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.

Recent Advancements in Continuous Crystallization of Proteins

“…Chen et al. [ 24 ] have demonstrated the influence of various parameters on the mean particle size and insulin recovery of a CSFC. The parameters varied were: pH, initial insulin concentration, and gas and liquid flow rates.…”

“…Gas is injected into the stream at regular intervals to make small packets of solution. [21][22][23][24] The shearing of liquid with the walls causes circulation, which helps ensure a uniform supersaturation while also preventing deposition and clogging to some extent. Clogging may still occur due to the smaller internal tube diameter and the lack of other agitation sources.…”

“…Chen et al, 2021 [24] Insulin CSFC (unseeded) solutions were mixed 1:1 so the crystallization mixture would contain 5 mm zinc sulphate, 10 mm buffer, and 15% (v/v) acetone. The slug aspect ratio was maintained close to 1.…”

Rational Development of a Carrier-Free Dry Powder Inhalation Formulation for Respiratory Viral Infections via Quality by Design: A Drug-Drug Cocrystal of Favipiravir and Theophylline

“…The resulting larger mean MMAD is attributed to the increased solute content in each atomized droplet, leading to an increased feed viscosity and enlarged primary particle size [87]. This positive effect could also result from a stronger propensity for particle agglomeration at a high degree of local supersaturation [76,88,89]. A low solute concentration imparts long interparticle distance with diffused nuclei, thereby minimizing agglomeration, which is favorable to pulmonary drug delivery.…”

Spectroscopic insights into multi-phase protein crystallization in complex lysate using Raman spectroscopy and a particle-free bypass

“…In practice, harvest broth from biotechnological processes involves mixtures of proteins, impurities, and only a small quantity of the target molecule. While a lot of research was reported on scaled-up protein crystallization in solutions containing only traces of impurities or even none ( Judge et al, 1995 ; Lee et al, 2000 ; Peters et al, 2005 ; Hebel et al, 2013 ; Yang et al, 2019 ; Chen et al, 2021 ; Tian et al, 2023 ; Jul-Jørgensen et al, 2024 ), the challenges imposed by complex solutions in capture processes have received relatively little attention ( Takakura et al, 2006 ; Smejkal et al, 2013 ; Hekmat et al, 2017 ; Grob et al, 2020 ).…”