Exploring 3D Printing in Drug Development: Assessing the Potential of Advanced Melt Drop Deposition Technology for Solubility Enhancement by Creation of Amorphous Solid Dispersions

Abstract

Background: Melt-based 3D printing technologies are currently extensively evaluated for research purposes as well as for industrial applications. Classical approaches often require intermediates, which can pose a risk to stability and add additional complexity to the process. The Advanced Melt Drop Deposition (AMDD) technology, is a 3D printing process that combines the principles of melt extrusion with pressure-driven ejection, similar to injection molding. This method offers several advantages over traditional melt-based 3D printing techniques, making it particularly suitable for pharmaceutical applications.

Objectives: This study evaluates the AMDD printing system for producing solid oral dosage forms, with a primary focus on the thermo-stable polymer polyvinyl alcohol (PVA). The suitability of AMDD technology for creating amorphous solid dispersions (ASDs) is also examined. Finally, the study aims to define the material requirements and limitations of the raw materials used in the process.

Methods: The active pharmaceutical ingredients (APIs) indometacin and ketoconazole were used, with PVA 4-88 serving as the carrier polymer. Powders, wet granulates, and pellets were investigated as raw materials and characterized. Dissolution testing and content analyses were performed on the printed dosage forms. Solid-state characterization was conducted using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Degradation due to thermal and mechanical stress was analyzed using nuclear magnetic resonance spectroscopy (NMR).

Results/Conclusions: The results demonstrate that the AMDD 3D printing process is well-suited for producing solid dosage forms. Tablets were successfully printed, meeting mass uniformity standards. Adjusting the infill volume from 30% to 100% effectively controlled the drug release rate of the tablets. Solid-state analysis revealed that the AMDD process can produce amorphous solid dispersions with enhanced solubility compared to their crystalline form. The experiments also demonstrated that powders with a particle size of approximately 200 µm can be directly processed using AMDD technology.

Introduction

Recent decades have witnessed a transformative shift in drug research. A deeper understanding of the evolution and progression of various diseases has enabled the creation of more targeted therapies [1]. This shift is evident in the emergence of personalized medicine, a paradigm that is reshaping both medicine and drug development [2]. A significant percentage of adverse drug effects, estimated between 75% and 85%, are attributed to inappropriate dosing or dose combinations [3,4]. Consequently, there is a growing demand for methods to customize dosage forms to meet the specific needs of individual patients [5]. However, current conventional pharmaceutical manufacturing processes fall short in this regard, as they do not readily allow for tailored dosing [6]. This challenge is where Additive Manufacturing, or 3D Printing (3DP), comes into play. 3DP offers significant advantages, such as the ability to fabricate complex solid oral dosage forms (SODFs), enabling the customization and personalization of medicines with individually tailored doses [7]. Moreover, 3DP allows the production of 3D structures with high shape complexity [8], which enables printing SODFs with modified drug release rates [9]. Additionally, 3DP can accelerate the drug development timeline from initial human clinical trials to mainstream medical care [10].

In the pharmaceutical industry, 3DP is revolutionizing traditional manufacturing processes, especially for SODFs [11]. This revolution is particularly important considering that a large proportion of new active pharmaceutical ingredients (API), around 70%, have poor solubility [12]. Enhancing solubility often involves producing amorphous solid dispersions (ASD). One method to produce ASD is through hot melt extrusion. During this process, the crystalline structure of the API is disrupted by both thermal and mechanical energy, and the amorphous components are embedded into a polymer matrix [13]. The traditional method for processing these ASDs into SODFs involves milling the extrudate and tableting it with the addition of excipients [14]. However, this process can be challenging in early clinical trials due to the need for various dosages and different tablet formulations, especially when only small quantities of API are available [15].

Fused deposition modeling (FDM) is gaining popularity in pharmaceutical research due to its affordability and compatibility with HME, a well-established technology in the pharmaceutical field [16]. FDM is an extrusion-based system that uses a filament as the starting material. This filament, produced through HME and capable of being drug-loaded [17], is fused by a heated printer extrusion head. The head moves along the x and y axes, depositing the material through a nozzle onto a building surface [18]. The quality of the final printed form depends on various parameters, including infill density, extrusion speed, layer height, and nozzle/building platform temperature [17,19,20]. Infill density is particularly important in personalizing medicine as it allows modification of drug release rates in SODF [21]. However, producing filaments for FDM presents challenges. They must have mechanical stability to be receptive to the print head, necessitating specific mechanical properties [22,23]. Consequently, a thorough evaluation of active ingredient-containing filaments is essential, as mechanical stability varies with each active ingredient, leading to time-consuming and resource-intensive investigations. Furthermore, while several thermoplastic polymers have been assessed for pharmaceutical applications, the number of pharmaceutically approved polymers is limited, and many lack the required properties for FDM [18,24].

A novel solution to these challenges is Advanced Melt Drop Deposition (AMDD) technology, as demonstrated in the Arburg Plastic Freeforming (APF) process [25]. AMDD stands out because it uses standard granulation for printing, a significant advantage over other melt-based techniques like FDM. Utilizing powder granulation allows production of SODFs without prior processing. Moreover, AMDD technology could further process pelletized extrudate using bulk material instead of filament strands, which eliminates the need for specific mechanical properties and enables on-demand sales.

The printer in AMDD combines the principles of hot melt extrusion with pressurized ejection, like injection molding processes (Figure 1). In this system, the polymer granulate is heated and melted within a plasticizer barrel. A rotating screw then moves the molten material to the nozzle tip, generating high pressures (up to 600 bar) inside the barrel. This molten substance is then precisely discharged as individual droplets, controlled by a piezo actuator that modulates a nozzle closure mechanism. The high velocity of these droplets ensures their cohesion, enabling the construction of complex structures.

Figure 1. Illustration of the AMDD technology.

The aim of this study is to evaluate the AMDD technology for use in pharmaceutical applications. Initial applications of the AMDD system were described by Welsh et al., who printed a Dapivirine-containing vaginal ring from polyurethane and optimized its release rate. Furthermore, they significantly reduced the amount of active pharmaceutical ingredient (API) compared to conventional thermoplastic production techniques [26]. A second paper by Zhang et al. explored the AMDD process for the production of oral dosage forms. They studied Paracetamol, a highly soluble BCS (Biopharmaceutics Classification System) Class 1 drug, in a polymer matrix composed of hypromellose acetate succinate and a portion of polyethylene oxide. Their research focused on the impact of porosity on the release kinetics of swellable and erodible solid dosage forms [27].

This study sheds light on two areas that have not yet been explored in a pharmaceutical context: firstly, the impact of various initial intermediates on the processability. For this purpose, various intermediates, such as powder mixtures, wet granulates, and HME pellets, were examined. In this context, the limits of the system in terms of the processability of the starting materials are evaluated. The second focus is on the solubility enhancement of poorly soluble drugs through the formation of ASDs using the AMDD system. Ketoconazole (KTZ) and indometacin (IND), both BCS Class 2 drugs, were chosen as model compounds, covering both slightly acidic (IND) and slightly basic (KTZ) model substances. These were printed into a PVA matrix. The influence of the starting intermediates on the solid-state status of the ASDs was also examined. The analysis included particle size distribution (PSD), flow properties, rheology, differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), tablet properties such as mass and scanning electron microscopy (SEM) images, determination of drug content with nuclear magnetic resonance (NMR), and high-performance liquid chromatography (HPLC), as well as in vitro dissolution studies.

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Materials

Polyvinyl alcohol (Parteck® MXP 4-88) as well as PVA 4-88 Flakes were purchased from Merck Life Science KGaA (Darmstadt, Germany). Indometacin (IND) was purchased from Sigma Aldrich (St. Louis, MO, USA). Ketoconazole (KTZ) was purchased from Fagron (Rotterdam, The Netherlands). All other reagents used for high-performance liquid chromatography (HPLC), and dissolution were of chromatography or analytical grade.

Lamrabet, N.; Hess, F.; Leidig, P.; Marx, A.; Kipping, T. Exploring 3D Printing in Drug Development: Assessing the Potential of Advanced Melt Drop Deposition Technology for Solubility Enhancement by Creation of Amorphous Solid Dispersions. Pharmaceutics 2024, 16, 1501. https://doi.org/10.3390/pharmaceutics16121501