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The four parts of a dry powder formulation (the formulation, excipient, composition and processing) must be thoroughly understood in order to develop and optimize adhesive mixtures for inhalation. In addition, their interactions can be highly complex. This article gives examples and discusses the complex interaction between the formulation and the device. 22 August 2022 Inhalation Formulation development of adhesive mixtures for inhalation—A multi-factorial optimization challenge: Part 2 Addressing complex interactions among the four parts of a dry powder formulation Kyrre Thalberg, PhD Drawings by Peter Elfman, MSc Emmace Consulting AB Synopsis In the first of two articles in this series, we described the four parts that, together, constitute a dry powder inhaler (DPI) formulation, i.e., the active pharma- ceutical ingredient (API), the excipients, the com- position and the blending process. Each of these must be thoroughly understood in order to develop and optimize adhesive mixtures for inhalation. In this second article, we give examples of interactions among the different parts. Moreover, the influence of the device is discussed. Obviously, the formulation and the device must work well together as their com- bined action determines the pharmaceutical perfor- mance of the inhaled DPI product. Complex interactions e active pharmaceutical ingredient (API) (or APIs in a combination drug product), the excipients, the composition and the processing are all critical to the performance of a dry powder inhaler formulation [1]. Furthermore, these four parts interact in com- plex ways. e challenge for the formulation scien- tist is to capture the nature of the interactions and design experiments that enable quantification of the interaction effects. In principle, development work would be carried out by varying all relevant param- eters within reasonable limits in an extensive design of experiment (DOE). However, besides being extremely costly in labor and materials, a compli- cation with this approach is that many interaction effects are multi-factorial and non-linear, which makes them difficult to unravel in such designs. We will present examples of complex interactions and discuss how they can be understood. e interaction between processing and composition for formulations with a coating agent A complex interaction is one among the drug, the coating agent (also called the force control agent), the composition and the mixing process. An extensive study on formulations that include coating agents blended using high shear mixing was recently pub- lished [2]. e performance of budesonide (Bud) adhesive mixtures with leucine-coated lactose carrier, shown in Figure 1, can serve as an example. Dispers- ibility profiles for 1% and 5% Bud in adhesive mix- tures with 1% leucine are plotted as function of the

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