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5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 179
swelling occurs at acidic pH due to protonated amino groups and the appearance
of repulsions between the polymer chains, increasing the viscosity of the gel (Irimia
et al.
2018). Chitosan hydrogels have been explored for the topical delivery of
lidocaine and levofloxacin from anaesthetic wound dressings (Teoh et al.
as a blend with pectin for lidocaine delivery (Long et al.
2019).
2021) and
Another natural polymer explored in the SSE technique is sodium alginate,
a copolymer formed by blocks of mannuronic (M) and glucuronic (G) acid, at
different proportions and arranged in a consecutive or alternate manner that impacts
directly on its physicochemical properties. The higher the M block content, the
higher the viscosity, while a higher content of G blocks results in greater gelling
properties (Łabowska et al.
alginate hydrogels can be reached by physical crosslinking, notably with Ca
2021). An increase of the mechanical properties of
2+
A better definition of the printed dosage form can be achieved by increasing the
concentration of this crosslinker. Falcone and coworkers explored the ionotropic
gelation of alginate in the development of SSE 3D printed floating drug delivery
systems containing propranolol hydrochloride (Falcone et al.
zole (Falcone et al.
2022).
2021) and ricobenda-
5.2.3 Polymeric Blends
Although there are many types of polymers, they are not always suitable for the
formulation of printable feedstocks (or printing ink). For example, polymers may
present high elasticity or break tendencies, which makes their deposition on the
printing table difficult, or adhesion properties that hamper the system flowability.
Blends of polymers with distinct properties are therefore being explored to achieve
a successful printing ink by tailoring its consistency or flowability, or aiming to
reach a specific drug release profile from the 3D printed dosage forms.
To improve the texture and consistency of the semi-solid after extrusion,
Sjöholm et al. (
hydroxypropyl cellulose EXF or hydroxypropyl cellulose LF. According to the
authors, a proper texture needs to be smooth and uniform, not too viscous and not
too fluid (Sjöholm et al.
and gelatin (Herrada-Manchón et al.
al.
2021), and gelatin and HPMC (Tagami et al. 2021) are examples of polymeric
blends used to improve the printability and flow properties of hydrogels, to reach a
defined rheological behaviour that prevents the collapse of the structure, but is also
not too viscous to clog the nozzle.
Polymeric blends are explored not only to improve the physical characteristics
of the hydrogel, but also to modify the drug release rate from the 3D printed dosage
form, as reported for the use of blends composed of hydroxypropyl methylcellulose
K100 M (HPMC K4100) or E5 (HPMC E5), sodium alginate, microcrystalline
cellulose and lactose (Fang et al.
each polymer was evaluated on the drug release rate. The higher the ratio of HPMC
K4100, the lower the drug release rate. On the other hand, the presence of sodium
2020) produced polymeric blends using polyethylene oxide and
2020). Similarly, corn starch, xanthan gum, carrageenan
2020), gelatin and PVP or PVA (Jovanovic et
2022), where the influence of the percentage of
.
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alginate in the blend did not influence the drug release from the tablets. However,
the use of polymer blends may also be focused on improving the pharmaceutical
effect of the dosage form per se. In the development of a diabetic wound dressing,
Ilhan et al. (
2020) prepared sodium alginate and PEG hydrogels based on the
compatibility of the resulting 3D printed film with the skin. These two polymers
have high biocompatibility, low toxicity and were also chosen due to their ability to
accelerate the healing process by promoting tissue regeneration.
5.2.4 Food Additives
SSE has also been explored in the alliance between medicines and food. Adherence
to treatment is very important for the success of pharmacological therapy, but it is
quite variable among the paediatric population, depending on the characteristics of
the drug, such as palatability and organoleptic properties (taste, colour, smell and
texture, among others). In this sense, studies have shown promising results when
printing food containing drugs (Zajicek et al.
chocolate were reported as alternative feedstocks to develop 3D printed paediatricfriendly dosage forms with improved acceptance and to facilitate the administration
of paracetamol and ibuprofen to children.
Cereal-based 3D printed dosage forms have been developed, to be administered
during breakfast in association with milk. Dissolution studies were performed
mimicking the gastric and intestinal environments, in fasted state and fed state, in the
presence of high-fat or low-fat milk. Results showed that paracetamol dissolution
was not affected by the presence of milk, resulting in a total drug release in less than
75 min. Meanwhile, ibuprofen (a more hydrophobic drug) displayed a slower release
in comparison to paracetamol; however, the ibuprofen dissolution rate increased
with a high-fat content milk (drug release of 64% in low-fat milk and 81% in highfat milk after 240 min) (Karavasili et al.
2022).
An alternative approach was presented by developing cartoon-shaped 3D printed
dosage forms using bitter chocolate and corn syrup as feedstock materials. Both
hydrophilic (paracetamol) and hydrophobic (ibuprofen) drugs were molecularly
dispersed into the chocolate-based formulations and showed a pH-dependent drug
release when evaluated in simulated salivary (pH 7.0) and gastric (pH 2.0) fluids.
Complete paracetamol release was observed after 2 h at pH 2.0, while a slower
ibuprofen release was observed in the same medium (16.98 ± 4.68%) (Karavasili et
al.
2020).
As previously mentioned, food additives are an interesting choice when paediatric appeal is required. Their alliance with SSE 3D printing shows some
advantages, mainly because of the possibility of dose adjustment according to the
patient’s characteristics, to improve palatability and to make the pharmacotherapy
more attractive. However, these approaches should be considered carefully, as this
alliance of drugs and food may impair the rational use of medicines or could incite
drug intoxication in children.
2013). As an example, cereal and
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 181
5.2.5 Lipids
Lipid-based drug delivery systems are of particular interest in the development of
3D printed pharmaceuticals due to their potential to solubilise poorly soluble drugs
and improve their bioavailability, with or without the use of a specific temperature.
These systems involve natural or synthetic oils and surfactants, alone or combined,
and are divided into four classes: type I, oil solutions; type II, self-emulsifying
drug delivery systems; type III, microemulsifying/nanoemulsifying drug delivery
systems; and type IV, blends with a higher proportion of hydrophilic surfactants and
cosolvents, and a lower proportion of oils (Pouton
Only a few reports are available in the literature regarding the use of lipid-based
SSE feedstocks in the development of formulations for oral (Vithani et al.
Lafeber et al.
Seoane-Viaño et al.
feasibility of achieving an adequate viscosity of feedstocks using blends of lipid
excipients such as Gelucire
2021; Johannesson et al. 2021) and rectal (Seoane-Viaño et al. 2020;
2021b) administration. Overall, these studies demonstrate the
®
(PEG 32 mono and diesters of stearic and palmitic
acid), coconut and soybean oils, and Kolliphor
propylene oxide), among others. The blends reported were able to improve the
solubility of poorly soluble drugs and resulted in different drug release profiles from
pharmaceutical dosage forms.
2000; Vithani et al. 2019b).
2019a;
®
(copolymer of ethylene oxide and
5.3 Printing Ink Properties
The development of feedstocks with suitable properties for SSE 3D printing can
be considered challenging. As previously discussed, excipients of different natures
can be used to obtain printable semi-solids as printing inks for a SSE 3D printing
process. However, the unique properties given by the intrinsic characteristics of the
excipients used to formulate the feedstock materials, as much as their blends and
the different printer setups available on the market, make it difficult to establish
the properties required by a formulation for its optimal 3D printing performance.
Many efforts have been made to find the optimal properties of gels and pastes so
that they perform well during the 3D printing process, but a final conclusion and
understanding have yet to be established.
Up to now, rheological evaluation and texture analysis are the most discussed
characterisation tests in this sense, providing information that can help researchers
to predict the behaviour of semi-solid formulations during and after the printing
process. In addition, they can supply data such as minimum strength to initiate
flow, viscoelastic behaviour, shape recovery, gelation kinetics of thermosensitive
hydrogels, extrudability and cohesiveness, among others (Rahimnejad et al.
Zidan et al.
2019).
The viscosity of the printing inks has a direct impact on the resolution of the
printed object. The flow of the material is more difficult to control in less viscous
formulations, often presenting variations between the physical properties designed
2021;
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in the printer software and the real properties of the 3D printed structure, such as
filament width, infill percentage and geometry. Moreover, the lack of consistency
hampers the printing of a first strong solid layer to support the subsequent layers,
reducing the resolution of the printed product. On the contrary, formulations that are
too viscous may result in nozzle clogging or non-homogeneous extrusion, which
influences the properties of the object and the 3D printing reproducibility. In this
case, the deposition of subsequent layers will be more difficult due to the presence
of holes in the structure. Additionally, both circumstances will have a direct impact
on the drug content and drug release from the 3D printed dosage forms (Rahimnejad
et al.
2021; Decante et al. 2021).
In general, SSE formulations exhibit non-Newtonian flow behaviour and a shearthinning characteristic, meaning that a decrease in viscosity is observed with
increased stress (Mohammed et al.
2021). Moreover, viscoelastic feedstocks are
preferred as they present a balance between an uncontrolled flow (due to a lower
viscous modulus, G) and the need for a high force to initiate flow (higher elastic
modulus, G
), which indicates formulations with a clogging tendency (Zidan et al.
2019). Ideally, the elasticity (G) takes over during rest or low stress, and a higher
G is observed with increasing stress (Fig.
5.2). This crossover point of elastic and
viscous moduli reveals the yield point where the fluid starts to flow and behave
Fig. 5.2 Elastic modulus (G) and viscous modulus (G) variation during extrusion process. After
a force is applied to the syringe, polymer chains align facilitating flow (G >G
before and after printing, elasticity takes over (G <G
) to guarantee structure maintenance
). During rest,
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 183
more like a liquid. Once the stress is stopped and the formulation is deposited at
the printer table, the viscosity is expected to return as close to the original values
as possible (thixotropy), in order to guarantee structure maintenance during layer
deposition, and printing accuracy (Mohammed et al.
2021).
Mechanical evaluation has also been an important characterisation tool to
evaluate the semi-solid properties of the printing ink. The texture analyser (TA)
is a versatile piece of equipment that allows the use of different probes to mimic
diverse process conditions, through extrusion, compression, adhesion, and tensile
tests, for example. Regarding the 3D printing of pharmaceuticals, the TA can
be applied to measure the consistency, hardness, springiness, cohesiveness and
extrudability of feedstocks. These properties can report information about the
force needed to extrudate a gel through the printing nozzle (extrudability); shape
recovery after extrusion (hardness, resilience); the extrudate swelling phenomenon
of feedstocks after extrusion through the nozzle (springiness), which impacts on
printing accuracy; and the adhesive force between the inner particles of semi-solids
(cohesiveness), and between the semi-solid and the syringe wall (adhesiveness);
among others (Anukiruthika et al.
2020).
Despite the important contributions of the TA (Schmidt et al. 2022; de Oliveira et
2022; Zidan et al. 2019), this characterisation technique has been little explored
al.
in the SSE of pharmaceuticals so far, with most efforts being in the field of food
development. In addition to formulation development, there is also the potential to
explore the TA in the characterisation of the final printed dosage form, regarding
properties such as elasticity, hardness, adhesion to skin or mucosae, gumminess
(which correlates hardness and cohesiveness) and chewiness (related to elastic
resistance) (Stable Microsystems
2022).
To enhance the rheological and textural properties of feedstocks, studies have
explored the use of polymer blends and their particular characteristics, such as
their stimuli-responsiveness. The use of thermosensitive pastes can be a strategy
to improve the printability of semi-solids, as some SSE printers provide the option
of adjusting the temperature (5
◦
Cto40◦C, for example) in the printer head and
table. In this way, it is possible to adjust the flowability of a paste by controlling
the temperature in the printer head, while changes in the table temperature can
guarantee structure maintenance due to a faster recovery in the viscosity (Yang et
al.
2020; Rahimnejad et al. 2022).
Although some semi-solids present a suitable consistency for printing, a postprinting treatment can be required to assure structure rigidity. Therefore, the use
of chemical crosslinkers have been described, especially in bioprinting. In this procedure, the feedstock can either be printed inside a crosslinking solution, immersed
after being printed or photocrosslinked. However, this step can be challenging in the
development of drug delivery systems, as drug release may occur once the matrix
is immersed in an aqueous medium. Also, the photocrosslinking of polymers may
form toxic subproducts, whereas the use of a UV source can degrade the drug,
reducing the efficacy of the treatment or forming toxic degradation products.
As a post-process step is usually required to obtain the final product, other
treatments can be used to avoid the risk of degradation of the raw materials or
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drugs. Drying processes have been used to guarantee evaporation of the solvent
present in the gel or paste (printing ink). Generally, the printed material is submitted
to drying for 24 h (Sjöholm and Sandler
2019) to 48 h (Schmidt et al. 2022) at room
temperature, until a constant weight is reached. However, higher temperatures have
been also used in this post-treatment step (Khaled et al.
and a vacuum dryer has even been used (El Aita et al.
2018; Karavasili et al. 2022)
2019; Zidan et al. 2019). The
drying time can vary, depending on the material used, and this process can also
interfere with the product’s final shape, leading to shrinking or deformation due
to solvent loss (El Aita et al.
2019; Seoane-Viaño et al. 2021a). Moreover, higher
temperatures can form bubbles, colour changes and uneven and fragile dosage forms
(Sjöholm et al.
2020; Falcone et al. 2021).
As discussed above, broad possibilities are given by the use of different characterisation techniques to evaluate the properties of feedstocks and shorten the path
to reach a printable semi-solid profile. However, along with the optimisation of the
printing ink properties, there are other critical parameters related to the mechanical
printing process that can directly affect the success and accuracy of the printed
products, as will be discussed next.
5.4 Critical Parameters of the Printing Process
SSE involves the printing of a semi-solid material, which is added to a syringe and
extruded through a nozzle, forming a filament that is deposited on the printer table,
layer-by-layer, until the dosage form is complete, as explained previously. However,
this process is not always as easy as it seems, and different process parameters can
affect the properties and behaviour of the object, or more specifically, of the 3D
printed dosage form.
Initially, a 3D model is created using computer-aided design (CAD) software and
converted into a .stl file, which is imported into slicing software. At this point, the
3D model will be sliced into layers, and all the printing parameters, such as infill
density and pattern; shape and size; printing speed; layer height; number of layers
and all the commands that the printer will perform, are generated through a G-code
file that is finally imported to the printer software.
It is important to understand how these software work because some may not
allow changes to the printing route when there is more than one dosage form
being printed at the same time, which may affect the weight distribution (Lafeber
et al.
2021). This limitation happens because the printer head may pass over the
structure being printing, deforming it or even depositing extra material on its
structure, leading to mass variation and lower reproducibility. These variations are
not appropriate for drug delivery, as they can result in drug content variation per
dosage form. Therefore, it is important to know how changes to the 3D model and
3D printing process parameters may benefit the properties of the final dosage form,
according to the original design.
These software provide different types of infill patterns of the printed object,
such as rectilinear (Sjöholm et al.
2020), grids (Hollander et al. 2018; O’Reilly
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 185
et al. 2021) and concentric (Li et al. 2019; Falcone et al. 2022), among others.
The ideal infill pattern is the one that most resembles the structure to be printed,
which will guarantee a good structuring of the dosage form. The infill density
can also be modified from 0 to 100%. The infill pattern usually interferes with
the dissolution and disintegration time (Cui et al.
2019; El Aita et al. 2020). At
a lower infill percentage, the dosage form will be leakier, which may generate a
faster disintegration and dissolution time (Panraksa et al.
2022), while a higher
infill percentage may delay this time. The number of layers, the external geometry
(Khaled et al.
2018) and the excipients added to the feedstock material can also
interfere with the disintegration and dissolution time. In addition, it should be
highlighted that the infill percentage also has an influence on the drug content of
the dosage form: the lower the infill percentage, the lower the drug content of the
3D printed dosage form.
Once the 3D model and the printing parameters are settled, the next step is to
choose the right nozzle diameter for the material to be printed, as this can affect
the size and shape of the extruded filament and the printing accuracy (Gibson
et al.
2015; Gilliespie et al. 2020; Bom et al. 2022). Nozzles with a high inner
diameter, short length and conical shape (instead of a cylindrical shape) increase
the extrudability of semi-solid inks (Cai et al. 2020), whereas those with a lower
inner diameter provide a higher resolution of the printed object (Seoane-Viaño et al.
2021a).
However, the smaller the inner diameter of the nozzle, the greater the chances of
partial or full nozzle clogging. Partial nozzle clogging can lead to material dragging
and the deposition of a smaller amount of material, leading to a failure in printing
accuracy and reproducibility. Meanwhile, full nozzle clogging delays the printing
process because it requires the nozzle to be cleaned, leading to material loss and the
whole process needing to be restarted (Bom et al.
2022).
The distance between the nozzle and the printer table can also interfere with the
behaviour of the printing process. Some printer software execute this calibration
automatically, while others require manual calibration, using the axes (X, Y and
Z) of the printer software to adjust this distance. The ideal distance is the one
where the filament can be easily extruded without deformation, providing a uniform
deposition on the printer table. If this distance is too close, the flow may be partially
or completely interrupted, resulting in a low printing accuracy. Meanwhile, if the
distance is too far, the filament will not be able to deposit correctly on the printer
table or could even get stuck in the nozzle tip, forming an agglomerate that can settle
or be dragged over the printer table (Firth et al.
2018).
Another critical parameter of the printing process is the travel speed of the
printing head. A high travel speed may result in inconsistent deposition of the
extruded material, whereas a slow travel speed may lead to a higher deposition
of material than expected at the same printing position. The ideal speed should
be optimised and is reached when the filament has enough time to adhere to the
printing table with no failure or inconsistent deposition (Seoane-Viaño et al.
2021a).
Regarding the printing pressure, the flow adjustment is carried out manually in some
printers, which is not suitable since the pressure can vary significantly if no specific
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pressure value is used. Ideally, the printing pressure should be set on the printer’s
software, to assure the same flow and working pressure for all samples.
With all these process parameters optimised and set, the 3D printing of the
pharmaceutical dosage form can begin. Ideally, the first printed layer should have
no failure of filament deposition and no other imperfections, as it needs to be well
structured to receive the subsequent layers, otherwise these subsequent layers may
not deposit properly, causing deformation of the dosage form structure.
Therefore, considering the most common problems discussed above, after the
development of a printing ink with suitable rheological properties, optimisation of
the printing process parameters is necessary, including choosing a nozzle with an
adequate size to allow the filament to be properly extruded, adjusting the printing
speed to ensure correct deposition of the filament and selecting an adequate distance
from the printing table. The adjustment of all these parameters, among others
discussed in this section, will ensure the deposition of a homogeneous first printing
layer, which is essential to host the following layers and thus develop homogeneous
pharmaceutical dosage forms according to the originally designed properties and
performance.
5.5 Applications of Semi-Solid Extrusion (SSE)
in Pharmaceutics
In recent years, SSE has been gaining visibility as an innovative approach for
the development of pharmaceuticals. Applications of SSE 3D printing in the
development of human and veterinary medicines have raised their manufacture to
a customised level, making their translation into the clinic a real possibility (Fig.
5.3). One of the great advantages of this technique is the possibility of applying it
to the manufacture of different dosage forms, to be administered by different routes,
whose drug dose and drug release profile can be adjusted (Rahman and Quodbach
2021). In this section, the applications of SSE in the development and manufacture
of medicines will be presented, including studies exploring dosage forms intended
for oral administration, which is most reported for SSE, as well as topical and rectal
routes.
The first application of SSE in the manufacture of drug dosage forms was in
2014, when Khaled and colleagues produced bilayer tablets containing guaifenesin
for oral administration. The first layer was composed of HPMC 2910, providing
an immediate drug release, whereas the second layer was composed of HPMC
2208, affording a sustained release profile to the tablet. The printed forms showed
mechanical and physical properties within the acceptable range, as defined by the
United States Pharmacopeia (USP) (Khaled et al.
2014). This study opened new
horizons in the development of customised medicines using SSE 3D printing.
In the following years, novel studies were carried out to demonstrate the
application of SSE in the development of oral dosage forms, whose manufacture
increased in complexity. SSE was used to produce complex polypills, where several
drugs could be printed in a single dosage form (Firth et al.
2018). Khaled et al.
5 Semi-Solid Extrusion (SSE) in Pharmaceuticals 187
Fig. 5.3 Semi-solid extrusion technique in the pharmaceutical development of human and
animal treatments, the main drug therapeutic classes employed and other applications. *ODS
Orodispersible
(2015b) employed SSE to produce a polypill for the controlled release of captopril,
nifedipine and glipizide (Fig.
5.4a). HMPC was used as the hydrophilic polymeric
matrix, and captopril was incorporated at a porous osmotic compartment at the
bottom of the tablet, while nifedipine and glipizide were individually placed inside
an upper open compartment that allowed the sustained diffusion of the drugs. The
authors demonstrated the feasibility of producing a tablet containing three drugs,
located in separated compartments to avoid incompatibility issues and with different
and defined release mechanisms (Khaled et al.
2015b).
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Fig. 5.4 (a) Polypill containing captopril in the bottom compartment, and nifedipine (hole I)
and glipizide (hole II) individually located in the sustained release compartments (Khaled et al.
2015b); (b) Gastric-floating clarithromycin delivery system (Chen et al. 2021); (c) Chocolate-
based formulations containing paracetamol and ibuprofen (Karavasili et al.
paediatric gummy formulations (Herrada-Manchón et al.
2020); (e) Oral mucoadhesive film
2020); (d) Ranitidine
containing triamcinolone acetonide-loaded mesoporous silica particles (Schmidt et al.
Tacrolimus suppositories (Seoane-Viaño et al.
(Sjöholm et al.
2022); (h) Redispersible 3D printed tablet containing resveratrol and curcumin co-
encapsulated in organic nanocarriers (de Oliveira et al.
2021b); (g) Gabapentin ChewTs for veterinary use
2022). All the figures are reproduced with
permission from Copyright Elsevier (please see the Acknowledgements section for details)
2022); (f)
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