On the relationship between blend state and dispersibility of adhesive mixtures containing active pharmaceutical ingredients

Jonas Rudén,Göran Frenning,Tobias Bramer,Kyrre Thalberg,Göran Alderborn

doi:10.1016/j.ijpx.2020.100069

Jonas Rudén, Göran Frenning + Show 3 more

Open Access

https://doi.org/10.1016/j.ijpx.2020.100069

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Abstract

The objectives of this investigation were to study the evolution in blend state of adhesive mixtures containing the active pharmaceutical ingredients (APIs) salbutamol, budesonide and AZD5423 and to study the relationship between blend state and dispersibility of the mixtures, as assessed by the fine particle fraction (FPF). A series of adhesive mixtures of varied fines concentration were prepared for each API using the same type of carrier. Based on visual examination and powder mechanics, blend states were identified and summarized as blend state maps for each API. The dispersibility of the mixtures was studied using a Fast Screening Impactor (FSI) equipped with a ScreenHaler. The evolution in blend state differed between the APIs in terms of the width of the blend states. The structure of the adhesion layer also differed between the APIs, from relatively uniform to a heterogeneous layer with small agglomerates dispersed on the carrier surface. All three APIs expressed a similar type of bended relationship between FPF and fines concentration. However, the initial rate of increase and the fines concentration of the plateau differed between the APIs. The adhesive mixtures of all APIs followed the three main states in terms of structural evolution and the overall shape of the FPF-fines concentration profiles could be explained by the evolution in blend state. It is proposed that the structure of the adhesion layer is an important factor explaining the differences in blend state - blend dispersibility relationships between the APIs.

Highlights

Inhalation powders are often formulated as adhesive mixtures (de Boer et al 2017; Grasmeijer et al 2015) which consist of a special type of agglomerate formed from micron-sized drug particles mixed with larger, inert, carrier particles
Based on experiments using one type of lactose carrier and one type of lactose micro-particle (Ruden et al 2018), we have proposed that a blend state model can consist of up to four regions and in-between each state a transition step or transition interval exists
In an earlier paper (Ruden et al 2018), we introduced a blend state concept as a means to describe the different states an adhesive mixture may undergo with the addition of increasing proportions of fines

Summary

Introduction

Inhalation powders are often formulated as adhesive mixtures (de Boer et al 2017; Grasmeijer et al 2015) which consist of a special type of agglomerate formed from micron-sized drug particles mixed with larger, inert, carrier particles. The role of the carrier material is to ensure homogeneity, powder flow and aerosolization performance during manufacturing and use (Thalberg et al 2004). These types of formulations have been exten sively investigated and discussed in the literature either by experiments, e.g. (Nguyen et al 2015; Sarangi et al 2019) and the structural evolution of an adhesive mixture with increasing proportions of micro-particles (increased drug loading) have been described in the literature in terms of a consecutive series of blend structures (Hertel et al 2018; Young et al 2011). The blend state model can be used to map different combinations of micro-particles and carriers (i.e. blend state map)

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