Pharmaceutics, Drug Delivery and Pharmaceutical Technology Processability of poly(vinyl alcohol) Based Filaments With Paracetamol Prepared by Hot-Melt Extrusion for Additive Manufacturing Joana Macedo a , Aseel Samaro b , Val  erie Vanhoorne b , Chris Vervaet b , Jo ~ ao F. Pinto a, * a iMed.ULisboa, Faculdade de Farm acia, Universidade de Lisboa, Lisboa, Portugal b Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium article info Article history: Received 21 May 2020 Revised 31 August 2020 Accepted 10 September 2020 Keywords: Differential scanning calorimetry Drug delivery system(s) Drug-excipient interaction(s) Extrusion Hygroscopicity Materials science Mechanical properties Printing (3D) Solid dosage form(s) Stability abstract 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 (0e50%w/w) and storage conditions (temperature: 20e40  C and humidity: 11e75%). 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. Disso- lution 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. © 2020 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Introduction Three-dimensional (3D) printing, also known as additive manufacturing, has been intensively studied, especially after the approval of the first 3D printed tablet (Spritam®, Aprecia Phar- maceuticals) by the U.S. Food and Drug Administration (FDA). 1 This technique allows the construction of objects, built layer-by-layer, with almost any shape and complexity. 1,2 Several technologies have been employed to obtain 3D printed objects with fused deposition modelling (FDM), a hot-melt extrusion-based technol- ogy, receiving much attention for the preparation of drug delivery systems. Applying this technology, a drug-loaded filament is used as the feedstock material for the printer. The filament is forced to pass between the printer feeding gears towards the heated nozzle where it softens to allow the accurate deposition on the platform or building plate. Consequently, the mechanical properties of the filament are paramount to enable the accurate printing of each layer. 3,4 Printing of materials is considered by many industries for different applications. In the pharmaceutical arena, one of the most promising and desired uses of 3D printing technology is for the individualization of medicines. 1,2 The technology allows to print tablets with different doses of active pharmaceutical ingredients (APIs) in a single printing cycle and enables small-scale produc- tion. 1 Therefore, 3D printing could be performed at point-of-care locations, namely in hospital or community pharmacies, providing a new dimension to the current practice on compound- ing. 5 Nevertheless, introducing this manufacturing technology in pharmacies comes along with several concerns and challenges. However, guidelines and regulations applying to printed dosage Abbreviations: API, Active pharmaceutical ingredient; ASD, Amorphous solid dispersion; ATR, Attenuated total reflection; DSC, Differential scanning calorimetry; E, Young's modulus of elasticity (GPa); FDA, Food and Drug Administration; FDM, Fused deposition modelling; FTIR, Fourier-transformed infrared; f 2 , Similarity fac- tor; HME, Hot-melt extrusion; HPMCAS, Hydroxypropyl methylcellulose acetate succinate; PAR, Paracetamol; PAT, Process analytical technology; PVA, Poly(vinyl alcohol); RH, Relative humidity (%); T g , Glass transition temperature (  C); T m , Melting temperature (  C); T nozzle , Nozzle temperature of the 3D printer (  C); T plat- form , Platform temperature on the 3D printer (  C); w, Moisture content (%); XRPD, X- ray powder diffraction; 3D, Three-dimensional; ε, Strain at break (%); s, Stress at maximum load (MPa). * Corresponding author. Faculdade de Farm acia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. E-mail address: jfpinto@ff.ul.pt (J.F. Pinto). Contents lists available at ScienceDirect Journal of Pharmaceutical Sciences journal homepage: www.jpharmsci.org https://doi.org/10.1016/j.xphs.2020.09.016 0022-3549/© 2020 American Pharmacists Association ® . Published by Elsevier Inc. All rights reserved. Journal of Pharmaceutical Sciences xxx (2020) 1-9