(603a) Continuous Manufacturing of Pharmaceutical Mini-Tablets for Pediatric Patients Using Drop-on-Demand Printing

The pharmaceutical industry has traditionally used mass manufacturing to produce medications for all patients, with drugs being manufactured in a limited range of dose strengths that cater to the majority of the population. This negatively impacts vulnerable patient groups like children as their drug needs differ significantly from that of the adult populace (Trenfield et al., 2018). In order to achieve successful therapeutic outcomes, pediatric patients often require medication with flexible dosing, taste masking, and ease of swallowing. Conventional treatment methods for these patients have included dosage forms like powders, liquid oral drug products and extemporaneously prepared medications. While these drug forms satisfy some of the above requirements, they are hampered by several limitations such as absence of controlled release, poor long-term stability, dosing accuracy, and challenges with excipient compatibility (Ivanovska et al., 2014).

In recent years, numerous studies have developed methods to improve the administration of the conventional drug forms and to create novel dosage forms that can address the shortcomings of these dosage types. Some of these innovations include development of scoring friendly tablets, modified feeding bottles, orodispersible films, and mini-tablets. Among these, pharmaceutical mini-tablets are one of the most promising novel dosage types. They are small-sized drug products, with a diameter of less than 4mm, and can safely be administered to children over the age of 1. The amount of drug dispensed can also be easily tailored by simply adjusting the number of mini-tablets given. They possess many of the features of regular-sized tablets such as supporting delayed or sustained drug release, long term product stability, and taste masking etc. (Zuccari et al., 2022). Current methods to manufacture mini-tablets include powder-based techniques like direct compression and granulation, and 3D printing based methods like hot melt extrusion and fused deposition modeling.

This study aims to introduce a new method to make mini-tablets using a drop-on-demand (DoD) 3D printing platform. DoD is a type of inkjet printing where drug products are made by printing drops of a liquid formulation on inert substrates (like capsules or placebo tablets). In this technique the API is dispersed in a molten carrier fluid, which is then printed as precise droplets using the DoD printer. These generated drops are captured in an inert solvent bath and solidified to yield individual mini-tablets. There are several advantages of manufacturing mini-tablets with this method including avoiding powder processing challenges, manufacturing dosages with high content uniformity, and ease of adaptation of Industry 4.0 technologies (Sundarkumar et al., 2022a, 2022b).

The first part of this study focuses on developing a framework to design the inert solvent bath. Based on the size and temperature of the droplets, dimensions of the solidification vessel and solvent amount are computed. In the next part, the proposed process is tested for a variety of drug loadings, excipients and formulation types, and the release behavior and content uniformity of dosages produced are measured. Finally, the entire process is run continuously by integrating the DoD printer with a carousel filter unit (Liu et al., 2019). Solidified mini-tablets are transferred into the carousel filter where they are washed, dried and dispensed as ready-to-use mini-tablets. Real time monitoring capabilities are also implemented for the system, to determine drug loading a camera and an ultraviolet spectrophotometer probe are installed on-line. The camera image is used to obtain an estimate of dosage volume while the probe measures active ingredient concentration in the ink. The combination of these measurements results in a real time estimate of the drug loading in each mini-tablet. Test results indicate that mini-tablets can be consistently produced in acceptable dosage amount and content uniformity. In conclusion, this study presents a novel, continuous 3D printing process for manufacturing pharmaceutical mini-tablets which can flexibly and reliably meet pediatric patients’ needs.

References:

Ivanovska, V., Rademaker, C. M. A., Van Dijk, L., & Mantel-Teeuwisse, A. K. (2014). Pediatric drug formulations: A review of challenges and progress. In Pediatrics (Vol. 134, Issue 2). https://doi.org/10.1542/peds.2013-3225

Liu, Y. C., Domokos, A., Coleman, S., Firth, P., & Nagy, Z. K. (2019). Development of Continuous Filtration in a Novel Continuous Filtration Carousel Integrated with Continuous Crystallization. Organic Process Research and Development, 23(12). https://doi.org/10.1021/acs.oprd.9b00342

Sundarkumar, V., Nagy, Z. K., & Reklaitis, G. V. (2022a). Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production. Journal of Pharmaceutical Sciences. https://doi.org/10.1016/j.xphs.2022.03.009

Sundarkumar, V., Nagy, Z. K., & Reklaitis, G. V. (2022b). Machine learning enabled integrated formulation and process design framework for a pharmaceutical 3D printing platform. AIChE Journal. https://doi.org/10.1002/aic.17990

Trenfield, S. J., Awad, A., Goyanes, A., Gaisford, S., & Basit, A. W. (2018). 3D Printing Pharmaceuticals: Drug Development to Frontline Care. In Trends in Pharmacological Sciences (Vol. 39, Issue 5). https://doi.org/10.1016/j.tips.2018.02.006

Zuccari, G., Alfei, S., Marimpietri, D., Iurilli, V., Barabino, P., & Marchitto, L. (2022). Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics. In Pharmaceuticals (Vol. 15, Issue 1). https://doi.org/10.3390/ph15010108