(M1430-05-28) Development of 3D Printed Tablets of Weakly Acidic Drug-Flurbiprofen by Acid-Base Super-Solubilization at Lower Extrusion Temperature and Improved Printability

Purpose: Three-dimensional (3D) printing of pharmaceutical formulations for dose personalization and on-demand medications is increasingly being researched. A literature review on drugs used in FDM 3D printing showed that 74% belonged to BCS class II or IV, indicating challenges due to low solubility and dissolution (Pereira et al., 2019). To achieve higher dissolution and improved bioavailability, it is critical that poorly soluble drugs are present as amorphous solid dispersions (ASD) in polymeric carriers for 3D printing (Serajuddin, 2023). However, FDM-based 3D printing has challenges such as high printing temperatures, lack of printability of polymers, and slow release from tablets. Although there is limited research on the use of ASD in FDM 3D-printing, earlier work from our lab developed 3D-printed tablets of weakly basic drugs using counter acids by acid-base supersolubilization (ABS) principle (Patel and Serajuddin, 2021). ABS is a novel approach to increase the aqueous solubility of ionic drugs by interaction with a weak counter ion that would not form a salt. The solution of this mixture forms ASD either upon drying or melting together. In the present scope of work, instead of a basic drug, a weakly acidic drug, flurbiprofen, has low aqueous solubility of 0.005-0.010 mg/mL (5-10 µg/mL). is utilized. Meglumine was used as a weakly basic counterion to form ASD. This was performed by hot melt extrusion of flurbiprofen and meglumine with polymers into filaments to prepare fast-release 3D-printed tablets at lower temperatures.

Methods: Flurbiprofen formulations with polymers and with/without meglumine were evaluated for complex viscosity as a function of temperature to determine optimal extrusion conditions. Melt extrusion was performed using a Thermo Scientific 11 mm twin screw extruder. Filaments were evaluated for mechanical strength and printability by 3-point bend test using a texture analyzer. Additives such as Aeroperl 300, a mesoporous silica, was added to enhance printability. 3D printing was performed by MakerBot^® Replicator 2 3D-printer. Drug crystallinity evaluations were performed by DSC and PXRD. The dissolution of 3D printed tablets was studied at pH 2 and pH 6.8 using the USP dissolution apparatus II at 50 RPM using 250 mL of dissolution medium at 37⁰C.

Results: Flurbiprofen formed ASD with and without meglumine in the presence of Kollidon® VA 64 as a polymer. Flurbiprofen has a melting point of 111°C and meglumine at 128 °C , while Kollidon® VA 64 has a glass transition temperature of 105-109°C. The addition of meglumine lowered the complex viscosity of the mixture, and, consequently, the hot melt extrusion temperature of the flurbiprofen- Kollidon^® VA mixture could be lowered from 150°C in absence to meglumine to 120°C in presence of meglumine. With the addition of meglumine, the dissolution of flurbiprofen from 3D-printed tablets was almost immediate and the total amount dissolved increased from ~40% to ~80%, thus demonstrating a major impact acid-base supersolubilization (ABS) on the performance of 3D-printed tablets. However, the filaments of both formulations, with and without meglumine, were too brittle to print. The addition of 5% Aeroperl® 300 improved the filament's mechanical strength and flexibility, showing good printability. Dissolution rate evaluation of 3D printed flurbiprofen tablets at 20% drug loading and containing Aeroperl 300 showed similar behavior as extrudates of earlier formulations without Aeroperl ® 300. Both 60% and 100% infill tablets of Aeroperl® 300 formulation without meglumine showed about 40 % drug release. Aeroperl® 300 3D printed tablets with meglumine showed 80% drug release. All extruded formulations showed no sign of crystallinity confirmed by DSC and PXRD.

Conclusion: The results of this study showed the successful development of the FDM 3D printed tablets for a poorly soluble drug, flurbiprofen, using meglumine as the supersolubilizing agent and for converting the drug into amorphous material. Kollidon VA64 was used as the polymeric matrix for the tablets. The presence of meglumine could increase drug loading in the tablets up to 20% by the interaction of flurbiprofen with meglumine as per the ABS principle. However, the filaments of drug-polymer mixtures, with and without meglumine, were not printable; the addition of Aeroperl^® 300 improved printability. Additionally, the incorporation of meglumine in the formulation decreased the extrusion temperature and printing temperature to 120°C. Applying the ABS principle to the acidic drug flurbiprofen showed a rapid and higher dissolution rate. Similarly, the acid-base super solubilization principle could be utilized by FDM 3D printing for weakly ionic high-melting drugs to be able to process at lower printing temperatures. Thus, the results of the present study contribute to major advancements in FDM 3D printing technology.

References: Patel, N.G., Serajuddin, A.T.M., 2021. Development of FDM 3D-printed tablets with rapid drug release, high drug-polymer miscibility and reduced printing temperature by applying the acid-base supersolubilization (ABS) principle. Int. J. Pharm. 600, 120524. https://doi.org/10.1016/j.ijpharm.2021.120524
Pereira, B.C., Isreb, A., Forbes, R.T., Dores, F., Habashy, R., Petit, J.-B., Alhnan, M.A., Oga, E.F., 2019. ‘Temporary Plasticiser’: A novel solution to fabricate 3D printed patient-centred cardiovascular ‘Polypill’ architectures. Eur. J. Pharm. Biopharm. 135, 94–103. https://doi.org/10.1016/j.ejpb.2018.12.009
Serajuddin, A., 2023. Challenges, current status and emerging strategies in the development of rapidly dissolving FDM 3D-printed tablets: An overview and commentary. ADMET DMPK 11, 33–55. https://doi.org/10.5599/admet.1622


Formulation Composition 1


Complex Viscosity versus temperature profile of Kollidon® VA 64 only formulations with and without meglumine (F2 and F4) and Kollidon® VA 64 with Aeroperl® 300 formulations with and without meglumine and lastly (F12 and F14).


Dissolution profiles of A) crushed Extrudates of Kollidon ® VA64 with and without meglumine at 20% drug loading B) 60% infill and 100% infill tablets of Kollidon ® VA64with 5% w/w Aeroperl® 300 with and without meglumine at 20% drug loading. Each data point represents an average of 3 determinations.