Sheffield, UK.

Mer information

Senast uppdaterat

2020-05-19