3D-Printed Solid Pharmaceutical Formulations: Physicochemical Properties and Modified Release

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 43513

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Section of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15784 Athens, Greece
Interests: drug carriers; drug delivery; biopolymers; nanotechnology; nanomaterials
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Dear Colleagues,

In recent years, 3D printing (3DP), especially towards the production of personalized solid oral formulations, has attracted the vivid interest of academia, the chemical industry and pharma. However, commercially available 3D printers are limited with regards to the materials that can be processed—only a few types of thermoplastic polymers are suitable, and these may often not be pharmaceutically approved biomaterials and/or ideal for optimizing the dosage form performance of poorly water-soluble active substances. In this special section of Pharmaceutics, articles that bring a new insight into the design principles of controlled release formulations using 3DP technology are hosted. The manuscripts presented herein report the interplay of the miscibility between excipients in the blends, the solubility of the bioactive substances in the aqueous dissolution media and the nature/stereoelectronic features of the biopolymers used to manipulate the drug release rate of the dispersions.

Prof. Dr. Marilena Vlachou
Guest Editor

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Keywords

  • 3DP solid dispersions
  • poorly water-soluble drugs
  • polymer blends
  • modified release

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Published Papers (11 papers)

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Research

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14 pages, 3476 KiB  
Article
Binder Jet 3D Printing of Compound LEV-PN Dispersible Tablets: An Innovative Approach for Fabricating Drug Systems with Multicompartmental Structures
by Xiaoxuan Hong, Xiaolu Han, Xianfu Li, Jiale Li, Zengming Wang and Aiping Zheng
Pharmaceutics 2021, 13(11), 1780; https://doi.org/10.3390/pharmaceutics13111780 - 25 Oct 2021
Cited by 14 | Viewed by 2612
Abstract
Three-dimensional (3D) printing is an emerging technology that has high application potential for individualized medicines and complex solid dosage forms. This study is designed to explore binder jet 3D printing (BJ-3DP) for the development of high-precision and repeatable compound levetiracetam-pyridoxine hydrochloride (LEV-PN) multicompartmental [...] Read more.
Three-dimensional (3D) printing is an emerging technology that has high application potential for individualized medicines and complex solid dosage forms. This study is designed to explore binder jet 3D printing (BJ-3DP) for the development of high-precision and repeatable compound levetiracetam-pyridoxine hydrochloride (LEV-PN) multicompartmental structure dispersible tablets. PN was dissolved in printing ink directly and accurately jetted into the middle, nested layer of the tablet, and precise control of the drug dose was achieved through the design of printing layers. With modification of the drying method, the “coffee ring” effect caused by drug migration during the curing and molding of the tablets was overcome. Furthermore, 3D topography showed that the tablets have a promising surface morphology. Scanning electron microscopy and porosity results indicated that the tablets have a loose interior and tight exterior, which would ensure good mechanical properties while enabling the tablet to disintegrate quickly in the mouth and achieve rapid release of the two drugs. This study used BJ-3DP technology to prepare personalized multicompartmental structures of drug systems and provides a basis for the development of complex preparations. Full article
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24 pages, 6233 KiB  
Article
A QbD Approach for Evaluating the Effect of Selective Laser Sintering Parameters on Printability and Properties of Solid Oral Forms
by Yanis A. Gueche, Noelia M. Sanchez-Ballester, Bernard Bataille, Adrien Aubert, Jean-Christophe Rossi and Ian Soulairol
Pharmaceutics 2021, 13(10), 1701; https://doi.org/10.3390/pharmaceutics13101701 - 15 Oct 2021
Cited by 9 | Viewed by 1812
Abstract
The aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature [...] Read more.
The aim of this work was to investigate the effect of process parameters on the printability of a formulation containing copovidone and paracetamol, and on the properties of solid oral forms 3D-printed through selective laser sintering. Firstly, the influence of the heating temperature was evaluated individually, and it was revealed that this parameter was critical for printability, as a sufficiently high temperature (100 °C) is necessary to avoid curling. Secondly, the effects of laser power, scan speed, and layer thickness were determined using a Box–Behnken design. The measured responses, printing yield, height, weight, hardness, disintegration time, and percentage of drug release at 10 min showed the following ranges of values: 55.6–100%, 2.92–3.96 mm, 98.2–187.2 mg, 9.2–83.4 N, 9.7–997.7 s, and 25.8–99.9%, respectively. Analysis of variance (ANOVA) proved that the generated quadratic models and the effect of the three–process parameters were significant (p < 0.05). Yield improved at high laser power, low scan speed, and increased layer thickness. Height was proportional to laser power, and inversely proportional to scan speed and layer thickness. Variations in the other responses were related to the porosity of the SOFs, which were dependent on the value of energy density. Low laser power, fast scan speed, and high layer thickness values favored a lower energy density, resulting in low weight and hardness, rapid disintegration, and a high percentage of drug release at 10 min. Finally, an optimization was performed, and an additional experiment validated the model. In conclusion, by applying a Quality by Design approach, this study demonstrates that process parameters are critical for printability, but also offer a way to personalize the properties of the SOFs. Full article
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15 pages, 4135 KiB  
Article
3D-Printed Mucoadhesive Collagen Scaffolds as a Local Tetrahydrocurcumin Delivery System
by Mireia Andonegi, Teresa Carranza, Alaitz Etxabide, Koro de la Caba and Pedro Guerrero
Pharmaceutics 2021, 13(10), 1697; https://doi.org/10.3390/pharmaceutics13101697 - 15 Oct 2021
Cited by 1 | Viewed by 2169
Abstract
Native collagen doughs were processed using a syringe-based extrusion 3D printer to obtain collagen scaffolds. Before processing, the rheological properties of the doughs were analyzed to determine the optimal 3D printing conditions. Samples showed a high shear-thinning behavior, reported beneficial in the 3D [...] Read more.
Native collagen doughs were processed using a syringe-based extrusion 3D printer to obtain collagen scaffolds. Before processing, the rheological properties of the doughs were analyzed to determine the optimal 3D printing conditions. Samples showed a high shear-thinning behavior, reported beneficial in the 3D printing process. In addition, tetrahydrocurcumin (THC) was incorporated into the dough formulation and its effect on collagen structure, as well as the resulting scaffold’s suitability for wound healing applications, were assessed. The denaturation peak observed by differential scanning calorimetry (DSC), along with the images of the scaffolds’ surfaces assessed using scanning electron microscopy (SEM), showed that the fibrillar structure of collagen was maintained. These outcomes were correlated with X-ray diffraction (XRD) results, which showed an increase of the lateral packaging of collagen chains was observed in the samples with a THC content up to 4%, while a higher content of THC considerably decreased the structural order of collagen. Furthermore, physical interactions between collagen and THC molecules were observed using Fourier transform infrared (FTIR) spectroscopy. Additionally, all samples showed swelling and a controlled release of THC. These results along with the mucoadhesive properties of collagen suggested the potential of these THC–collagen scaffolds as sustained THC delivery systems. Full article
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13 pages, 3732 KiB  
Article
Impact of Drug Loading Method on Drug Release from 3D-Printed Tablets Made from Filaments Fabricated by Hot-Melt Extrusion and Impregnation Processes
by Kasitpong Thanawuth, Lalinthip Sutthapitaksakul, Srisuda Konthong, Supakij Suttiruengwong, Kampanart Huanbutta, Crispin R. Dass and Pornsak Sriamornsak
Pharmaceutics 2021, 13(10), 1607; https://doi.org/10.3390/pharmaceutics13101607 - 03 Oct 2021
Cited by 15 | Viewed by 2956
Abstract
The purpose of this study was to investigate the impact of the drug loading method on drug release from 3D-printed tablets. Filaments comprising a poorly water-soluble model drug, indomethacin (IND), and a polymer, polyvinyl alcohol (PVA), were prepared by hot-melt extrusion (HME) and [...] Read more.
The purpose of this study was to investigate the impact of the drug loading method on drug release from 3D-printed tablets. Filaments comprising a poorly water-soluble model drug, indomethacin (IND), and a polymer, polyvinyl alcohol (PVA), were prepared by hot-melt extrusion (HME) and compared with IND-loaded filaments prepared with an impregnation (IMP) process. The 3D-printed tablets were fabricated using a fused deposition modeling 3D printer. The filaments and 3D printed tablets were evaluated for their physicochemical properties, swelling and matrix erosion behaviors, drug content, and drug release. Physicochemical investigations revealed no drug–excipient interaction or degradation. IND-loaded PVA filaments produced by IMP had a low drug content and a rapid drug release. Filaments produced by HME with a lower drug content released the drug faster than those with a higher drug content. The drug content and drug release of 3D-printed tablets containing IND were similar to those of the filament results. Particularly, drug release was faster in 3D-printed tablets produced with filaments with lower drug content (both by IMP and HME). The drug release of 3D-printed tablets produced from HME filaments with higher drug content was extended to 24 h due to a swelling-erosion process. This study confirmed that the drug loading method has a substantial influence on drug content, which in turn has a significant effect on drug release. The results suggest that increasing the drug content in filaments might delay drug release from 3D-printed tablets, which may be used for developing dosage forms suited for personalized medicine. Full article
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14 pages, 2088 KiB  
Article
Understanding Direct Powder Extrusion for Fabrication of 3D Printed Personalised Medicines: A Case Study for Nifedipine Minitablets
by Sergio A. Sánchez-Guirales, Noelia Jurado, Aytug Kara, Aikaterini Lalatsa and Dolores R. Serrano
Pharmaceutics 2021, 13(10), 1583; https://doi.org/10.3390/pharmaceutics13101583 - 29 Sep 2021
Cited by 26 | Viewed by 3435
Abstract
Fuse deposition modelling (FDM) has emerged as a novel technology for manufacturing 3D printed medicines. However, it is a two-step process requiring the fabrication of filaments using a hot melt extruder with suitable properties prior to printing taking place, which can be a [...] Read more.
Fuse deposition modelling (FDM) has emerged as a novel technology for manufacturing 3D printed medicines. However, it is a two-step process requiring the fabrication of filaments using a hot melt extruder with suitable properties prior to printing taking place, which can be a rate-limiting step in its application into clinical practice. Direct powder extrusion can overcome the difficulties encountered with fabrication of pharmaceutical-quality filaments for FDM, allowing the manufacturing, in a single step, of 3D printed solid dosage forms. In this study, we demonstrate the manufacturing of small-weight (<100 mg) solid dosage forms with high drug loading (25%) that can be easily undertaken by healthcare professionals to treat hypertension. 3D printed nifedipine minitablets containing 20 mg were manufactured by direct powder extrusion combining 15% polyethylene glycol 4000 Da, 40% hydroxypropyl cellulose, 19% hydroxy propyl methyl cellulose acetate succinate, and 1% magnesium stearate. The fabricated 3D printed minitablets of small overall weight did not disintegrate during dissolution and allowed for controlled drug release over 24 h, based on erosion. This release profile of the printed minitablets is more suitable for hypertensive patients than immediate-release tablets that can lead to a marked burst effect, triggering hypotension. The small size of the minitablet allows it to fit inside of a 0-size capsule and be combined with other minitablets, of other API, for the treatment of complex diseases requiring polypharmacy within a single dosage form. Full article
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23 pages, 4226 KiB  
Article
Predicting Drug Release from 3D Printed Oral Medicines Based on the Surface Area to Volume Ratio of Tablet Geometry
by Hellen Windolf, Rebecca Chamberlain and Julian Quodbach
Pharmaceutics 2021, 13(9), 1453; https://doi.org/10.3390/pharmaceutics13091453 - 11 Sep 2021
Cited by 34 | Viewed by 4778
Abstract
3D printing offers the advantage of being able to modify dosage form geometry, which can be exploited to modify release characteristics. In this study, we investigated the influence of the surface area to volume ratio (SA/V) to change and predict release profiles of [...] Read more.
3D printing offers the advantage of being able to modify dosage form geometry, which can be exploited to modify release characteristics. In this study, we investigated the influence of the surface area to volume ratio (SA/V) to change and predict release profiles of 3D printed dosage forms. Geometries with varying SA/V and dosages were designed and printed, and drug dissolution was investigated. Three drug substances were used: pramipexole, levodopa (both BCS I) and praziquantel (BCS II). Two polymers were chosen as matrix formers: polyvinyl alcohol (water-soluble) and ethylene vinyl acetate (inert). Drug release was characterized using the mean dissolution time (MDT) and established equations that describe complete dissolution curves were applied. Predictions were validated with previously un-printed dosage forms. Based on an identified MDT-SA/V correlation, the MDT can be predicted with a deviation of ≤5 min for a given SA/V. Using correlations of fit parameters and SA/V, RMSEP values of 0.6–2.8% and 1.6–3.4% were obtained for the BCS I formulations and RMSEP values of 1.0–3.8% were obtained for the BCS II formulation, indicating accurate prediction over a wide range of dissolution profiles. With this approach, MDT and release profiles of dosage forms with a given SA/V can be precisely predicted without performing dissolution tests and vice versa, the required SA/V can be predicted for a desired release profile. Full article
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21 pages, 5289 KiB  
Article
Production of Reproducible Filament Batches for the Fabrication of 3D Printed Oral Forms
by Stéphane Roulon, Ian Soulairol, Valérie Lavastre, Nicolas Payre, Maxime Cazes, Laurent Delbreilh and Jean Alié
Pharmaceutics 2021, 13(4), 472; https://doi.org/10.3390/pharmaceutics13040472 - 31 Mar 2021
Cited by 9 | Viewed by 2177
Abstract
Patients need medications at a dosage suited to their physiological characteristics. Three-dimensional printing (3DP) technology by fused-filament fabrication (FFF) is a solution for manufacturing medication on demand. The aim of this work was to identify important parameters for the production of reproducible filament [...] Read more.
Patients need medications at a dosage suited to their physiological characteristics. Three-dimensional printing (3DP) technology by fused-filament fabrication (FFF) is a solution for manufacturing medication on demand. The aim of this work was to identify important parameters for the production of reproducible filament batches used by 3DP for oral formulations. Amiodarone hydrochloride, an antiarrhythmic and insoluble drug, was chosen as a model drug because of dosage adaptation need in children. Polyethylene oxide (PEO) filaments containing amiodarone hydrochloride were produced by hot-melt extrusion (HME). Different formulation storage conditions were investigated. For all formulations, the physical form of the drug following HME and fused-deposition modeling (FDM) 3D-printing processes were assessed using thermal analysis and X-ray powder diffraction (XRPD). Filament mechanical properties, linear mass density and surface roughness, were investigated by, respectively, 3-point bending, weighing, and scanning electron microscopy (SEM). Analysis results showed that the formulation storage condition before HME-modified filament linear mass density and, therefore, the oral forms masses from a batch to another. To obtain constant filament apparent density, it has been shown that a constant and reproducible drying condition is required to produce oral forms with constant mass. Full article
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17 pages, 5043 KiB  
Article
Digital Light Processing (DLP) 3D Printing of Atomoxetine Hydrochloride Tablets Using Photoreactive Suspensions
by Mirjana Krkobabić, Djordje Medarević, Nikola Pešić, Dragana Vasiljević, Branka Ivković and Svetlana Ibrić
Pharmaceutics 2020, 12(9), 833; https://doi.org/10.3390/pharmaceutics12090833 - 31 Aug 2020
Cited by 26 | Viewed by 4014
Abstract
Three-dimensional (3D) printing technologies are based on successive material printing layer-by-layer and are considered suitable for the production of dosage forms customized for a patient’s needs. In this study, tablets of atomoxetine hydrochloride (ATH) have been successfully fabricated by a digital light processing [...] Read more.
Three-dimensional (3D) printing technologies are based on successive material printing layer-by-layer and are considered suitable for the production of dosage forms customized for a patient’s needs. In this study, tablets of atomoxetine hydrochloride (ATH) have been successfully fabricated by a digital light processing (DLP) 3D printing technology. Initial materials were photoreactive suspensions, composed of poly(ethylene glycol) diacrylate 700 (PEGDA 700), poly(ethylene glycol) 400 (PEG 400), photoinitiator and suspended ATH. The amount of ATH was varied from 10.00 to 25.00% (w/w), and a range of doses from 12.21 to 40.07 mg has been achieved, indicating the possibility of personalized therapy. The rheological characteristics of all photoreactive suspensions were appropriate for the printing process, while the amount of the suspended particles in the photoreactive suspensions had an impact on the 3D printing process, as well as on mechanical and biopharmaceutical characteristics of tablets. Only the formulation with the highest content of ATH had significantly different tensile strength compared to other formulations. All tablets showed sustained drug release during at least the 8h. ATH crystals were observed with polarized light microscopy of photoreactive suspensions and the cross-sections of the tablets, while no interactions between ATH and polymers were detected by FT-IR spectroscopy. Full article
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Review

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21 pages, 3350 KiB  
Review
Multi-Organs-on-Chips for Testing Small-Molecule Drugs: Challenges and Perspectives
by Berivan Cecen, Christina Karavasili, Mubashir Nazir, Anant Bhusal, Elvan Dogan, Fatemeh Shahriyari, Sedef Tamburaci, Melda Buyukoz, Leyla Didem Kozaci and Amir K. Miri
Pharmaceutics 2021, 13(10), 1657; https://doi.org/10.3390/pharmaceutics13101657 - 11 Oct 2021
Cited by 13 | Viewed by 6555
Abstract
Organ-on-a-chip technology has been used in testing small-molecule drugs for screening potential therapeutics and regulatory protocols. The technology is expected to boost the development of novel therapies and accelerate the discovery of drug combinations in the coming years. This has led to the [...] Read more.
Organ-on-a-chip technology has been used in testing small-molecule drugs for screening potential therapeutics and regulatory protocols. The technology is expected to boost the development of novel therapies and accelerate the discovery of drug combinations in the coming years. This has led to the development of multi-organ-on-a-chip (MOC) for recapitulating various organs involved in the drug–body interactions. In this review, we discuss the current MOCs used in screening small-molecule drugs and then focus on the dynamic process of drug absorption, distribution, metabolism, and excretion. We also address appropriate materials used for MOCs at low cost and scale-up capacity suitable for high-performance analysis of drugs and commercial high-throughput screening platforms. Full article
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36 pages, 2247 KiB  
Review
Eudragit®: A Versatile Family of Polymers for Hot Melt Extrusion and 3D Printing Processes in Pharmaceutics
by Juliana dos Santos, Guilherme Silveira da Silva, Maiara Callegaro Velho and Ruy Carlos Ruver Beck
Pharmaceutics 2021, 13(9), 1424; https://doi.org/10.3390/pharmaceutics13091424 - 08 Sep 2021
Cited by 46 | Viewed by 6421
Abstract
Eudragit® polymers are polymethacrylates highly used in pharmaceutics for the development of modified drug delivery systems. They are widely known due to their versatility with regards to chemical composition, solubility, and swelling properties. Moreover, Eudragit polymers are thermoplastic, and their use has [...] Read more.
Eudragit® polymers are polymethacrylates highly used in pharmaceutics for the development of modified drug delivery systems. They are widely known due to their versatility with regards to chemical composition, solubility, and swelling properties. Moreover, Eudragit polymers are thermoplastic, and their use has been boosted in some production processes, such as hot melt extrusion (HME) and fused deposition modelling 3D printing, among other 3D printing techniques. Therefore, this review covers the studies using Eudragit polymers in the development of drug delivery systems produced by HME and 3D printing techniques over the last 10 years. Eudragit E has been the most used among them, mostly to formulate immediate release systems or as a taste-masker agent. On the other hand, Eudragit RS and Eudragit L100-55 have mainly been used to produce controlled and delayed release systems, respectively. The use of Eudragit polymers in these processes has frequently been devoted to producing solid dispersions and/or to prepare filaments to be 3D printed in different dosage forms. In this review, we highlight the countless possibilities offered by Eudragit polymers in HME and 3D printing, whether alone or in blends, discussing their prominence in the development of innovative modified drug release systems. Full article
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37 pages, 2295 KiB  
Review
3D-Printed Oral Dosage Forms: Mechanical Properties, Computational Approaches and Applications
by Danae Karalia, Angeliki Siamidi, Vangelis Karalis and Marilena Vlachou
Pharmaceutics 2021, 13(9), 1401; https://doi.org/10.3390/pharmaceutics13091401 - 03 Sep 2021
Cited by 33 | Viewed by 4853
Abstract
The aim of this review is to present the factors influencing the mechanical properties of 3D-printed oral dosage forms. It also explores how it is possible to use specific excipients and printing parameters to maintain the structural integrity of printed drug products while [...] Read more.
The aim of this review is to present the factors influencing the mechanical properties of 3D-printed oral dosage forms. It also explores how it is possible to use specific excipients and printing parameters to maintain the structural integrity of printed drug products while meeting the needs of patients. Three-dimensional (3D) printing is an emerging manufacturing technology that is gaining acceptance in the pharmaceutical industry to overcome traditional mass production and move toward personalized pharmacotherapy. After continuous research over the last thirty years, 3D printing now offers numerous opportunities to personalize oral dosage forms in terms of size, shape, release profile, or dose modification. However, there is still a long way to go before 3D printing is integrated into clinical practice. 3D printing techniques follow a different process than traditional oral dosage from manufacturing methods. Currently, there are no specific guidelines for the hardness and friability of 3D printed solid oral dosage forms. Therefore, new regulatory frameworks for 3D-printed oral dosage forms should be established to ensure that they meet all appropriate quality standards. The evaluation of mechanical properties of solid dosage forms is an integral part of quality control, as tablets must withstand mechanical stresses during manufacturing processes, transportation, and drug distribution as well as rough handling by the end user. Until now, this has been achieved through extensive pre- and post-processing testing, which is often time-consuming. However, computational methods combined with 3D printing technology can open up a new avenue for the design and construction of 3D tablets, enabling the fabrication of structures with complex microstructures and desired mechanical properties. In this context, the emerging role of computational methods and artificial intelligence techniques is highlighted. Full article
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