Impact of Laser Speed and Drug Particle Size on Selective Laser Sintering 3D Printing of Amorphous Solid Dispersions

This research demonstrates the influence of laser speed and the drug particle size on the manufacturing of amorphous solid dispersions (ASD) and dosage forms thereof using selective laser sintering 3-dimensional (3D) printing. One-step manufacturing of ASD is possible using selective laser sintering 3D printing processes, however, the mechanism of ASD formation by this process is not completely understood and it requires further investigation. We hypothesize that the mechanism of ASD formation is the diffusion and dissolution of the drug in the polymeric carrier during the selective laser sintering (SLS) process and the drug particle size plays a critical role in the formation of said ASDs as there is no mixing involved in the sintering process. Herein, indomethacin was used as a model drug and introduced into the feedstock (Kollidon® VA64 and Candurin® blend) as either unprocessed drug crystals (particle size > 50 µm) or processed hot-melt extruded granules (DosePlus) with reduced drug particle size (<5 µm). These feedstocks were processed at 50, 75, and 100 mm/s scan speed using SLS 3D printing process. Characterization and performance testing were conducted on these tablets which revealed the amorphous conversion of the drug. Both MANOVA and ANOVA analyses depicted that the laser speed and drug particle size significantly impact the drug’s apparent solubility and drug release. This significant difference in performance between formulations is attributed to the difference in the extent of dissolution of the drug in the polymeric matrix, leading to residual crystallinity, which is detrimental to ASD’s performance. These results demonstrate the influence of drug particle size on solid-state and performance of 3D printed solid dispersions, and, hence, provide a better understanding of the mechanism and limitations of SLS 3D printing of ASDs and its dosage forms.

Nanoparticles and Nanocrystals by Supercritical CO2-Assisted Techniques for Pharmaceutical Applications: A Review

Many active ingredients currently prescribed show limited therapeutic efficacy, mainly due to their dissolution rate inadequate to treat the pathology of interest. A large drug particle size creates an additional problem if a specific site of action in the human body has to be reached. For this reason, active ingredient size reduction using micronization/nanonization techniques is a valid approach to improve the efficacy of active compounds. Supercritical carbon-dioxide-assisted technologies enable the production of different morphologies of different sizes, including nanoparticles and nanocrystals, by modulating operating conditions. Supercritical fluid-based processes have numerous advantages over techniques conventionally employed to produce nanosized particles or crystals, such as reduced use of toxic solvents, which are completely removed from the final product, ensuring safety for patients. Active compounds can be processed alone by supercritical techniques, although polymeric carriers are often added as stabilizers, to control the drug release on the basis of the desired therapeutic effect, as well as to improve drug processability with the chosen technology. This updated review on the application of supercritical micronization/nanonization techniques in the pharmaceutical field aims at highlighting the most effective current results, operating conditions, advantages, and limitations, providing future perspectives.

Orally Inhaled Drug Particle Transport in Computerized Models of Laryngotracheal Stenosis

Objective Adjuvant management for laryngotracheal stenosis (LTS) may involve inhaled corticosteroids, but metered dose inhalers are designed for pulmonary drug delivery. Comprehensive analyses of drug particle deposition efficiency for orally inhaled corticosteroids in the stenosis of LTS subjects are lacking. Study Design Descriptive research. Setting Academic medical center. Methods Anatomically realistic 3-dimensional reconstructions of the upper airway were created from computed tomography images of 4 LTS subjects—2 subglottic stenosis and 2 tracheal stenosis subjects. Computational fluid dynamics modeling was used to simulate airflow and drug particle transport in each airway. Three inhalation pressures were simulated, 10 Pa, 25 Pa, and 40 Pa. Drug particle transport was simulated for 100 to 950 nanoparticles and 1 to 50 micron-particles. Particles were released into the airway to mimic varying inhaler conditions with and without a spacer chamber. Results Based on smallest to largest cross-sectional area ratio, the laryngotracheal stenotic segment shrunk by 57% and 47%, respectively, for subglottic stenosis models and by 53% for both tracheal stenosis models. Airflow resistance at the stenotic segment was lower in subglottic stenosis models than in tracheal stenosis models: 0.001 to 0.011 Pa.s/mL vs 0.024 to 0.082 Pa.s/mL. Drug depositions for micron-particles and nanoparticles at stenosis were 0.06% to 2.48% and 0.10% to 2.60% for subglottic stenosis and tracheal stenosis models, respectively. Particle sizes with highest stenotic deposition were 6 to 20 µm for subglottic stenosis models and 1 to 10 µm for tracheal stenosis models. Conclusion This study suggests that at most, 2.60% of inhaled drug particles deposit at the stenosis. Particle size ranges with highest stenotic deposition may not represent typical sizes emitted by inhalers.