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Semi-Solid Extrusion (SSE) in Pharmaceuticals
Nadine Lysyk Funk, Júlia Leão, Thayse Viana de Oliveira,
and Ruy Carlos Ruver Beck
Abstract
Semi-solid extrusion (SSE) is an extrusion-based 3D printing technique, widely
employed in food printing and bioprinting. In pharmaceutics, SSE is becoming
the most explored technique to obtain solid dosage forms with specific characteristics, such as chewable, fast-dissolving or gastro-floating tablets, polypills,
oral and topical films, and rectal suppositories, among others. The advantages of
SSE include a low work temperature, with less risk of drug instability, and the
availability of a broad range of excipients (e.g., natural or synthetic polymers,
lipids and food additives) as feedstock materials to obtain gels or pastes in the 3D
printing process. However, the properties of the dosage forms can be impacted
by formulation-related factors, like the semi-solid rheological behaviour, the
size of the dispersed materials, and the geometrical shape of the dosage form,
as well as the parameters of the printing process, such as printing speed, infill
pattern and number of layers. Due to this versatility, SSE has become a powerful
tool to produce innovative dosage forms with clinical relevance for specific
groups, including paediatric, geriatric and veterinary populations, as personalised
medicines.
5
Keywords
Additive manufacturing · Drug delivery · Hydrogels · Nanomedicine ·
Polymeric blend · Printing parameters
N. L. Funk · J. Leão · T. V. de Oliveira · R. C. R. Beck ()
Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade
Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
nadine.lysyk@ufrgs.br; julialeao@ufrgs.br; ruy.beck@ufrgs.br
e-mail:
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404-2_5
171
172 N. L. Funk et al.
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5.1 Introduction
Material extrusion techniques, including fused deposition modelling (FDM) and
semi-solid extrusion (SSE), have been the most explored 3D printing technologies
in pharmaceutical development in the past few years (dos Santos et al.
Since the first report on the development of drug dosage forms using the SSE
technique (Khaled et al.
2014), many authors have studied its advantages to produce
personalised medicines, affording an increase in scientific publications involving its
use in the manufacture of drug dosage forms by 3D printing.
SSE is a 3D printing technique that utilises semi-solid formulations as feedstock
material. Formulations are placed inside a syringe, usually disposable, and extruded
through a nozzle that can vary in diameter, according to the formulation or printing
requirements. Mechanisms of extrusion can include pneumatic, mechanical or
solenoid extrusion (Fig.
5.1). Following the application of pressure to the syringe
plunger, the material is deposited on the printer table in a layer-by-layer manner
until the desired dosage form size and geometry are complete. After printing, a
solidification step is required to maintain the structure, justifying why water-based
formulations are the most explored form so far (Seoane-Viaño et al.
2021a).
One of the most important advantages of SSE is the possibility of working at
room temperature, making it possible to use this 3D printing technique for thermolabile active substances. On the other hand, some printers allow the temperature in
the printer table and head to be varied within a specific range. Another benefit that is
easily observed in the pharmaceutical field is the simplicity of the process of adding
the active substance to the material to be printed, as it can be directly added to the
base gel, cream or paste, together with the excipients. This process makes it easy to
customise the drug dose and/or its release profile (Firth et al.
2018).
Although SSE appears to be an easy technique in terms of the ink formulation and
printing process, some critical aspects have an impact on the quality of the printed
material. Regarding the ink formulation, its rheological and textural characterisation
plays a crucial role in the success of the printing process. The greatest challenge
while developing a gel or paste for SSE is finding the right viscosity for printing.
Less viscous feedstocks make it difficult to control the flow through the nozzle,
while a higher viscosity may result in the nozzle clogging or having inadequate
flow (Rahimnejad et al.
2021), as depicted in Fig. 5.1.
Compared to other techniques, like FDM, SSE prints at low resolution, mainly
because of the characteristics of the printed material. Also, a drying step is usually
needed after the printing process, which can lead to shrinking, deformation and even
to a loss of shape of the final product. Despite the limitations mentioned above, SSE
has been widely explored in the pharmaceutical field due to its versatility (Vithani
et al.
2019a; Karalia et al. 2021).
In this scenario, a great variety of drug delivery systems manufactured by SSE 3D
printing have been reported in the literature, such as polypills (Haring et al.
chewable tablets (Goyanes et al.
(Wang et al.
2020; Elbadawi et al. 2021), fast-dissolving or gastro-floating tablets
2019; Karavasili et al. 2020), oral and topical films
2021).
2018),
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 173
mechanisms, parameters and nozzle diameter), and types of feedstock materials
Fig. 5.1 Schematic illustration of the semi-solid extrusion 3D printing technique (left side), the critical parameters related to the extrusion process (extrusion
174 N. L. Funk et al.
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(Falcone et al. 2021) and rectal suppositories (Seoane-Viaño et al. 2021b), among
others. These reports reinforce the versatility of the technique to develop different
types of dosage forms for specific groups, as personalised medicines.
New findings and perspectives can be observed due to the increased number
of scientific reports about the 3D printing of pharmaceuticals embracing the SSE
technique in the past few years. Thus, this chapter will describe and discuss the
main critical parameters of the SSE printing process in pharmaceutics, such as the
feedstock materials, the printing ink properties and the printing process. At the end,
a broad view will be presented about the application of the SSE technique in the
development of pharmaceuticals.
5.2 Feedstock Materials
The main difference among the different extrusion-based 3D printing techniques
is the type of feedstock employed. Due to its easier process requirements, the
SSE technique enables the use of semi-solid materials that are directly extruded
through a nozzle to form the desirable dosage form. Semi-solids are formulations
obtained by the dispersion or solubilisation of one excipient or blend of excipients
in an appropriate solvent to reach a suitable viscosity. Examples include creams,
ointments, pastes and gels, among others (European Pharmacopoeia 10.0
Gels are preferred in the 3D printing of pharmaceuticals and are the most explored
semi-solid so far, due to the high amount of water present in their formulation, which
rapidly evaporates after deposition on the printer table, guaranteeing that the dosage
form structure is maintained.
Reports on the 3D printing of pharmaceuticals describe the use of natural,
semi-synthetic and synthetic polymers (individually or blended), food additives
and lipid-based formulations to produce 3D printed dosage forms by SSE for
administration by different routes (Table
5.1). The main excipient must be chosen
according to its rheological properties and the release profile intended for the
printed dosage form and must be generally recognised as safe (GRAS), guaranteeing
the biocompatibility of the formulation. Depending on the nature of the polymer,
crosslinking reactions can be employed before or after printing to improve the
mechanical strength of the feedstock or the printed product. Crosslinking methods
include chemical (e.g., photo and thermal crosslinking), physical (e.g., addition of
multivalent cations) or enzymatic crosslinking (GhavamiNejad et al.
external stimulations promote changes in the sol-gel state of the polymers, enabling
researchers to control some properties, such as the viscosity of the feedstock (Fan
et al.
2022). These approaches are interesting not only to adjust and improve the
printability of the ink formulations, but also to achieve a desirable drug release
profile.
Regarding the drug release profiles, the development of immediate drug release
3D printed dosage forms by SSE has explored the use of different polymers,
including hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC),
polyvinylpyrrolidone (PVP), Gelucire
®
48/16 and poly(vinyl alcohol)-polyethylene
2019).
2020). These
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 175
(continued)
Tagami et al. (2021)
Ilhan et al. (2020)
treatment
patients
Hydrogel dressing Teoh et al . ( 2021)
de Oliveira et al. (2022)
Redispersible 3D printed oral
solid forms
Díaz-Torres et al.
Sjöholm et al. (2020)
(2021)
printlets for paediatric use
veterinary use
Tab le 5 .1 Feedstock material employed in the development of pharmaceutical dosage forms by the SSE 3D printing technique, drugs loaded in the
formulation and its main application
Chitosan methacrylate Lidocaine hydrochloride and
Main ink formulation material Drug Main application Reference
Natural Sodium alginate Ricobendazole Gastro-retentive dosage form Falcone et al. (2022)
levofloxacin
co-encapsulated in
nanocapsules
CMC Resveratrol and curcumin
Synthetic and
HPMC Phenytoin sodium Fast-disintegrating tablets Panraksa et al. (2022)
semi-synthetic
PVP 30 K Hydrochlorothiazide Orodispersible
HPC Prednisolone Orodispersible films for
Chitosan:Pectin (1:4 v/v) Lidocaine Wound dressing Long et al. (2019)
Polymeric
blends
Propranolol hydrochloride Mucoadhesive buccal films Jovanovic et al. (2021)
Ofloxacin Gastric-floating systems Fang et al. (2022)
Gelatin:PVP (1:1 w/w) and Gelatin:PVA
HPMC K100M:HPMC E5:Sodium
alginate (15:15:10)
Sodium alginate:PEG (5:1 w/w) Satureja cuneifolia extract Scaffold for diabetic wound
(1:1 w/w)
Gelatin:HPMC (at different w/w ratio) Lamotrigine Gummy for paediatric
176 N. L. Funk et al.
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Karavasili et al. (2020)
form
(2020)
Self-nanoemulsifying tablet Algahtanietal.(2021)
Dapagliflozin propanediol
monohydrate
44/14:Coconut oil (4:1) Tacrolimus Suppository Seoane-Viaño et al.
48/16 Furosemide and sildenafil Paediatric dosage form Lafeber et al. (2021)
®
®
Liquid phase—Caproyl 90:Octanoic
acid:PEG 400 (2:2:1)
Solid phase—Poloxamer 188:PEG 6000
Cereal Paracetamol and ibuprofen Child-friendly dosage form Karavasili et al. (2022)
Main ink formulation material Drug Main application Reference
Food additive Bitter chocolate Paracetamol and ibuprofen Paediatric-friendly dosage
Tab le 5 .1 (continued)
Gelucire
Gelucire
Lipid-based
formulation
(1:1)
CMC Carboxymethyl cellulose, HPMC Hydroxypropyl methylcellulose, HPC Hydroxypropyl cellulose, PVP 30 K Polyvinyl pyrrolidone 30 K, PVP
Polyvinyl pyrrolidone, PVA Poly(vinyl alcohol), PEG Polyethylene glycol
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 177
glycol (PVA-PEG) graft copolymers (Kolicoat ® IR) (Funk et al. 2022). Whenever a
faster drug release is preferred, the addition of disintegrants to formulations, such as
croscarmellose sodium (Conceição et al.
2015a), has also been reported as a suitable approach. It is also possible
et al.
2019) and sodium starch glycolate (Khaled
to attain controlled drug release behaviours using the SSE technique, comprising
different release mechanisms depending on the feedstock material. One of the most
explored polymers to afford controlled release profiles by SSE is HPMC (Khaled
et al.
2014; Wen et al. 2019; El Aita et al. 2020), with its increased concentration
generally delaying drug release from the 3D printed form (Cui et al.
2019; Cheng et
al. 2020).
Along with the rational choice of the polymer, the SSE technique allows some
parameters of the printing process that can tailor the drug release from the 3D
printed dosage forms to be changed, according to the requested treatment of a
specific patient or group of patients. Changes in geometry, infill percentage, layer
thickness, and width and height of the dosage form have been explored as a strategy
to achieve immediate or controlled drug release formulations.
In the following subsections, the most described classes of feedstock material
used to produce 3D printed dosage forms by SSE will be discussed individually.
5.2.1 Semi-Synthetic and Synthetic Polymers
Currently, semi-synthetic and synthetic polymers have been extensively utilised as
feedstock material for SSE 3D printing, mostly cellulosic polymers like HPMC,
carboxymethyl cellulose (CMC) and HPC. Most of these cellulosic polymers are
commercially available with different substitution degrees and molecular weights,
and these modifications impact on their physicochemical properties (Zamboulis et
al.
2022).
Different grades and concentrations of HPMC have been explored to produce
diverse dosage forms, such as mucoadhesive oral films (Tagami et al.
ophthalmological patches (Tagami et al.
et al.
2022), and gastro-floating tablets (Li et al. 2018), showing different release
2022), tablets (Cui et al. 2019; Panraksa
2019),
profiles, depending on the concentration of HPMC. In addition, the higher the
molecular weight and viscosity of the HPMC, the slower the drug release. Regarding
the mechanism of drug release, hydrophobic drugs are usually released by gel
erosion, and hydrophilic drugs through diffusion from the gel layer formed by the
HPMC (Funk et al.
2022).
CMC has also been recently reported in the development of orodispersible films
(O’Reilly et al.
Oliveira et al.
bioprinting (Rahman and Quodbach
2021), mucoadhesive films (Schmidt et al. 2022) and tablets (de
2022). Most research involving CMC is based on its use in 3D
2021). One of the advantages of its use as a
feedstock material for SSE 3D printing is its capacity to form hydrogels with an
elastic solid behaviour at low concentration, which favours shape recovery after the
printing step (Rahman and Quodbach
2021).
178 N. L. Funk et al.
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Other synthetic and semi-synthetic polymers have also been described as the
main formulation material for SSE 3D printed dosage forms, usually formulated as
blends, which will be described next in this chapter. PVA-PEG graft copolymer and
PVA have been reported for the development of SSE 3D printed tablets (El Aita
et al.
2019; Dores et al. 2020), whereas PVP was reported for the manufacture of
gelatin-based mucoadhesive films (Jovanovic et al.
2021).
As mentioned earlier in this chapter, crosslinking reactions can be employed
before, during or after printing. For some synthetic and semi-synthetic polymers,
pH and temperature are employed as parameters to change the sol-gel state of the
materials, promoting reticulation of the polymeric chains and changing a solution
to a semi-solid, which can be useful in a SSE 3D printing process.
The stimuli-responsiveness of some polymers can also be employed to improve
the printability of feedstocks during printing. Temperature changes in the printer
head and table can promote a proper flow and structure rigidity, for example
(Herrada-Manchón et al.
2020). Photocrosslinking can be employed during and
after printing, to guarantee reticulation of the polymeric chains and decrease the
time needed for the printed material to dry (Hollander et al.
2018). Additionally,
immersing the printed material in acidic or basic solutions is usually reported as a
post-printing treatment in bioprinting to ensure the structural integrity of the object
(Sadeghianmaryan et al.
2020).
Examples of stimuli-responsive polymers include carbomers, such as Carbopol,
which form a solution in water and rapidly acquire viscosity when agents such as
NaOH are added to increase the formulation pH (Zidan et al.
2022). Although less explored in the development of 3D printed dosage forms,
al.
2019; Alayoubi et
thermosensitive feedstocks have already been reported in bioprinting (Rahimnejad
et al.
2022) and food development (Liu et al. 2018), comprising the use of polymers
such as gelatin, collagen, methylcellulose and poloxamers.
5.2.2 Natural Polymers
Polymers with natural origin are commonly used as excipients in pharmaceuticals
because of their safety, biocompatibility and biodegradability, which are desirable
characteristics for the development of dosage forms by SSE. These polymers
have mainly been applied in wound dressing tissue engineering and artificial skin
development by SSE 3D printing (Zamboulis et al.
alginate (Falcone et al.
(Goyanes et al.
2019) and polymeric blends with natural polymers (Long et al. 2019;
Herrada-Manchón et al.
2021; Falcone et al. 2022), chitosan (Teoh et al. 2021), pectin
2020) have been reported as semi-solid ink components for
the manufacture of 3D printed drug delivery systems.
Chitosan is a natural polymer extracted from the exoskeletons of crabs and
shrimps and has mucoadhesive properties, attributed to its positive charges due
to the presence of amino groups in its structure, which can be interesting for the
development of mucoadhesive formulations (Whyte et al.
undergoes the sol-gel transition by physical gelling through pH variation, as its
2022). In pharmaceutics, sodium
2019). This polymer
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