Integrated Continuous Crystallization and Spray Drying of Insulin for Pulmonary Drug Delivery

Abstract

Pulmonary delivery of insulin in the form of a dry powder is an attractive alternative in comparison to conventional subcutaneous delivery. Insulin crystals have potential advantages such as sustained release and higher stability in comparison to amorphous particles. However, the design of crystallization processes that can reliably produce insulin crystals in a suitable size range for pulmonary delivery is challenging. A continuous process involving the integration of a tubular crystallizer and a spray dryer is characterized for the production of inhalable insulin. Supersaturation is created via cooling and a pH shift at the inlet of the crystallizer, aiming at a high nucleation rate. The recovery of insulin in the crystallizer exceeds 90%, and the insulin particles appear crystalline under most of the tested conditions. Integration with a spray dryer produces a dry powder with favorable properties for pulmonary drug delivery. The emitted fraction of insulin from a capsule in a commercial inhaler is in the range of 84.3–93.1%, which shows good powder dispersibility. Furthermore, the fine particle fraction of the insulin crystals ranges from 22.0% to 36.4%, which indicates a good potential for pulmonary delivery.