Amorphous solid dispersion of a binary formulation with felodipine and HPMC for 3D printed floating tablets

This study focuses on the combination of three-dimensional printing (3DP) and amorphous solid dispersion (ASD) technologies for the manufacturing of gastroretentive floating tablets. Employing hot melt extrusion (HME) and fused deposition modeling (FDM), the study investigates the development of drug-loaded filaments and 3D printed (3DP) tablets containing felodipine as model drug and hydroxypropyl methylcellulose (HPMC) as the polymeric carrier. Prior to fabrication, solubility parameter estimation and molecular dynamics simulations were applied to predict drug-polymer interactions, which are crucial for ASD formation. Physical bulk and surface characterization complemented the quality control of both drug-loaded filaments and 3DP tablets. The analysis confirmed a successful amorphous dispersion of felodipine within the polymeric matrix. Furthermore, the low infill percentage and enclosed design of the 3DP tablet allowed for obtaining low-density systems. This structure resulted in buoyancy during the entire drug release process until a complete dissolution of the 3DP tablets (more than 8 h) was attained. The particular design made it possible for a single polymer to achieve a zero-order controlled release of the drug, which is considered the ideal kinetics for a gastroretentive system. Accordingly, this study can be seen as an advancement in ASD formulation for 3DP technology within pharmaceutics.

Introduction

Three-dimensional printing (3DP) is an innovative additive manufacturing technique capable of converting 3D computer models into real objects through the sequential deposition of material layer by layer. The ability to manufacture complex structures has opened new possibilities in the design of pharmaceutical dosage forms with different shapes, sizes, dosages, as well as drug release characteristics and multiple drug combinations (Ayyoubi et al., 2021, dos Santos et al., 2023, Parulski et al., 2022, Sadia et al., 2018, Shojaie et al., 2023, Verstraete et al., 2018, Zhang et al., 2017). Three-dimensional printing offers a solution to a major drawback of conventional gastroretentive drug delivery systems (GDDS), which is the limitation of the tablet design. With 3D printing, it is possible to design personalized dosage forms with complex geometries and specific characteristics to improve gastric retention and controlled release of the drug in the stomach. It allows the density and composition of the formulation to be precisely adjusted, which can be beneficial in achieving controlled flotation in the gastric environment (Dumpa et al., 2020, Huanbutta and Sangnim, 2019, Khizer et al., 2023, Melocchi et al., 2021, Mora-Castaño et al., 2023). 3DP is introducing a new approach to personalized treatment, as it enables pharmaceutical forms to be manufactured adapted to the individual needs of patients.

Currently, one of the most evaluated 3DP techniques in the pharmaceutical area is fused deposition modeling (FDM), due to the low cost of the printer, the good quality of the final product, high reproducibility, and the potential for innovative drug management strategies. FDM is based on the extrusion of a filament from a heated extrusion head through a nozzle. In this process, materials are melted and deposited layer by layer on a platform that moves in the x and y axes. As the plate descends, the object is built from the bottom up. The ability to precisely control processing parameters allows FDM to have enormous potential and utility for the preparation of personalized medicine (Cailleaux et al., 2021, Dumpa et al., 2021, Melocchi et al., 2021, Pereira and Figueiredo, 2020).

However, one of the main drawbacks of FDM is that it requires prior preparation of drug-loaded filaments, usually by hot melt extrusion (HME) (Bandari et al., 2021, Mora-Castaño et al., 2022, Zhao et al., 2022). The high dependence on the physical and mechanical properties of the filaments for the viability of printing and the difficulty of filament preparation are the main drawbacks of this technology (Bandari et al., 2021, Mora-Castaño et al., 2022). HME is a process in which a blend of materials, mainly polymers, drugs, and eventual additives, is melted or softened under elevated temperature and pressure to pass under force along a barrel containing rotating screws. The final product emerges from the barrel through a die that shapes the extruded product (Tan et al., 2018). HME offers many advantages, such as the absence of organic solvents and a low number of processing steps. The possibility of continuous processing and scalability allows its use for pharmaceutical development (Alzahrani et al., 2022, Bandari et al., 2021, Jennotte et al., 2022, Tambe et al., 2021).

HME and 3D extrusion-based printing technologies are also innovative tools for formulating amorphous solid dispersions (ASDs), which consist of amorphous drugs dispersed and stabilized on a polymeric support (Bhujbal et al., 2021). Obtaining ASD formulations is a strategy to improve the apparent solubility of drugs and potentially increase their absorption and bioavailability (Alzahrani et al., 2022, Yani et al., 2017).

Among the drawbacks that ASDs present, we can highlight the risk of degradation due to hydrolysis or oxidation, as the amorphous drug is more hygroscopic than its crystalline form, and the possibility of drug recrystallization. These drawbacks can be overcome by stabilizing the amorphous drug with a carrier, usually a polymer (Jennotte et al., 2022). The polymer must have the ability to raise the energy threshold necessary for the nucleation and crystallization of the drug and decrease the mobility of the molecules. These mechanisms inhibit drug crystallization during dissolution tests, maintaining the supersaturation state (Jennotte et al., 2022, Vo et al., 2017, Xiang and Anderson, 2017).

Factors such as drug-polymer miscibility, solubility of the drug in the polymer, residual crystallinity, molecular mobility, drug-polymer interaction, and the manufacturing process also influence the stability of ASDs, as well as the temperature and humidity of storage. (Alzahrani et al., 2022).

A rational approach is preferred to select suitable drugs and excipients for manufacturing ASD, thereby reducing time to market and minimizing costs associated with development (DeBoyace and Wildfong, 2018, Han et al., 2019, Tambe et al., 2022, Zhang et al., 2023). Understanding and predicting the miscibility between the carrier and the drug is a crucial aspect of ASDs to ensure the physical stability of the drug (Xiang and Anderson, 2017, Zhang et al., 2023).

Different analytical technologies used to characterize the amorphous solid state (Deon et al., 2022) and verify the results obtained in theoretical predictions made in previous stages are valuable tools. Confirming the compatibility and miscibility of the components of the amorphous dispersion is essential to ensure the safety and efficacy of 3D printed dosage forms formulated with amorphous solid dispersion (Kim et al., 2021, Skowyra et al., 2015, Zhao et al., 2022).

Felodipine (FEL) is a class II hydrophobic drug in the Biopharmaceutics Classification System, with a poor water solubility of 0.58 μg/mL at 25° C, a melting point of 145 °C at crystalline state and a glass transition temperature (Tg) of 47 °C at amorphous state (Karavas et al., 2006, Lu et al., 2019). ASD technology has emerged as a promising strategy to improve the solubility and dissolution rate of felodipine (FEL) (Lu et al., 2019, Marsac et al., 2009, Marsac et al., 2006, Palazi et al., 2018, Vo et al., 2017, Yi et al., 2019). In conjunction with this technique, GDDS can be used to improve drug release and absorption by maintaining a low concentration around the dosage forms, avoiding in situ recrystallization and allowing gradual drug absorption. GDDS have the ability to maximize the absorption area of drug molecules on the surface of the gastrointestinal tract, ensuring optimal absorption. In contrast, conventional controlled-release pharmaceutical forms can rapidly pass through the small intestine, which restricts their effectiveness (H. Blaesi and Saka, 2024, Vo et al., 2017).

The aim of this work was to manufacture FDM 3D printed (3DP) floating tablets composed of an ASD of felodipine with a hydrophilic polymer. For this purpose, the polymer Affinisol™ 15 LV (AFF) has been used as the carrier. Theoretical methods were employed to predict the drug-polymer interactions. Subsequently, the drug-loaded filaments and the 3DP tablets were studied using different analytical techniques for physical characterization and to complement the modeling predictions of the drug-excipient interactions. In addition, the buoyancy and release kinetics of the 3DP tablets were studied.

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Materials

Felodipine (Carbosynth Ltd., Compton, Berkshire, UK) was used as the model drug. Hydroxypropyl methylcellulose (HPMC) Affinisol™ 15 LV, a hydrophilic, amorphous polymer, was kindly donated by The Dow Chemical Company (Midland, MI, USA).

Gloria Mora-Castaño, Mónica Millán-Jiménez, Andreas Niederquell, Monica Schönenberger, Fatemeh Shojaie, Martin Kuentz, Isidoro Caraballo, Amorphous solid dispersion of a binary formulation with felodipine and HPMC for 3D printed floating tablets, International Journal of Pharmaceutics, Volume 658, 2024, 124215, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124215.