Extrusion-Based 3D Printing of Pharmaceuticals—Evaluating Polymer (Sodium Alginate, HPC, HPMC)-Based Ink’s Suitability by Investigating Rheology
Abstract
Three-dimensional printing is promising in the pharmaceutical industry for personalized medicine, on-demand production, tailored drug loading, etc. Pressure-assisted microsyringe (PAM) printing is popular due to its low cost, simple operation, and compatibility with heat-sensitive drugs but is limited by ink formulations lacking the essential characteristics, impacting their performance. This study evaluates inks based on sodium alginate (SA), hydroxypropyl cellulose (HPC H), and hydroxypropyl methylcellulose (HPMC K100 and K4) for PAM 3D printing by analyzing their rheology. The formulations included the model drug Fenofibrate, functional excipients (e.g., mannitol, polyethylene glycol, etc.), and water or water–ethanol mixtures. Pills and thin films as an oral dosage were printed using a 410 μm nozzle, a 10 mm/s speed, a 50% infill density, and a 60 kPa pressure. Among the various formulated inks, only the ink containing 0.8% SA achieved successful prints with the desired shape fidelity, linked to its rheological properties, which were assessed using flow, amplitude sweep, and thixotropy tests. This study concludes that (i) an ink’s rheological properties—viscosity, shear thinning, viscoelasticity, modulus, flow point, recovery, etc.—have to be considered to determine whether it will print well; (ii) printability is independent of the dosage form; and (iii) the optimal inks are viscoelastic solids with specific rheological traits. This research provides insights for developing polymer-based inks for effective PAM 3D printing in pharmaceuticals.
Introduction
Three-dimensional (3D) printing, also known as additive manufacturing, is the process of building a three-dimensional object by placing multiple successive layers of material [1,2,3]. Three-dimensional printing can be used to make custom-designed objects quickly, easily, and affordably [4]. To create an object using a 3D printer, a digital three-dimensional design of the object is created in a computer program such as SolidWorks, and this file is later used to instruct the printing device on how to construct the object [1,5]. In recent years, 3D printing has secured a foothold in the pharmaceutical industry due to its ability to customize drug products by adjusting how much drug is loaded, allowing for complex dosage forms, producing medicine on demand, and delivering pills containing multiple drugs or active pharmaceutical ingredients (APIs), etc., while the current manufacturing methods in the pharmaceutical industry, which employ a one-size-fits-all approach, are limited by scientific and technological constraints in achieving such capabilities [6,7,8,9]. Although there are many types of 3D printing, an extrusion-based 3D printing type known as pressure-assisted microsyringe (PAM) printing is gaining popularity in the pharmaceutical industry because it is simple, low-cost, and scalable and does not require heat (allowing for the use of heat-sensitive drugs) [1,4,6,10]. PAM printing involves the use of pressurized syringes to extrude polymer-based ink [11]. The PAM-type extrusion-based 3D printing process can be divided into three primary steps (shown in Figure 1): 1. ink preparation; 2. ink extrusion; and 3. ink deposition and 3D structure formation. Each step is essential to ensure acceptable printability with good reproducibility. Generally, the polymer and functional excipients are chosen to make sure they will provide the ink with suitable rheological properties, thus making the ink extrudable and giving it the ability to maintain the desired shape of the 3D-printed object [12]. The ink’s ability to flow through the print head nozzle and maintain its structure after 3D printing relies on the ink’s rheological properties, which are determined by parameters such as viscosity, viscoelasticity, recovery, etc. [4].
In general, 3D printing is performed based on trial and error, which is time-consuming and resource-intensive, especially for high-value products such as pharmaceuticals, regenerative medicine, etc. [13,14]. The difficulty with PAM 3D printing comes from the ability to develop polymer-based inks with a suitable rheology that can be extruded smoothly through the print head and hold their shape after being printed [15]. If the polymer-based ink does not have the proper rheological characteristics, it may create issues during the printing process, such as clogging the print head nozzle or defective printing [16,17]. It is also noted that suitable printing process parameters are essential to obtain printability and good reproducibility, and these parameters rely on the ink’s rheological properties [12,18]. Hence, developing a polymer-based ink suitable for PAM-type 3D printing is extremely challenging [17].
The polymers sodium alginate (SA), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose (HPMC) are commonly used in the pharmaceutical industry [19,20,21,22]. These polymers are classified as generally regarded as safe (GRAS) [23]. Recently, ink preparation using these polymers, sodium alginate [24,25], HPC [26,27], and HPMC [28,29], which are suitable for extrusion-based 3D printing, has been discussed. However, no study has evaluated all three of these polymers, compared the different rheological properties of these polymeric inks, and eventually connected them with the 3D printing outcomes for various oral dosages. This research study aims (i) to assess inks prepared using the polymers SA, HPC H, or HPMC K100 or K4 by investigating and comparing their rheology and connecting the rheological data with the ink’s applicability to PAM-type 3D printing and (ii) to observe whether there are any variations in the printing outcomes due to dosage variations such as pills and films, which are the most commonly used in an oral dosage form. The novelty of this research work relies on the exploration of these aims. To prepare the ink, Fenofibrate (FNB), used to treat high cholesterol levels, was used as the model drug, along with several functional excipients, including mannitol, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and sodium dodecyl sulfate (SDS). Each of these excipients provides functionality and contributes to the ink’s overall rheological properties, i.e., its viscosity. It is noted that even though the functional excipients contribute to the rheology, this study focuses on the rheological variations caused by the polymers. Hence, the concentrations of the functional excipients were kept the same. Only the polymer’s concentration or type was varied. The ink’s rheological properties (i.e., viscosity, storage and loss modulus, viscoelasticity, flow behavior, recovery after shear, etc.) were evaluated using an Anton Paar MCR 302 rheometer (Graz, Austria). The ink was then used to 3D-print various dosage forms (i.e., pills, films) using a Cellink BioX PAM-type 3D printer.
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Materials
The polymers sodium alginate (alginic acid sodium salt), HPC H, and HPMC (K100 (Methocel™ K100M Premium CR) or K4) were purchased from Acros Organics (Fair Lawn, NJ, USA), donated by Nisso America Inc. (New York, NY, USA), and donated by Colorcon® (Harleysville, PA, USA), respectively. The molecular structures of these polymers are depicted in Figure 2. Here, sodium alginate and HPMC are biopolymers, while HPC is a synthetic derivative of the natural polymer cellulose. The model drug Fenofibrate was purchased from Tokyo Chemical Industry Co, Ltd., (Tokyo, Japan). The functional excipients D-mannitol 97%+, polyethylene glycol 6000 (PEG 6000), polyvinylpyrrolidone K 30 (PVP K30), and sodium dodecyl sulfate (SDS) were purchased from Alfa Aesar (Haverhill, MA, USA), Tokyo Chemical Industry Co, Ltd., (Tokyo, Japan), Alfa Aesar (Haverhill, MA, USA), and TCI America (Portland, OR, USA), respectively. It is noted that (i) mannitol was used as filler to increase the ink’s solid content and subsequently its viscosity [30], (ii) PEG was used as a plasticizer [31], (iii) PVP was used to improve the dispersion of the hydrophobic model drug FNB in the ink [32], and (iv) SDS is a surfactant and was used as a wetting agent [33]. Ethanol 89.5–91.5% (v/v), ACS-reagent-grade, was purchased from Ricca Chemical Company (Arlington, TX, USA).
Rony, F.K.; Kimbell, G.; Serrano, T.R.; Clay, D.; Ilias, S.; Azad, M.A. Extrusion-Based 3D Printing of Pharmaceuticals—Evaluating Polymer (Sodium Alginate, HPC, HPMC)-Based Ink’s Suitability by Investigating Rheology. Micromachines 2025, 16, 163. https://doi.org/10.3390/mi16020163
Read also our introduction article on Mannitol here:
