Lessons to learn for 3D printing of drug products by semisolid extrusion (SSE)

Abstract

Semisolid extrusion (SSE) 3DP technology is emerging due to its simplicity and potential for on-site manufacturing of personalized drug products with tailored functionality (dose, release profile), as well as recognizability (size, shape, color). However, even a minor change in the composition of the ink (the feedstock material) and the printing process parameters can largely influence the outcome of printing. This paper summarizes the recent SSE 3D printing studies, where the important factors affecting the quality of the printed drug products are discussed. Further challenges are showcased by introducing a case study focusing on the design of oral theophylline immediate-release drug products. The identified crucial factors, such as the printing hardware and connected software, printing parameters, and composition of the ink are discussed. Especially, the rheological properties of the ink during the printing process, together with solidification, mechanical properties, and morphology studies of already printed products are deliberated to gain more understanding of the printability of drug products by SSE. This work aims to provide an overview of design aspects related to SSE-based fabrication of personalized drug products.

Introduction

3D printing is a manufacturing method aiming to build structures in a layer-by-layer manner according to in silico-designed models. It has been widely applied for mass customization in multiple fields including aerospace industries, food printing, agriculture, art, and healthcare1,2. Nowadays, the increased focus has been directed towards the application of 3D printing in the pharmaceutical industry with the belief that this technology holds great revolutionary potential within this sector3. In contrast to traditional drug manufacturing methods, 3D printing allows for a swift and convenient adjustment of the dose and drug release profile of the drug product through digital modification of the in silico model, e.g., the size and shape of the object to be printed4,5. This on-demand manufacturing can be cost-effective and simple to implement in clinical practice and beyond. Furthermore, it can be the enabling element to make personalized medicine a tangible and achievable concept.

Semisolid extrusion (SSE) is a promising micro-extrusion-based 3D printing technology in the pharmaceutical field6. It can also be recognized with alternative names, such as pressure-assisted micro-syringe (PAM) printing7 and micro-extrusion8. In SSE, the ink as the feedstock material is loaded in a syringe and extruded into a cylindrical filament with the dimensions of the syringe nozzle onto the build plate at relatively low temperatures (typically up to 40°C). Besides SSE, there are four main 3D printing technologies, which are proven to be feasible for pharmaceutical products: (1) fused-deposition modeling (FDM), (2) binder jetting (BJ), (3) selective laser sintering (SLS), and (4) stereolithography (SLA)3. FDM is also an extrusion-based technology. However, it requires a high temperature to melt or soften the pre-made drug-polymer filament with the risk of thermal degradation for both drug and dominantly polymeric excipients9. In contrast to FDM, SSE applies to a broader spectrum of drugs, including thermosensitive active pharmaceutical ingredients (APIs). In turn, SLS utilizes the laser beam to melt the powder bed, i.e., commonly the mixture of an API and a polymer, to create a solid object. The high energy of the laser beam may lead to degradation of the API. BJ employs a binding liquid to aggregate powder particles to form a cohesive solid object. The API can be incorporated either in the binding liquid or the powder bed. BJ possesses the advantage of building high-resolution porous structures, and it is, therefore, suitable for the production of fast-disintegrating tablets10. However, BJ drug products may suffer from poor mechanical strength as powder particles in the tablets are held together only by the presence of internal and/or external binding agent(s)11. SLA employs high-energy light to solidify liquid resins that are non-pharmaceutical-grade excipients, and the residuals of toxic monomers can still be present in the printed object, confronting its safety3. The typical formulations for SSE are based on pharmaceutical-grade excipients, which makes it an attractive manufacturing solution for drug products.

In recent years, there has been a growing number of research devoted to implementing SSE into clinical practice. For instance, Aita et al. developed dose-adjustable immediate-release tablets, containing levetiracetam, with the intent to make available flexible doses of antiepileptic drug products on-demand for pediatric patients7. Commercial guaifenesin bi-layered tablets were mimicked with SSE printed tablets that consisted of the sustain-release layer and the immediate-release layer12. Manchon et al. employed SSE 3DP to produce ranitidine hydrochloride-containing gummies in different shapes and colors with the intention of improving medication adherence by pediatric patients13. SSE 3D printed levothyroxine sodium-containing tablets were proven to achieve more precise doses compared to the manual division of commercially available tablets in the treatment of infant patients14. Bioequivalence studies with healthy volunteers were conducted with SSE-printed sildenafil drug products designed for pediatric patients15.

SSE is a relatively new technology in the pharmaceutical field. The existing scientific literature has addressed some major concerns of SSE in 3DP of drug products, such as the influence of the ink composition and the choice of the printing equipment on the printing outcome. However, this design process is still trial and error based, and there is a lack of comprehensive elucidation of nuances of the manufacturing process that can be of critical importance. In this paper, we provide an insight into the critical points related to ink formulation and its characterization, printing settings, and post-printing steps (Fig. 1). Here, these points are discussed with the selected examples from the published scientific literature and further illustrated with a case study based on the use of SSE for designing an immediate-release drug product containing theophylline. Our ambition is to provide an illustrative overview of possibilities and challenges when using SSE for drug products. This review can be used to avoid unanticipated manufacturing problems and speed up the research and development of drug products for the unmet medical needs.

Materials

Theophylline anhydrate and mannitol (Parteck® M200) from Merck (Germany) were used as the model drug and the filler, respectively. Hydroxypropyl methylcellulose (HPMC) (Pharmacoat® 603, 3 mPa∙s for 2% (w/v) aqueous dispersion, Shin-Etsu Chemical Co., Ltd, Tokyo, Japan) and HPMC (HME 4M AFFINISOL™, kindly donated by DuPont, Switzerland) were used as the gel-forming polymers. Ultrapure water (PURELAB® flex, ELGA LabWater, UK) was used as the solvent.

Weining Sun, Jukka Rantanen, Natalja Genina, Lessons to learn for 3D printing of drug products by semisolid extrusion (SSE), Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2024.05.032.