(T1430-10-57) Envisioning New Concepts for 3D Printing and Solubility Enhancement: Tablet Manufacturing of Loaded Parteck^® SLC through Z-Form Binder Jetting Technology

Purpose: 3D printing of pharmaceuticals is an emerging technology enabling personalization of medicines and accelerating drug development in the pharmaceutical industry. Notably, the 3D printing technology known as binder jetting (BJ) provides the benefits of rapid manufacturing and scalable production (1). In BJ layers of powder material are fused together through the precise application of droplets of a binding liquid onto a powder bed. A novel form of BJ is the Z-Form Flex technology developed by Aprecia Pharmaceuticals, LLC. In contrast to selectively printing specific regions of a powder bed and recovering the printed dosage forms from the unprinted powder, the in-cavity technology deposits powder into preformed blister cavities and forms the finished dosage forms layer-by-layer directly in their primary packaging. While BJ technology has been applied for developing highly soluble drugs, the majority of drug substances in development exhibit poor solubility (2). To address solubility challenges, an innovative approach has been developed utilizing mesoporous silica. The drug molecules can be encapsulated and stabilized in the nanosized silica pores in an amorphous state, thereby enhancing solubility. The purpose of this study was to integrate the use of sterically stabilized drug in mesoporous silica with BJ to expedite the manufacturing of solid dosage forms for poorly soluble drugs.

Methods: Silica loading: Parteck^® SLC (Merck KGaA, Darmstadt, Germany) was loaded with carbamazepine (CTX Lifesciences Pvt. Ltd., Surat, India). Carbamazepine and Parteck® SLC were weighed on a balance (XS1203S, Mettler Toledo, Gießen, Germany) and transferred to a 2 L round-bottom flask and filled up with dichloromethane. Targeted drug load was 30%. The solvent was evaporated in a rotary evaporator (Heidolph Instruments GmbH & CO KG, Schwabach, Germany) at 30 °C and 90 rpm over 105 min by applying a vacuum stepwise from ambient pressure to 200 mbar. Printing: Loaded Parteck^® SLC was blended with excipients using the composition provided in Table 1 and used to manufacture rapidly disintegrating carbamazepine tablets by 3D printing directly into preformed blister cavities (Z-Form, Aprecia Pharmaceuticals, Blue Ash, Ohio). Each tablet was comprised of 7 individual powder layers of 114.5 mg that were dosed independently into PVC/ACLAR blister cavities to form the final tablet. Subsequent dosing of each powder layer, an application of a hydro-alcoholic, povidone print fluid was applied at a DPI of 4800 (~75 pg drop size) to bind the powder substrate.  The surface of the wetted 3DP tablets were then lightly polished with a cylindrical tool to produce a smooth top surface finish and then dried for 120 min at 60°C. Analytics: X-ray powder diffraction (XRPD): XRPD measurements were performed on crushed tablets to determine the solid state using a MiniFlex (Rigaku, Tokyo, Japan) equipped with a D/teX Ultra 2 detector. A copper anode at 40 kV and 15 mA was used to generate X-rays. Scanning was performed from 3 – 50° with a step size of 0.02° and 0.8°/min. Scanning Electron Microscopy and energy-dispersive X-ray spectroscopy (SEM-EDS): Imaging was performed on a Tescan VEGA3 XMU (TESCAN, Dortmund, Germany) using a wolfram cathode with an acceleration voltage of 0.2 kV to 30 kV. Tablet was embedded in a polymer resin under UV-curing. Tablet was cut using a RM 2255 Mikrotom (Leica, Wetzlar, Germany). EDS was performed using a Quantax (Bruker, Billerica, USA) and a silicon drift detector.Content: Six tablets were weighed and dissolved in 250 mL of methanol. Content was measured via HPLC (Agilent 1260 Infinity, Santa Clara, USA) using a Ascentis Express ES-Cyano column (10 cm x 4.6 mm I.D., 2.7 µm) at 30 °C and a flow of 1.4 mL. Samples were measured at a wavelength of 230 nm. Dissolution: Tablet dissolution was performed in a AT 7 dissolution tester (Sotax, Aesch, Switzerland) equipped with paddles. Dissolution medium was 500 mL of deionized water. Paddle rotation speed was 75 rpm. Absorption was measured online using a photometer (Specord^® UV-Vis, Sotax) at 288 nm.<

Results: Tablets had an average mass of 806.2 mg with a RSD of 5.6% and a uniform drug content of 5.0% (RSD 1.6%). Furthermore, the even dispersion of the loaded silica within the tablet was visualized through SEM-EDS measurements shown in Fig. 1. Solid-state characterization further indicated that the carbamazepine was amorphous as no peaks related to carbamazepine were visible (data not shown). Notably, the tablets exhibited a rapid release with over 85% of carbamazepine being dissolved within 5 min (Fig 2).

Conclusion: This study demonstrated that Parteck^® SLC loaded with the poorly soluble drug carbamazepine can be successfully used in combination with binder jetting technology on Z-Form Flex. Tablets showed consistent appearance, uniform drug content and a rapid dissolution profile. Furthermore, the drug carbamazepine remained amorphous after printing. These findings collectively highlight the potential of combining the technologies binder jetting and loading of mesoporous silica in addressing solubility challenges and improving drug delivery.

References: (1) Tracy, T., Wu, L., Liu, X., Cheng, S., Li, X., 2023. 3D printing: Innovative solutions for patients and pharmaceutical industry. Int. J. Pharm. 631, 122480.
(2) Ting, J.M., Porter, W.W., Mecca, J.M., Bates, F.S., Reineke, T.M., 2018. Advances in polymer design for enhancing oral drug solubility and delivery. Bioconjug. Chem. 29, 939–952.

Table 1: Carbamazepine SLC Blend Composition

Figure 1: SEM image of tablet cross-section (a), EDS image of tablet cross-section showing distribution of silica (b)

Figure 2: Dissolution profile SLC preloaded carbamazepine 3D printed tablets vs. pure carbamazepine