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8 AUGUST 2015 Inhalation Considerations in spray dry drug development for inhalation delivery: An albuterol case study Introduction Spray drying can enable rapid dry powder inhaler (DPI) development timelines, powder homogeneity and active pharmaceutical ingredient (API) flexibility to deliver expedited proof of concept and clinical study test mate- rial for a wide range of APIs and dose ranges for inhala- tion and intranasal particle delivery. A streamlined and de-risked drug development approach, based on spray dry technology, has been developed and optimized for inhaled drug development. The approach integrates excipient understanding, API characteristics, specifi- cally-designed inhalation capsules and desired quality attributes with a focus on the final drug concept. This article presents a model of the Capsugel Dosage Form Solutions/Bend Research (Bend, OR, US) spray dry formulation platform. Process and formulation approaches are discussed, as is a case study where albuterol sulfate was formulated and spray dried into a dry powder for pulmonary delivery. In this case study, the anticipated delivered dose, physical API characteris- tics, performance criteria and anticipated stability were considered during formulating and spray dry manufac- ture. After manufacture, the resulting dry powder was characterized and encapsulated then aerosol properties were evaluated. Materials and methods Given the goaIs of this program, clinical application and long-term stability were not prioritized, however the excipients included in this study highlight excipient ratio- nale and utility. Lactose, with precedence in inhalation applications, was used as a bulking excipient and matrix component to the designed formulation. Lactose concen- tration relative to a desired API concentration can be modified to match a desired dose range. 1 Leucine was cho- sen to act as a surface-modifying excipient to enhance aerosolization. 2 In the developed formulation, the solubil- ity of leucine was much lower than other formulation components, which plays a role in the ability of leucine to functionalize the surface of spray dried particles. 3 Leucine positively impacts particle dispersal during delivery and decreases powder retention in devices. Sodium chloride was included in order to improve powder handling and powder encapsulation. Four spray dried batches of pow- der were created, which either varied albuterol loading or manufacturing. Spray dried powders for pulmonary delivery were manu- factured at two different scales using either a custom small- scale spray dryer (BLD-35—100 mg to 10 g scale) or a pilot-scale spray dryer (PSD-1—10 g to 1 kg scale) with dry nitrogen gas and the dryer outlet temperature (T out) ranged between 50°C and 70°C. The bench size BLD-35 was used to show the applicability of collecting powder in an API-sparing fashion, with batch requirements reduced to 300 mg. The same formulation was then manufactured on a PSD-1 spray dryer (Düsseldorf, Germany) in order to confirm to scale-up effects on powder quality. All for- mulation components were added directly to deionized water to produce a single aqueous solution. Following manufacture, bulk powders were subsequently analyzed to determine their solid-state and aerosol prop- erties. API loading, as well as scale of manufacture, can impact particle physical characteristics, which in turn, impact inhalation drug delivery. Characterization included: particle morphology by scanning electron microscopy (SEM); water content by Karl Fisher (KF); glass transition temperature (Tg) by modulated differen- tial scanning calorimetry (mDSC); physical composition by powder x-ray diffraction (XRPD); and mean geomet- ric particle size by Malvern Mastersizer. These tests were performed to better understand the physical state of the powders immediately after manufacture. Jeffrey Breit PhD, Michael Burke, Devon DuBose, David Vodak PhD Bend Research, a division of Capsugel Dosage Form Solutions A streamlined, de-risked approach, based on spray dry technology, has been optimized for inhaled drug development.