(M1330-02-13) Scalable Agile 3D Material Inkjet Printing and Analysis of Oral Pharmaceuticals – A Case Study for Digitally Prescribed Dose and In-Line Dose Verification

Purpose: Current mass production methods of oral dosage forms are not ideal for producing small volumes or for rapid customization. Often, multiple production methods are used to produce supplies during drug development and ultimately full scale manufacturing. There is a need for advanced manufacturing methods for flexible scale production that can quickly and easily produce variable volumes, while offering both process and product customization. 3D printing enables novel capabilities in pharmaceutical development (1), e.g., muti-drug pills, tailored release profiles, and potential for point of care production. 3D material inkjet printing uniquely provides a scalable one-step production of oral pharmaceutical dosage forms with novel digitally designed capabilities. Production flexibility, from a single to a million tablets per day, enables cost-effective short-run to medium-scale productions, e.g., preclinical to clinical, orphan diseases, specialty orals, and provides time-saving digital customizations. Digitally defined production process enables tuning of various process parameters to achieve various drug product characteristics without a need to reformulate (e.g., dose, size, desired drug release profiles, multi-drug tablets, direct formation of amorphous solid dispersions, etc.). Integrating in-line and rapid non-destructive characterization for quality control (QC) is important to inform not only the print process adherence but also product quality. We developed a unique, multi-material, high throughput 3D tablet printer prototype (100 pills in < 30min) and demonstrate digital control of drug dose in each tablet without needing reformulation. For integrated in-line QC, non-destructive Near Infrared (NIR) spectroscopy of printed tablets is developed and demonstrates printed tablet dose can be predicted subsequent to printing.

Methods: Printed tablets are comprised of Carvedilol (BCS Class 2, MP 118˚C) and a pharmaceutical lipid carrier, Compritol 888. Thermal characteristics, drug solubility, viscosities, and drug contents were evaluated using TGA, DSC, rheometric studies, and UV-Vis spectroscopy, respectively. Tablets with triangular mesh geometry were fabricated via coordinated precise drop localization using two Xerox M-series industrial inkjet heads at 900 dpi operated at 100˚C on PET substrates. NIR reflectance spectra of printed tablets were collected via a probe using a benchtop MPAII NIR spectrometer.

Results: The solvent-free ink used in our study was optimized for its phase-change properties, i.e., solid at room temperature and liquid at printing temperature with viscosities 5-12 c.p. A base formulation of ~10% w/w Carvedilol in Compritol 888 (MP 65-77˚C) was used to print tablets with dose ranging 8-20 mg by digitally defining and depositing a combination of the base formulation with pure excipient droplets (16-30 pL) to form desired ratios of drug-excipient uniformly distributed across tablet (Figures 1-A, 2). Digitally designed drug concentrations created by printing were confirmed measuring drug load by solvent extraction of drug from the tablets (Figure 2). The desired tablet dose along with API distribution is achieved by drop-level controlling of deposition within tablet volume and precise placement and fusion of formulation and excipient drops. The consistency of layer-by-layer printing was confirmed by measuring linear increase in drug content. A calibration model for NIR measurements is developed based on preparations of drug in lipid (0.9-9 w/w%) and successfully predicts drug concentrations (linearity of R2=0.991 and accuracy of RMSECV=0.265) (Figure 3). NIR dose measurements were verified with UV-Vis analysis after solvent extraction of drug from printed tablets.

Conclusion: The precision and droplet-level control of multi-material 3D inkjet print system combined with non-destructive dose verification show that inkjet printing can provide novel strategies for just-in-time digital dose titration and evaluation of printed products, with flexible throughput for drug development.

References: (1) Lion A, Wildman RD, Alexander MR, Roberts CJ. Pharmaceutics 2021, 13(10), 1679.

Acknowledgements: Lipid was kindly donated by Gattefossé (NJ, USA).


Figure 1. A) Digital dose control is achieved by precise deposition and droplet-level control (20-30µm droplets) within tablet volume control via 880 inkjet nozzles of each print head. B) Non-destructive NIR measurement of the titrated tablets informs layer by layer print process consistency as well as total dose for printed tablet. C) Printed 10mg carvedilol tablet.


Figure 2. Tablets with digitally designed dose are created by printing and demonstrated target concentrations are achieved as designed. Drug loading of printed tablets are confirmed by measuring drug content via solvent extraction of drug from the tablets.


Figure 3. Multivariate calibration model shows the correlation between NIR predicted values and the direct measured reference concentrations, showing NIR test results are proportional with drug concentrations at target range.