Real-Time Monitoring of Continuous Pharmaceutical Mixed Suspension Mixed Product Removal Crystallization Using Image Analysis

In this work, we developed an in-line image analysis system for the monitoring of the continuous crystallization of an active pharmaceutical ingredient. Acetylsalicylic acid was crystallized in a mixed suspension mixed product removal crystallizer, which was equipped with overflow tubing as an outlet. A steep glass plate was placed under the outlet onto which the slurry dripped on its surface. The glass plate spread and guided the droplets toward the product collection filter. A high-speed process camera was mounted above the glass plate to capture images of the crystals. Several light sources were tested in various positions to find the appropriate experimental setup for the optimal image quality. Samples were taken during continuous operation for off-line particle size analysis in order to compare to the crystal size distributions calculated from the images. The results were in good agreement, and the trends of the process could be followed well using the images. As a next step, image analysis was operated throughout the entire continuous crystallization experiment, and a huge quantity of information was collected from the process. The crystal size distribution of the product was calculated every 30 s, which provided a thorough and detailed insight into the crystallization process

Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability

The aim of this study was to develop antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPβCD) was used as a stabilizer and as an electrospinning matrix. In order to optimize the morphology of the fibers, electrospinning of various formulations was carried out using water, methanol/water (1:1), and methanol as solvents. The results showed that using methanol could be advantageous due to the lower viscosity threshold for fiber formation enabling higher potential drug loadings by using less excipient. To increase the productivity of electrospinning, high-speed electrospinning technology was utilized and HPβCD fibers containing 9.1% antisense oligonucleotide were prepared at a rate of ~330 g/h. Furthermore, to increase the drug content of the fibers, a formulation with a 50% drug loading was developed. The fibers had excellent grindability but poor flowability. The ground fibrous powder was mixed with excipients to improve its flowability, which enabled the automatic tableting of the mixture by direct compression. The fibrous HPβCD–antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPβCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning such as scale-up and downstream processing of the fibers