(M0930-07-40) Application of Binder Jetting to Develop 3D Printed Modified Release Tablets

Purpose: The advent of additive manufacturing techniques such as 3D-printing (3DP) have started to revolutionize the field of drug delivery. The unparalleled control on minute details that 3DP offers such as control on layer thickness, facilitating precision dosing, and enabling complex release kinetics has expedited the resolution of complex formulation challenges. This has helped in significantly accelerating the drug/formulation development process. Binder-jetting is one example of a 3DP process wherein the formulator has precise control on the amount and area to deposit the print fluid (PF) on a given powder substrate. With major research focus being on other 3DP processes, limited reports explore the effect of incorporating modified release polymers in binder jetting. The current research is focused towards evaluating two commonly used modified release polymers for performance in binder jetting 3DP.

Methods: Modified Release Blends: Levetiracetam (LEV) was selected as a model API for the study, exhibiting high solubility and high permeability. Two controlled release matrix polymers, polyacrylic acid (Carbopol^®; 971P/974P) and hydroxypropyl methylcellulose (HPMC; K4M), were assessed. The polymers were formulated into blends at various levels from 5-30% w/w containing the active at 50 or 28.6 %w/w. The remainder of the blends were comprised of either Mannitol (Pearlitol^®50C) or pregelatinized starch (Lycatab^®PGS) to further evaluate impact of the primary diluent on dissolution. Binder Print Fluid: The PF solution was formulated by incorporating povidone, glycerin and polysorbate 20 in a hydroalcoholic solution. Drop formation utilized a piezoelectric printhead at an established waveform and voltage to produce a target 75 pL drop size. Tablets Manufacturing: Tablets were manufactured using an in-cavity, 3DP binder jetting process (Z-Form™ Process). A predefined quantity of powder was added to a blister cavity and the powder was leveled prior to application of the binder print fluid. The process was repeated in a layer-by-layer fashion until a target tablet weight was achieved. Binder print fluid saturation levels (drops per inch (DPI) per mass of powder substrate) was optimized for each blend as needed, to achieve bound/intact tablets. The blister cards containing the 3DP formed tablets were dried in an oven at 60°C. Characterization: Tablets were physically assessed for weight, hardness and thickness. Release rate of the various formulations were assessed by in vitro dissolution studies with USP apparatus II conducted in phosphate buffer (pH 6.0). Swelling behavior of the 3DP tablet matrices were characterized using a TA.XT plus texture analyzer (2mm flat faced probe) (1,2).

Results: Initial print saturation assessments on the Carbopol^® blends were performed at 1000, 2000, and 4000 DPI. At 4000 DPI, micro gelation/swelling was observed during print fluid application which impeded the leveling process and yielded tablets with undesired appearance effects. Reducing the print fluid saturation to 1000 DPI resolved this issue while not impacting structural integrity of the dosage form. Higher print saturation levels were needed for HPMC based formulations. When PGS was used as primary diluent, a DPI of 9600 was needed to fully bind the powder substrate. The saturation level could be reduced to 6400 DPI when the diluent was changed to mannitol. Both polymer classes were able to slow down the in-vitro dissolution of the API in the formulations assessed. For Carbopol^®, it was observed that the 971P grade was able to retard the release slightly more than the 974P grade (Figure 1(a)). However, extending the release beyond 3 hours was not achievable despite increasing the Carbopol^®971P within the formulation to 17.5% w/w regardless of mannitol or starch as the primary diluent. In contrast, formulations of HPMC K4M were successful in extending the release beyond 8 hours. Just as with the Carbopol^® formulations, further significant delay in release was not observed upon increase to 30% w/w (Figure 1(b)). Physical tablet characterization data are provided in Table 1. Overall, tablets formed using HPMC had higher strength compared to tablets manufactured with Carbopol^®. This may be attributable to higher amounts of print fluid required for tablet manufacturing. Release differences between the polymers is not likely to be attributable to hardness as tablets manufactured using both polymers were observed to disintegrate into swelled granulates around 60-90 mins despite initially swelling as an intact tablet. This could be observed in the dissolution profiles by a slight change in rate of release. Formulations comprised of HPMC maintained modified release functionality despite the change in surface area associated with the disintegration of the tablet matrix.

Conclusion: From the current study, it is evident that binder jetting 3DP can be used to create modified release formulations. Tablets exhibiting modified release were successfully formulated even at incorporating a highly water soluble drug at 50% w/w. Similar to traditional pharmaceutical dosage form manufacturing, the choice of the modified release polymer plays a major role in product performance. Further investigations could help in exploring the capabilities of 3DP in addressing complex formulation requirements and pave the way for improved patient outcomes.

References: 1. Jamzad, S., et al. (2005). "Analysis of macromolecular changes and drug release from hydrophilic matrix systems." International Journal of Pharmaceutics 292(1): 75-85.
2. Li, H., et al. (2008). "Effect of drug solubility on polymer hydration and drug dissolution from polyethylene oxide (PEO) matrix tablets." AAPS PharmSciTech 9(2): 437-443.

In vitro dissolution profiles (phosphate buffer solution, pH 6.0) for levetiracetam 3DP Tablets: (a) Comparison of Carbopol® grade and concentration on release of levetiracetam 3DP tablets comprising 50% w/w active and (b) Comparison of HPMC on release of levetiracetam 3DP tablets at 28.6% w/w active.

Phyical tablet attributes of modified release 3DP tablets fabricated using Carbopol® and HPMC.