Abstract
Carrier-free spray-dried dispersions for pulmonary delivery, for which the demand is growing, frequently require the incorporation of dispersibility-enhancing excipients into the formulations to improve the efficacy of the dosage form. One of the most promising of such excipients, L-leucine, is expected to be approved for inhalation soon and has been studied exhaustively. However, during stability, small fibers protruding from the particles of leucine-containing powders have occasionally been observed. To clarify the origin of these fibers and assess their potential influence on the performance of the powders, three different classes of spray-dried leucine-containing formulation systems were studied over an 8-month accelerated stability program. These systems consisted of a large molecule biologic (bevacizumab) in conjunction with a glass former (trehalose), an amorphous small-molecular mass active (moxidectin), and a crystallizing active (mannitol). It was determined that the appearance of the fibers was due to the presence of small quantities of leucine in higher energy states, either because these were amorphous or present as a less stable crystalline polymorph. It was further shown that the growth of these leucine fibers caused no significant physicochemical instability in the powders. Nor, more importantly, did it decrease their aerosol performance in a dry powder inhaler or reduce the concentration of their active pharmaceutical ingredients.