Development of Diclofenac Sodium 3D Printed Cylindrical and Tubular-Shaped Tablets through Hot Melt Extrusion and Fused Deposition Modelling Techniques.

The present study aimed to develop 3D printed dosage forms, using custom-made filaments loaded with diclofenac sodium (DS). The printed tablets were developed by implementing a quality by design (QbD) approach. Filaments with adequate FDM 3D printing characteristics were produced via hot melt extrusion (HME). Their formulation included DS as active substance, polyvinyl alcohol (PVA) as a polymer, different types of plasticisers (mannitol, erythritol, isomalt, maltodextrin and PEG) and superdisintegrants (crospovidone and croscarmellose sodium). The physicochemical and mechanical properties of the extruded filaments were investigated through differential scanning calorimetry (DSC), X-ray diffraction (XRD) and tensile measurements. In addition, cylindrical-shaped and tubular-shaped 3D dosage forms were printed, and their dissolution behaviour was assessed via various drug release kinetic models. DSC and XRD results demonstrated the amorphous dispersion of DS into the polymeric filaments. Moreover, the 3D printed tablets, regardless of their composition, exhibited a DS release of nearly 90% after 45 min at pH 6.8, while their release behaviour was effectively described by the Korsmeyer-Peppas model. Notably, the novel tube design, which was anticipated to increase the drug release rate, proved the opposite based on the in vitro dissolution study results. Additionally, the use of crospovidone increased DS release rate, whereas croscarmellose sodium decreased it.

Development of Flow-Through Cell Dissolution Method for In Situ Visualization of Dissolution Processes in Solid Dosage Forms Using X-ray µCT.

Visualization of the dynamic behavior of pharmaceutical dosage forms during the dissolution process offers a better understanding of the drug release mechanism, enabling the design of customized dosage forms. In this study, an X-ray tomography-based approach is proposed to monitor and analyze the dynamics of the structure at the pore scale level during the dissolution process. A flow-through cell dissolution apparatus was developed, capable of mimicking the standard in vitro dissolution process, which can be easily positioned in an X-ray tomography setup. The method was utilized to study the dissolution of a Capa® (polycaprolactone)-based sustained-release 3D printed tablet. The impact of the flow rate on the active pharmaceutical ingredient (API) release rate was studied and 16 mL/min was selected as a suitable flow rate. Furthermore, cesium chloride (CsCl) was used as a contrast agent to increase the contrast between the sample and the dissolution medium. Data obtained with this novel technique were in a good agreement with the released drug rate acquired by the standard in vitro dissolution test (the similarity factor (f2) = 77%). Finally, the proposed approach allowed visualizing the internal structure of the sample, as well as real-time tracking of solution ingress into the product.

Poly(2-alkyl-2-oxazoline)s: A polymer platform to sustain the release from tablets with a high drug loading.

Sustaining the release of highly dosed APIs from a matrix tablet is challenging. To address this challenge, this study evaluated the performance of thermoplastic poly (2-alkyl-2-oxazoline)s (PAOx) as matrix excipient to produce sustained-release tablets via three processing routes: (a) hot-melt extrusion (HME) combined with injection molding (IM), (b) HME combined with milling and compression and (c) direct compression (DC). Different PAOx (co-)polymers and polymer mixtures were processed with several active pharmaceutical ingredients having different aqueous solubilities and melting temperatures (metoprolol tartrate (MPT), metformin hydrochloride (MTF) and theophylline anhydrous (THA)). Different PAOx grades were synthesized and purified by the Supramolecular Chemistry Group, and the effect of PAOx grade and processing technique on the in vitro release kinetics was evaluated. Using the hydrophobic poly (2-n-propyl-2-oxazoline) (P n PrOx) as a matrix excipient allowed to sustain the release of different APIs, even at a 70% (w/w) drug load. Whereas complete THA release was not achieved from the P n PrOx matrix over 24 â€‹h regardless of the processing technique, adding 7.5% w/w of the hydrophilic poly (2-ethyl-2-oxazoline) to the hydrophobic P n PrOx matrix significantly increased THA release, highlighting the relevance of mixing different PAOx grades. In addition, it was demonstrated that the release of THA was similar from co-polymer and polymer mixtures with the same polymer ratios. On the other hand, as the release of MTF from a P n PrOx matrix was fast, the more hydrophobic poly (2-sec-butyl-2-oxazoline) (P sec BuOx) was used to retard MTF release. In addition, a mixture between the hydrophilic PEtOx and the hydrophobic P sec BuOx allowed accurate tuning of the release of MTF formulations. Finally, it was demonstrated that PAOx also showed a high ability to tune the in vivo release. IM tablets containing 70% MTF and 30% P sec BuOx showed a lower in vivo bioavailability compared to IM tablets containing a low PEtOx concentration (7.5%, w/w) in combination with P sec BuOx (22.5%, w/w). Importantly, the in vivo MTF blood level from the sustained release tablets correlated well with the in vitro release profiles. In general, this work demonstrates that PAOx polymers offer a versatile formulation platform to adjust the release rate of different APIs, enabling sustained release from tablets with up to 70% w/w drug loading.

Can filaments, pellets and powder be used as feedstock to produce highly drug-loaded ethylene-vinyl acetate 3D printed tablets using extrusion-based additive manufacturing?

Personalized medicine, produced through 3D printing, is a promising approach for delivering the required drug dose based on the patient's profile. The primary purpose of this study was to investigate the potential of two different extrusion-based additive manufacturing techniques - fused filament fabrication (FFF) and screw-based 3D printing, also known as direct extrusion additive manufacturing (DEAM). Different ethylene-vinyl acetate (EVA) copolymers (9 %VA, 12 %VA, 16 %VA, 18 %VA, 25 %VA, 28 %VA, and 40 %VA) were selected and loaded with 50% (w/w) metoprolol tartrate (MPT). Hot-melt extrusion was performed to produce the drug-loaded filaments. These filaments were used for FFF in which the mechanical and rheological properties were rate-limiting steps. The drug-loaded filament based on the 18 %VA polymer was the only printable formulation due to its appropriate mechanical and rheological properties. As for the highest VA content (40 %VA), the feeding pinch rolls cause buckling of the filaments due to insufficient stiffness, while other filaments were successfully feedable towards the extrusion nozzle. However, poor flowability out of the extrusion nozzle due to the rheological limitation excluded these formulations from the initial printing trials. Filaments were also pelletized and used for pellets-DEAM. This method showed freedom in formulation selection because the screw rotation drives the material flow with less dependence on their mechanical properties. All drug-loaded pellets were successfully printed via DEAM, as sufficient pressure was built up towards the nozzle due to single screw extrusion processing method. In contrast, filaments were used as a piston to build up the pressure required for extrusion in filament-based printing, which highly depends on the filament's mechanical properties. Moreover, printing trials using a physical mixture in powder form were also investigated and showed promising results. In vitro drug release showed similar release patterns for MPT-loaded 3D printed tablets regardless of the printing technique. Additionally, pellets-DEAM enabled the production of tablets with the highest VA content, which failed in FFF 3D printing but showed an interesting delayed release profile.

Processability of poly(vinyl alcohol) Based Filaments With Paracetamol Prepared by Hot-Melt Extrusion for Additive Manufacturing.

The aim of this study was to evaluate the processability of poly(vinyl alcohol) (PVA)-based filaments containing paracetamol (PAR) prepared by hot-melt extrusion for fused deposition modelling (FDM) 3D printing, as function of drug content (0-50%w/w) and storage conditions (temperature: 20-40 °C and humidity: 11-75%). Thermal (DSC), crystallographic (XRPD), spectroscopic (FTIR), moisture content and mechanical tests were used to characterize the filaments, whereas their ability to produce tablets was confirmed by printing. XRPD revealed the absence of crystalline PAR in the extruded filaments with <30% PAR and FTIR confirmed interactions between PAR and PVA. Mechanical tests have shown a higher brittleness of the filaments with increasing PAR, making them non-printable. Throughout storage, temperature and moisture increased the plasticity of the filaments, which was reflected by changes on their thermal and mechanical properties improving the feeding performance on the printer. Filaments stored at low moisture remained unsuitable for printing with amorphous PAR being preserved. Dissolution tests have shown that the release of PAR from printed tablets was independent of the storage time of the filaments. The study highlights the need for optimized storage conditions of filaments for FDM and the dependency on the drug's content in such filaments.

Production of Drug Delivery Systems Using Fused Filament Fabrication: A Systematic Review.

Fused filament fabrication (FFF) 3D printing technology is widely used in many fields. For almost a decade, medical researchers have been exploring the potential use of this technology for improving the healthcare sector. Advances in personalized medicine have been more achievable due to the applicability of producing drug delivery devices, which are explicitly designed based on patients' needs. For the production of these devices, a filament-which is the feedstock for the FFF 3D printer-consists of a carrier polymer (or polymers) and a loaded active pharmaceutical ingredient (API). This systematic review of the literature investigates the most widely used approaches for producing drug-loaded filaments. It also focusses on several factors, such as the polymeric carrier and the drug, loading capacity and homogeneity, processing conditions, and the intended applications. This review concludes that the filament preparation method has a significant effect on both the drug homogeneity within the polymeric carrier and drug loading efficiency.