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A study of the influence of blend preparation and storage stability of a mannitol carrier material in DPI formulations. Inhalation OctOber 2018 17 Spray-granulated mannitol as a viable alternative to lactose in DPI formulations: Preparation of ordered mixtures and storage stability A study of the influence of blend preparation and storage stability of a mannitol carrier material in DPI formulations Nancy Rhein a ; Gudrun Birk, PhD b ; and Regina Scherließ, PhD a a Kiel University b Merck KGaA generally suitable as a carrier in various formulations. 4, 6, 7 Important aspects of carriers for dry powder inhalation (DPI) formulation are particle size distribution, flow- ability, dosability, 8 crystallinity and hygroscopicity, 9 as all of them can influence the aerodynamic behavior of the blend. Furthermore, the process of preparing the ordered mixture may also influence aerodynamic per- formance. Depending on the blending conditions, the powder blend is exposed to differing degrees of mechanical stress, which may influence these charac- teristics, especially over certain storage times. Electro- static charge, which is introduced by the mixing pro- cess, can be reduced during storage so that API parti- cles can be detached more easily from the carrier. Inversely, adsorption of moisture during storage can adhere API particles on the carrier particles, therefore it will be more difficult to detach them. Both factors influence fine particle fraction (FPF). e study presented in this article investigated the influ- ence of blend preparation, using a low shear Turbula ® tumble blender and a Picomix ® high shear mixer, on the aerodynamic performance of blends containing manni- tol for inhalation (Parteck ® M DPI). It is known from lactose-based blends, that the choice of blender type and blending conditions can strongly influence aerody- namic properties, 10 whereas this has not yet been exam- ined with mannitol-based blends. In addition, lac- tose-based blends are sensitive to humidity and their physical properties, as well as their aerodynamic behav- ior, may change depending on storage conditions. 11 erefore, the stability of mannitol-based blends stored under three different conditions for 14 months with mannitol as a carrier and two model APIs—namely budesonide (BUD) as a hydrophobic example and sal- Introduction e use of dry powder formulations for inhalation is common. Active pharmaceutical ingredient (API) par- ticles should have an aerodynamic particle size less than 5 µm to reach the lung. Yet these micronized powders come with some disadvantages such as high cohesive- ness, which can lead to poor flowability so they can be very difficult to handle. e most common method to improve these challenging powders is to formulate ordered mixtures in which large carrier particles are blended with micronized API particles to improve their bulk properties like flowability, powder homogeneity and uniformity of dose. During inhalation, the small API particles become detached from the carrier and fol- low the inspiration airflow to reach the lung. ese car- rier-based blends are a well-known formulation strategy in local treatment of asthma and chronic obstructive pulmonary disease. 1 Currently, lactose is the most established carrier in such carrier-based powder blends. 2 is material is mainly used as crystalline alpha lactose monohydrate, which is stable and not very susceptible to water vapor, but it is known that amorphous content can be introduced via processing such as milling or spray drying. 3 In addition, lactose is a reducing sugar, which could cause product stability concerns. It is also of animal origin, requiring certification as BSE/TSE-free. Mannitol as an alternative to lactose has been discussed for quite some time. 4 Mannitol is interesting because it is a non-reducing sugar, animal-origin-free and listed as a GRAS (generally recognized as safe) material by the United States Food and Drug Administration (FDA). 5 Previous studies have shown that mannitol is

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