1
Materials for 3D Printing

Thomas McDonagh, Bin Zhang and Sheng Qi

School of Pharmacy, University of East Anglia, Norwich, UK

1.1 Introduction

Three-dimensional printing (3DP), also known as Additive Manufacturing (AM), has emerged as an exciting technology for the manufacture of pharmaceutical products for personalised patient treatment. The interindividual variability of the human population is a constant challenge when striving for effective drug delivery because patients come in different shapes, sizes, ages, genetics, and necessities and so require medication personalised to their needs for the most effective outcomes [1, 2]. 3DP has been shown to be a flexible technique that can be used to manufacture drug delivery devices (DDDs) for a wide array of applications such as tablets, implants, microneedles, and suppositories [3-5]. In addition, compared to conventional large-scale production techniques such as tablet pressing, 3DP is much more flexible with the potential to simplify supply chains and accelerate development cycles. Such traits make 3DP an ideal candidate technology to produce on-demand personalised medicines and in turn improve patient quality of life. However, there are still several challenges hindering its adoption. Limited availability of biocompatible materials, the incompatibility of the active pharmaceutical ingredient) (API), and/or polymer with the printing conditions, and regulatory hurdles present a significant challenge when designing 3DP pharmaceutical products. This is highlighted by the presence of just one 3DP pharmaceutical product currently on the market as of 2023, Spritam® [6].

Material choice is a fundamental consideration when designing a pharmaceutical dosage form. All drug products are comprised of an API (the bioactive component) and inactive functional excipients which facilitate the release of the API to the target location in the body. With the advance of 3D-printing medicine, API carrier materials have an increasingly important role in not only protecting the API in a convenient printable package and disguising unpalatable ingredients but also in facilitating complex release profiles. Several 3D-printing techniques are applicable for manufacturing DDD: Thermal Extrusion-based deposition systems (TE); Semi-solid extrusion (SSE); Stereolithography (SLA); and Powder Bed fusion (PBF). Successful printing of pharmaceuticals requires consideration of the nature of the 3D-printing process. Each technique has its own benefits and limitations in terms of material compatibility, print quality, and scalability and so must be considered as a whole when designing a new DDD. The objective of this chapter is to first discuss each printing technique, exploring the key material characteristics and processing parameters that influence both printability and drug delivery performance. Subsequently, the materials which have shown suitability for 3DP manufacture of DDD will be discussed with a focus on the key material attributes relevant for printing and drug release properties.

1.2 Material Processability Considerations for Pharmaceutical 3DP

1.2.1 Thermal Extrusion-Based 3D Printing

Thermal extrusion (TE)-based 3D printing is a popular solvent free 3DP technique for printing thermoplastic polymer and API formulations. In TE printing, thermal energy is applied to a print head to melt material, enabling extrusion through a nozzle onto a build plate. Thermoplastic polymers are used because they are composed of long linear chains, held together by weak attraction forces. When subjected to high temperatures in the print head, they soften or melt to enable extrusion before solidifying upon cooling. The nozzle and/or build plate are controlled by linear actuators that enable precise deposition into a pre-defined geometry in a layer-by-layer fashion according to a 3D digital model. Good print resolution is achievable with resolutions typically between 100 µm and 400 µm [7, 8], depending on the diameter of nozzle used. A benefit of TE printing is the minimal post processing requirements. Printed parts are full strength immediately after printing and unlike other 3DP techniques, no washing or drying steps are required. Furthermore, release rates of TE drug products are highly tuneable by varying printing software parameters such as infill density [9]. Due to the mechanical stability of TE drug products, this technique appears to be more suitable for controlled or sustained release applications [10, 11], although immediate release pharmaceutical products have also been explored [12].

Most current TE 3DP technologies are not compatible with the direct printing of raw powder materials. Direct TE of powders presents challenges in terms of feeding (poor flowability), homogenous mixing, and degassing (trapped air between powder particles) [13]. As such, a prior hot-melt extrusion (HME) step is commonly used to sufficiently mix reagents and process them into a more attractive feedstock for printing. In HME, heat and mechanical shear is used to mix reagents producing a homogenous melt which can be extruded into uniform filaments. Most pharmaceutical polymers require a temperature of at least 15 °C to 60 °C above their glass transition (Tg) to be sufficiently molten for processing [14]. Filaments can be printed using the widespread, low-cost technology fused deposition modelling (FDM) or can be pelletised into granules for use with direct granule TE.

1.2.1.1 Thermal Considerations

The first material processability consideration for TE 3DP concerns the thermal processing. Thermal processing presents a challenge when working with pharmaceutical formulations because some API and polymers are thermolable and will begin to degrade at high temperatures, reducing the efficacy of the pharmaceutical product. Additionally, formulation viscosity is intrinsically linked to temperature. High temperatures increase the kinetics of a formulation, reducing its apparent viscosity [15]. Therefore, successful TE operates within a temperature window that sufficiently reduces the viscosity of the polymer melt (above Tmin) to enable good mixing and extrusion, whilst maintaining the API stability (below the thermal degradation temperature). To ensure solubility of API in the polymer melt, a third boundary temperature is often introduced, called the solubility line (Tc) [16]. This theoretical design space is shown in Figure 1.1. The design space can be seen to shrink for high drug load formulations due to the increased Tc required to solubilise the API. Additionally, increased residence time in the HME can be used to increase API dissolution but also increases the likelihood of thermal degradation. These same design constraints are also applicable when printing. Lower than optimal printing temperatures increase formulation viscosity that can cause nozzle blockages and low bond strength between printed layers [17] and high temperatures can result in further API degradation and poor print quality.

Figure 1.1 (a) The temperature-composition phase diagram of the hot-melt extrusion process. The temperature design space falls below the thermal degradation temperature and, depending on composition, above the solubility line or polymer's minimum processing temperature Tmin. Product phase behaviour is governed by the solubility line (formulation Tc) and formulation glass transition Tg. (b) Hot-melt extrusion process operating design space diagram. Three processing regimes (melting, dissolution, and suspension) can be delineated by temperature and kinetic considerations. (Source: Reproduced from [18] with permission from Elsevier 2018.)

Whilst some sensitive API may appear to be incompatible with TE due to low thermal degradation temperatures (Tdeg), strategies exist to reduce the thermal load on formulations enabling printing at lower temperatures. By using these techniques, a wide variety of polymers and API has been successfully printed, with drug loadings from 5% to 60% w/w shown to be feasible [19]. The first technique involves carefully selecting polymers and excipients which are extrudable at low temperatures. This generally involves use of plasticisers which act as a lubricant between segments of polymer chains, thus increasing the materials flexibility and softness. Kollamaram et al. succeeded in printing Ramipril and 4-aminosalicylic acid (4-ASA) loaded tablets using a PVP PVP-VA copolymer system plasticised with PEG 1500 [20]. Ramipril is transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point (109 °C) and 4-ASA begins to degrade at 130 °C. Filaments loaded with 3% drug were obtained by HME at 70 °C and tablets were printed at 90 °C. HPLC analysis confirmed that both drugs were stable with no signs of degradation, demonstrating how the careful selection of polymer and plasticiser can enable the printing of thermolabile API at low temperatures. Another technique involves avoiding the thermal and mechanical stress induced during HME altogether by using filament impregnation. The filament impregnation technique was first reported in 2014 [21], where API was loaded into the filament post HME by soaking in a saturated alcoholic drug solution. Whilst several authors have reported on the impregnation technique for DDD applications, drug loading is very low (<3% w/w) [22-24], limiting its use to drugs with therapeutic effects at low dose [25]....