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28 August 2022 Inhalation References 1. De Boer A, alberg K, 2021. Dry powder inhal- ers (DPIs). Book chapter in: Inhaled medicines. Optimizing development by integration of in sil- ico, in vitro and in vivo approaches. Eds. Kassinos S, Bäckman P, Conway J, Hickey A. Academic Press. Ch. 5, 99-146. 2. alberg K, Papathanasiou F, Fransson M, Nich- olas M, 2020. Controlling the performance of adhe- sive mixtures for inhalation using mixing energy. Int. J. Pharm. 592, 120055. 3. Littringer EM, Hertel M, Hauptstein S, Dogru M, Schwarz E, Scherließ R, Steckel H, 2016. e influ- ence of high shear mixing parameters on the perfor- mance of ternary dry powder inhaler formulations. Drug Delivery to the Lungs 27. 4. Hertel M, Schwarz E, Kobler M, Hauptstein S, Steckel H, 2017. e influence of high shear mixing on ternary dry powder inhaler formulations. Int. J. Pharm. 534, 242-250. 5. Kaialy W, 2016. On the effects of blending, phys- icochemical properties, and their interactions on the performance of carrier-based dry powders for inhala- tion – A review. Adv. Coll. Interface Sci. 235, 70-89. 6. Grasmeijer F, Hagedoorn P, Frijlink HW, de Boer A, 2013. Mixing time effects on the dispersion per- formance of adhesive mixtures for inhalation. PLOS ONE 8(7), e69263. 7. Faulhammer E, Zellnitz S, Wutscher T, Stran- zinger S, Zimmer A, Paudel A, 2014. Performance indicators for carrier-based DPIs: Carrier surface properties for capsule filling and API properties for in vitro aerosolization. Int. J. Pharm. 473, 617-626. 8. Eskandar F, Lejeune M, Edge S, 2011. Low pow- der mass filling of dry powder inhalation formula- tions. Drug Dev. Ind. Pharm. 37(1), 24-32. 9. alberg K, Berg E, Fransson M, 2012. Modeling dispersion of dry powders for inhalation. e con- cepts of total fines, cohesive energy and interaction parameters. Int. J. Pharm. 427, 224-233. 10. Shalash A, Molokhia A, Elsayed M, 2015. Insights into the roles of carrier microstructure in adhesive/ carrier-based dry powder inhalation mixtures: Car- rier porosity and fine particle content. Eur. J. Pharm. Biopharm. 96, 291-303. 11. Shalash A, Khalafallah N, Molokhia A, Elsayed M, 2018. e relationship between the permeabil- ity and the performance of carrier-based dry powder inhalation mixtures: New insights and practical guid- ance. AAPS PharmSciTech. 19 (2), 912-921. 12. Elsayed M, Shalash A, 2018. Modeling the per- formance of carrier-based dry powder inhalation formulations: Where are we, and how to get there? J. Control Release. 279, 251-261. Summary is article focuses on the pharmaceutical perfor- mance of adhesive mixtures for inhalation, also called ordered mixtures or carrier-based formulations. Adhesive mixtures consist of four parts: the API(s), the excipient(s), the composition and the processing. Several features from each part are critical to perfor- mance. Moreover, there are interactions among all four parts, many of which are highly complex. e challenge for the formulator is to understand the nature of the interactions and design experiments to correctly capture and quantify the effects. Binary formulations of API and lactose carrier can, in many cases, be blended using a low shear blender, which can offer the advantage of not damaging par- ticles, provided the applied mixing force, MF, is not too strong. e main challenge will be to achieve good blend uniformity, while dispersibility is less affected by the mixing process. Addition of fine lac- tose particles is a means to improve formulation per- formance with respect to FPF. Formulations that include a coating agent display complex behavior. To ensure efficient smearing of the coating agent, the use of a high shear blender is rec- ommended. e processing parameters will be critical to performance and must be thoroughly investigated. e applied mixing energy, ME, which combines the effects of carrier mass, bowl size (radius), mixing time and speed, has been identified as a key parameter that governs performance in terms of FPF. is parame- ter, together with the mixing force, MF, is believed to be key to understanding how particles are affected in the mixing process, and can be expected to facilitate formulation development as well as scale up. e interaction between the formulation and the device is another complex relationship. e air flow resistance of the device determines the flow rate to be used for performance characterization of the DPI product and the flow path geometry determines the modes available for fine particle dispersion. e device, therefore, plays a vital role with respect to the dispersibility of the inhaled drug product and may also set other requirements, for instance, regarding powder flowability. Furthermore, the device is obviously the interface to the user. e patient sees and interacts with the device but hardly experiences the formulation, except for a faint taste upon inhalation. erefore, the device/patient interface is the driver for a pos- itive patient experience and user (handling) studies in patient populations are a part of the DPI product development process and registration. Acknowledgement is work was supported by the Swedish Foundation for Strategic Research.