Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule

Abstract

Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule ‘shell’ and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension ‘.gcode’) were modified by creating discrete zones, so-called ‘zoning process’, with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work.

Introduction

Drug product development can be a long and complex process especially when there is a need to: a) increase drug solubility by converting the form of the active ingredient through processes such as spray drying (SD) or hot melt extrusion (HME), b) protect the drug from a specific region of the gut using delayed release or enteric coating for release beyond the stomach or, c) alter the drug release profile to avoid adverse outcomes or overcome pharmacokinetic restrictions using modified or controlled release technology such as osmotic tablets. For each of these examples, the development of the dosage form becomes complicated, time consuming, and expensive. However, 3D printing (3DP) can allow for a robust, facile, and cost-effective approach to drug development in which drug release profiles may be tailored to a particular outcome using a single manufacturing method. Moreover, 3DP allows for custom designs and dosing amounts such that the dosage forms may be tailored to a specific patient population.

Fused deposition modeling (FDM) is the method of choice, where molten polymer is precisely deposited one layer at a time to build up a part. Currently, there are limited pharmaceutically acceptable materials available in filament form, which is the raw material feedstock for FDM printers. Many traditional polymer excipients do not have the appropriate thermal and mechanical properties for filament processing or the physical properties are altered when drug is incorporated in the filaments. In order to have a robust filament the polymer must be sufficiently rigid to maintain its form as it is pushed from the compression gear through the hot end nozzle orifice of the printer. The polymer should be sufficiently tough so the extruder gear of the FDM printer can gently depress and grip the filament to generate extrusion force greater than the resistance from the molten polymer flow out of the nozzle. In addition, the melting temperature or glass transition temperature must be significantly higher than the temperature inside the printing enclosure to allow the forced air cooling to rapidly quench the extrudate. The melting temperature should also be below 250 °C, which is the maximum temperature allowed in most commercially available FDM printers. Finally, in order to maintain proper molten flow, the thermoplastic material must not degrade while it is held at elevated temperatures during the printing process for extended periods of time, usually on the order of minutes. Once a filament is extruded, X-ray computed tomography (XRCT) can be used as a quality check for surface or volumetric defects (du Plessis et al., 2016, Markl et al., 2017). Diameter variations in the filament tend to strongly correlate with the quality of the final print as most commercial printers do not dynamically change the extrusion rate based on the filament’s instantaneous diameter. Other challenges with this technology include the ability to extrude a tablet- or capsule-like product with good surface uniformity to encourage patient acceptance while limiting defect and internal cavity voids, as this influences active ingredient dissolution performance.

Over the past few years, there has have been numerous published references demonstrating successful fabrication of oral dosage forms using FDM. Hydroxypropyl cellulose (HPC) (Melocchi et al., 2015) has been used to print drug-free capsules which are manually filled and assembled post-printing. Additional work has highlighted the difficulties and limitations of using FDM for printing PVA capsules where the dosage forms were printed for hand filling with placebo liquids, followed by manual assembly and sealing, and external and internal surface roughness of the printed capsule walls were investigated. Typically, however, the filament that is loaded into the FDM 3D printer is pre-processed using extrusion to incorporate active ingredients, which are then used to print the final dosage form. Polyvinylpyrrolidone (PVP) (Okwuosa et al., 2017, Okwuosa et al., 2016) mixed with drug in a HME process has been used with FDM to construct oral dosage forms. Polyvinyl alcohol (PVA) has been most commonly used due to its beneficial mechanical and thermal properties aiding the FDM process (Goyanes et al., 2014, Goyanes et al., 2015a, Goyanes et al., 2015b, Goyanes et al., 2015c, Skowyra et al., 2015, Tagami et al., 2017, Markl et al., 2017). Recent work on manufacturing filaments for 3DP examined the use of Eudragit EPO®, a cationic acrylic polymer with dimethylamine-containing side chains, which is a polymer typically unsuitable for FDM due to its brittle properties (Sadia et al., 2016). This study showed that Eudragit EPO could be compounded with a plasticizer, triethyl citrate, and a non-melting filler, tricalcium phosphate, to optimize the hardness and flexibility properties to enable printing of the filament. The same research group demonstrated the feasibility of printing an enteric coated 3D printed caplet using the same plasticizer and filler approach with PVP and drug-free Eudragit EPO® (Okwuosa et al., 2017). Other extruded materials, where quinine was mixed individually with Eudragit RS, polycaprolactone, poly-L-lactic acid (PLLA), and ethyl cellulose at a 5 wt% drug loading, demonstrated viability for use as FDM filaments for preparing 3D printed implants (Kempin et al., 2017). It has also been demonstrated that soaking filaments in a poor or non-solvent solution containing drug can result in diffusion of drug into the filament, although the drug loading is intrinsically lower than extrusion methods (Goyanes et al., 2014). To date there are limited successful piloting examples of pharmaceutically acceptable filaments, and the surface quality of these printed dosage forms indicates more optimization is required before wide spread adoption can be realized. To sidestep many of these challenges, paste formulations have been printed using similar equipment as a FDM printer, except the hot end is replaced with a closed shot canister. Using this approach, Hydroxypropyl methylcellulose (HPMC) and polyacrylic acid (Carbopol® 974P), (Khaled et al., 2014) HPMC and lactose (Khaled et al., 2015a), and HPMC hydro-alcoholic gels (Khaled et al., 2015b) have been printed. Notably, this approach has been used for polypills, (Khaled et al., 2015a,b) which are single oral dosage forms that contain three or more isolated volumes each containing a different active ingredient. While paste formulations open doors to more material choices, this approach typically requires subsequent steps such as overnight drying of the print to remove any solvent or water from the dosage form for long term physical stability, it is unclear at this time how the mechanical robustness of paste printed dosage forms will endure secondary packaging and user handling.

In this work, the various challenges highlighted above are addressed with a new approach to manufacturing of pharmaceutical dosage: one-click FDM 3D print-and-fill capsules. We explore the idea and review the development work for a three step process integrated into a single FDM printer: 1) print an open faced capsule shell from a traditional polymer filament such that a formulation may be filled into the interior cavity, 2) fill the shell cavity with the desired dosage form, and 3) print the top of the capsule to close the opening for a fully sealed encapsulated oral dosage form. To accomplish this, the 3D printer files (.gcode) were modified through a process called zoning, where each individualized zone was printed with its own set of print conditions, namely extrusion rate, print speed, and quench rate. This zoning process eliminated macroscopic defects to the capsule shell and reduced sample to sample variation.