Development of Immediate Release (IR) 3D-printed oral dosage forms with focus on industrial relevance

Pharmaceutical 3D-printing represents a potentially new dosing and manufacturing approach for the pharmaceutical industry, with unique opportunities for personalization of dosage strengths. Fused deposition modelling (FDM) is a 3D-printing technique, which presents advantages for decentralized on-site manufacturing in hospitals and pharmacies. This study presents industrially relevant development of formulations for filaments with the required mechanical properties to be 3D-printable and providing immediate release (IR) dosage forms using safe materials approved also for pediatric use. Hydroxypropyl-cellulose (HPC) SSL was chosen as hydrophilic polymer and caffeine with a load of 5-20% as thermally stable model drug. Poly-(vinyl pyrrolidone-vinyl acetate) copolymer (Kollidon VA64) and poly-(vinyl alcohol-polyethylene glycol) graft copolymer (Kollicoat IR) were additional water-soluble polymers tested in combination with HPC and xylitol and polyethylene glycol (PEG) 4000 were evaluated as hydrophilic plasticizers and PEG4000 and maltodextrin as pore formers. Formulations were hot-melt extruded using a scalable twin-screw extruder and 3D-printed into honeycomb geometry solid dosage forms with high (100%) and low (80%) infill density. Rapid or very rapid release was achieved via formulation selection and tablet design parameters. PEG4000 in combination with Kollidon VA64 demonstrated superior processability and significantly accelerated release properties of the matrix independently of infill density. Lowering caffeine content improved hot-melt extrusion processability for each formulation but prolonged dissolution. The use of Kollicoat IR resulted in superior mechanical properties of the manufactured filaments, with easy handling and successful 3D-printing for drug load of 5 to 20%. For most formulations, lowering infill density of 3D-printed tablets yielded faster drug dissolution in agreement with the literature. However, the extent of the infill density effect varied depending on formulation. Caffeine was present in stable crystalline state in 3D-printed tablets. Printing temperature appeared to be critical for drug dissolution in vitro. This wide-ranging excipient investigation epitomizes the beginning of a toolbox approach targeting FDM processability in combination with immediate release characteristics of personalized dosage forms

Simplification of FDM 3D-Printing paradigm: feasibility of 1-step Direct Powder Printing for Immediate Release dosage forms production

Three-dimensional (3D)-printing of tablets via fused deposition modelling (FDM) is gaining attention for the production of flexible and personalized dosage forms. FDM presents advantages for decentralized on-site manufacturing in hospitals and pharmacies as no powder or solvents are involved in the printing process and post-processing can be avoided. However, the current FDM paradigm for dosage forms development is complex, and involves a hot-melt extrusion step and 3D printable drug-loaded filaments as intermediate products for tablet manufacturing. In this study, simplification of the current FDM set-up for rapid release dosage forms manufacturing was explored. Several powder blends were directly loaded into a cartridge-like head and were successfully printed directly with honeycomb design following heating of the extrusion cartridge. This served as a proof of concept for 1-step direct powder printing (DPP) with incorporation of in-built porosity allowing higher surface area. A heat processable, water soluble polymer, Hydroxypropylcellulose (HPC) SSL was chosen as rapid release matrix former and caffeine (10%) as thermally stable model drug. The effect of incorporation of a plasticizer/pore former (PEG4000) and a rapidly dissolving polymer (Kollidon VA64) on DPP processability and dissolution profiles was investigated. Formulations were directly 3D-printed into solid dosage forms with high (80%) and low (30%) infill density, and critical quality attributes analyzed (e.g. dissolution profiles, chemical stability and physical form). The obtained directly 3D-printed tablets demonstrated good weight and content uniformity. Low infill density tablets showed rapid release dissolution profiles independently of the formulation, whereas for high infill density tablets a combination of pore-former PEG4000 and rapidly-dissolving polymer Kollidon VA64 was required to achieve rapid release. Caffeine was found in crystalline state and in the desired polymorph in directly 3D-printed tablets. Direct Powder 3D-printing feasibility for immediate release dosage forms manufacturing was demonstrated. This technique might create an opportunity to skip the hot-melt extrusion step, allowing 3D-printing independent of mechanical properties of a filament. This might potentially prolong formulation shelf life as thermal stress is applied only once, shortly before the tablets production and dispensing. Moreover, this powder-in-a-cartridge technique might create a future opportunity for decentralized production: loading powder formulation in a cartridge at the industrial facility, and 3D-printing on clinical site potentially using in the same 3D-printer for implants, tablets and even tissues and organs

Benchtop-magnetic resonance imaging (BT-MRI) characterization of push-pull osmotic controlled release systems

The mechanism of drug release from push-pull osmotic systems (PPOS) has been investigated by Magnetic Resonance Imaging (MRI) using a new benchtop apparatus. The signal intensity profiles of both PPOS layers were monitored non-invasively over time to characterize the hydration and swelling kinetics. The drug release performance was well-correlated to the hydration kinetics. The results show that (i) hydration and swelling critically depend on the tablet core composition, (ii) high osmotic pressure developed by the push layer may lead to bypassing the drug layer and incomplete drug release and (iii) the hydration of both the drug and the push layers needs to be properly balanced to efficiently deliver the drug. MRI is therefore a powerful tool to get insights on the drug delivery mechanism of push-pull osmotic systems, which enable a more efficient optimization of such formulations

Immediate Release 3D-Printed Dosage Forms for Poorly Soluble Drugs: Development and Exploration of Morphology-Dissolution Relationship

3D-printing technologies such as Fused Deposition Modeling (FDM) bring a unique opportunity for personalized and flexible near patient production of pharmaceuticals, potentially improving safety and efficacy for some medications. However, FDM-printed tablets often exhibit tendency for slow dissolution due to polymer erosion based dissolution mechanisms. Development of Immediate Release 3D-printed dosage with poorly water-soluble model compounds is even more challenging, but required to ensure wide applicability of the technology within pharmaceutical development portfolios. In this work, morphology and process for a selected formulation were considered, using BCS class IV compound lumefantrine as a model drug. Basic butylated methacrylate copolymer (Eudragit EPO) as matrix former, as well as hydrophilic plasticizer xylitol and pore former maltodextrin were selected as a promising formulation approach to achieve fast dissolution rates. Tablets of size 9 x 5 x 4 mm, i.e. acceptable for children from 6 years old, were successfully 3D-printed. Tablets with 5% lumefantrine and corresponding placebo were printed, higher drug load as required for clinically relevant dosage strength however lead to increased brittleness incompatible with FDM printing. Residual crystallinity in manufactured tablets and filaments was explored by highly sensitive Raman mapping technique. Lumefantrine was present in the fully amorphous state in the tablets as intended. Grid-designed 3D-printed tablets with 65% infill density met rapid release criteria, while 80% and 100% showed slower dissolution. For the first time, the critical structural characteristics of 3D-printed tablets with non-continuous surface such as accessible porosity, specific surface area by weight and by volume were quantified by an automated micro-CT based methodology, and were confirmed to be responsible for the dissolution rate acceleration. Increase in accessible porosity, total surface area, specific surface area by weight and by volume and decrease in relative density appeared to be critical factors for modification of lumefantrine dissolution rate, whereas increase in closed pores volume did not contribute to accelerating dissolution rate. To conclude, Immediate Release FDM-tablets with BCS class IV compound were developed and key dissolution parameters were detected with non-destructive accurate morphological analysis