Direct powder extrusion (DPE) 3D-printing of mini-tablets for preclinical studies in rodents

Abstract

3D printing (3DP) plays a crucial role in accelerating formulation processes and significantly reduces the time needed to transition from concept to prototype. This technology is particularly valuable as it allows researchers to quickly adjust the structure and composition of dosage forms and efficiently evaluate multiple formulations for safety and efficacy. The following research explores the feasibility of using the direct powder extrusion (DPE) technique to produce 3D-printed mini tablets for eventual in vivo preclinical trials in rodents. The DPE method streamlines the manufacturing process into a single step and addresses the limitations commonly associated with Fused Deposition Modeling (FDM). It offers advantages such as customized small-batch production, optimized costs, and minimal waste. This allows pharmaceutical companies to quickly respond to market demands and improve overall product quality through detailed characterization. In this study cellulose-based polymers like Hydroxypropyl Cellulose (HPC-L) and Hydroxypropyl Methylcellulose (HPMC-15LV) were selected as the main matrix excipients, incorporating 10 % w/w of a model drug. The formulations were further optimized to achieve the best flowability and extrudability, as well as the most desirable printing resolution, to produce 3D-printed mini tablets resembling size 9 capsules. Based on the inner diameter of the cannula used for oral administration in rats, tablets measuring 8.6 × 1.8 × 1.8 mm were successfully printed. Thermal analysis (DSC and TGA) and solid-state characterization (FTIR, XRD) were employed to evaluate the physical properties of the powder blends and final 3D-printed products along with the assessment of desirable mechanical features. The successful production of small batches of model 3D-printed mini tablets that are suitable for in vivo testing and present comparable release profiles with conventional employed capsules demonstrated the possibility to implement DPE during preclinical development of novel formulations working independently from suppliers.

Introduction

3D printing (3DP) is an additive manufacturing technique that has found widespread applications across various fields, including pharmaceuticals, where it has spurred significant research and development in drug delivery (Konta et al., 2017). This innovative approach offers distinct advantages over traditional manufacturing methods by enabling the rapid, accurate, and cost-effective production of complex objects through rapid prototyping (Zema et al., 2017). Moreover, 3DP facilitates the on-demand production of fully customizable dosage forms that vary in size, shape, release kinetics, and drug loading (Milliken et al., 2024), thereby enhancing their suitability for in vivo trials in rodents or eventually other species. In preclinical studies, 3DP may play a pivotal role in accelerating formulation development.

It can be employed for quick small-batch production during testing of new drugs, significantly reducing the time from concept to prototype (Tracy et al., 2023). This capability is crucial as it enables researchers to efficiently evaluate multiple formulations for efficacy and safety. Furthermore, the flexibility of the 3DP process empowers researchers to rapidly adjust the composition and structure of dosage forms. This agility facilitates exploration into various release mechanisms and drug combinations, thus optimizing therapeutic outcomes. The small batch production capability of 3DP is a significant advantage in preclinical research. By enabling the cost-effective production of drugs in small quantities, it minimizes waste and reduces costs, particularly beneficial in the early stages of drug development where large quantities are unnecessary (Sánchez-Guirales et al., 2021). This flexibility also allows for the creation of customized doses tailored to specific preclinical study requirements, supporting more precise and targeted research endeavors. Essentially, 3DP through its additive manufacturing approach revolutionizes drug development in pharmaceuticals by enhancing speed, flexibility, and cost-effectiveness. By accelerating formulation development, it supports customization (Pandey, 2020), thereby advancing preclinical studies and paving the way for more efficient clinical trials and eventual commercialization of novel therapies.

Among the various 3DP techniques, direct powder extrusion (DPE) has recently garnered significant interest (Goyanes et al., 2019). DPE streamlines the production process into a single step by allowing the direct feeding and processing of powder or pellet blends into the printer (Fanous et al., 2020, Liu et al., 2019). Specifically, the process involves feeding the material through a hopper, controlled heating, and then extruding the molten material through the nozzle. Currently, when testing in vivo oral dosage forms, small empty capsules are purchased from suppliers and manually filled with the selected formulation and administered to rats via a dosing cannula or syringe. The application of DPE to develop mini tablets for oral administration in rodents in vivo studies offers pharmaceutical companies several advantages: i) customized production in small batches, ii) optimized costs, iii) minimized waste (Pistone, 2023, Pistone, 2022) iv) independent work from suppliers. Flexibility in customizing tablets in terms of size, shape, and release characteristics enhances the accuracy of in vivo trials reaching ethical requirements. Moreover, the rapid prototyping enabled by DPE speeds up the manufacturing of pharmaceutical formulations (Boniatti, 2021), enabling companies to promptly respond to market needs and improve overall product quality through detailed characterization.

The aim of this project is to investigate the potential application of DPE technique to develop small batches of mini tablets that could be administered orally to rats for in vivo studies during the development of new drugs. Fo this reason, 10 % of a model drug (e.g., caffeine or naproxen) was incorporated. Having different melting temperatures, caffeine and naproxen were chosen as models, thus an evaluation of the different thermal behaviours in the molten polymer matrices was possible. A variety of cellulose-based excipient matrices were screened to identify the most suitable for the DPE 3DP process in terms of extrudability and printability. Additionally, the formulation and printing parameters (e.g. addition of plasticizing agents, printing temperatures, nozzle diameter) were adjusted and optimized to provide a model platform that can be easily employed according to the needs to produce 3D-printed mini dosage forms and loaded with drugs that must be tested in vivo. Furthermore, the most suitable formulations were thoroughly characterized. Thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC) were conducted to assess the thermal stability and suitability of the 3DP process towards both the raw materials and the final products.

Crystallinity of the system evaluated through Powder X-Ray Diffraction (XRPD) and scanning electron microscopy (SEM) was employed to observe the morphology of the 3D-printed products. Additional characterization included Fourier-transform infrared spectroscopy (FTIR), mass uniformity, drug loading, and dissolution studies. The mechanical properties of the mini tablets were also investigated.

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Materials

Hydroxypropyl celluloses (HPC-L MW 140 kDa, and HPC-SSL MW 40 kDa) were obtained from Nippon Soda (Japan), while hydroxypropyl methylcellulose (AFFINISOL ™, HPMC HME 15LV and AFFINISOL (T)M, HPMC HME 100LV) from DuPont (USA). Caffeine from Carlo Erba (Italy) and naproxen from BLD Pharm (Germany) were selected as model drugs. Polyox WSR N10 (PEO, MW 100 kDa) was purchased from Colorcon (UK); while mannitol from Farmalabor (Italy) and PEG 6 kDa from Merck (Germany). The salts (NaCl, KCl, Na2HPO4*2H2O, KH2PO4) employed for preparing PBS, methanol and formic acid were purchased from Merck (Italy). All solvents used were analytical grade.

Costanza Fratini, Sofia Moroni, Davide De Angelis, Mattia Tiboni, Anna Giulia Balducci, Alessandra Rossi, Annalisa Aluigi, Francesco Amadei, Luca Casettari, Direct powder extrusion (DPE) 3D-printing of mini-tablets for preclinical studies in rodents, International Journal of Pharmaceutics, Volume 675, 2025, 125542, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125542.

Read also our introduction article on Mannitol here: