(T1130-09-62) Manufacture of Low-Dose Rapidly Disintegrating Dosages Using 3DP Binder Jetting

Purpose: Achieving acceptable content uniformity when manufacturing dosage forms from direct blends presents challenges during development of low dose/micro dose drug products. In this study, the need for a homogenous blend was circumvented by incorporating the active into the dosage form by directly printing it from solution onto a powder substrate using 3D printing (3DP) Binder Jetting technology. Factors of drop size, # droplets per tablet and drops per inch (DPI) were adjusted and/or controlled to establish a manufacturing approach to precisely maintain a target amount of print fluid applied with the intent to establish whether acceptable content uniformity could be achieved.

Methods: Tablets containing 100 mg to 10 mg levetiracetam were manufactured via Binder Jetting (a 3D powder-bed technology that works by using a print head to apply a liquid onto layers of powder, bonding the powder particles together) using binder print fluids that contained levetiracetam dissolved at concentrations of 2.50% and 0.25% w/w. Printing parameters for each batch are provided in Table 1. The dose was targeted by controlling the drop count per tablet and assuming a theoretical drop size when creating the print image file. An ‘assay adjusted target drop size (ng)’ was then calculated based on the analytical assay of the print fluid and the drop count for the associated image to be printed. Prior to printing, adjustments in the voltage applied to the piezoelectric print head were performed, as needed, to bring the actual drop size to within +/-1% of the calculated target drop size. Tablets manufactured were tested for assay and content uniformity, in addition to physical assessments of weight, hardness and disintegration time. Print fluids manufactured were characterized for assay, viscosity and surface tension.

Results: Tablets had an average hardness from 9.9 kp with a disintegration of 17 sec for the higher DPI resolution print to 0.5 kp with a disintegration of 3 sec for the lower DPI resolution. Assay was observed to be slightly above target for the batches tested at ~103% independent of dose. Tablet weight variation was observed to be less than 1.8% for all batches produced. The assay variation (%RSD) as determined during content uniformity testing (n=10 tablets, randomly sampled) ranged from 1.0% to 1.8%. Assay variation was observed to decrease when the drop size was calculated using the jetting output associated with the specific print image file versus the jetting output associated with the print head in its entirety. Assay variation was also observed to increase when drop count was decreased (dosage strength maintained).

Conclusion: Dosages were manufactured at active concentrations as low as 0.06% by weight. Acceptable content uniformity data were obtained over a range of drop counts ranging from ~4 million to as low as ~42,000, with only slight variation in the assay % RSD across that range. The tested assay did not correlate to actual tablet mass, which can be explained by the active being incorporated into the dosage via the print fluid applied and not by blending into the powder matrix. These data support precise control in jetting from the piezoelectric print heads and suggest that incorporation of an active into a dosage form from the print solution as part of a 3DP manufacturing process is a viable approach for reducing dose-content-uniformity issues that are associated with dry blends in more traditional pharmaceutical manufacturing operations.