We investigated the effect of process parameters and a co-spray-dried excipient on the polymorphism and stability of spray-dried mannitol. It is known that mannitol has different crystal forms. On the other hand, the spray-drying process can possibly induce change in the crystal forms. The dispersibility of dry powder inhalers (DPI) is affected by various powder properties. Recent studies have shown that different spray-dried-mannitol polymorphisms have different dispersibility. Therefore, it is valuable to investigate the effect of the process and formulation on the polymorphism of spray-dried mannitol. Co-spray drying of mannitol and polyethylene glycol (PEG) in water produced mainly a-form in contrast to spray drying of mannitol alone, which resulted in mainly b-form. Polymorphism of co-spray-dried mannitol with PEG was affected by both process parameters related to drying efficiency and formulation. Less b-form was observed with faster drying, a higher PEG to mannitol ratio and a smaller molecular weight of PEG. The polymorphic stability also depended on the PEG ratio. At 40°C/75%RH, the transformation from a-form to b-form was faster than recrystallized a-form when co-spray drying was conducted at a low PEG ratio (1%£) while no transformation was observed with a high PEG ratio (10%). Considering the hygroscopicity of PEG, PEG could have two opposite effects, accelerating transformation and stabilizing crystal form, on the polymorphic state of co-spray-dried mannitol. Consequently, polymorphism of co-spray-dried mannitol with PEG was suggested to be controllable by process and formulation. The polymorphic stability was also regulated by the PEG ratio added to the spray-drying system.