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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5427_Библиотеки_им_академика_М_И_Перельмана
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2 Fused Deposition Modeling (FDM) of Pharmaceuticals 67
Fig. 2.12 Surface morphology of TPU filaments containing 0, 20 or 60% of unmilled (a) or milled
(b) methformin hydrochloride, illustrating the necessity to control drug particle size. (Reprinted
with permission from Verstraete et al.
2018)
the nozzle of the printer, especially if the clusters are larger than the nozzle
opening. This phenomenon was noted with pantoprazole sodium agglomerates in a
variety of filaments produced via ram extrusion, again emphasizing the importance
of manufacturing a properly mixed filament (Kempin et al.,
2018). Next, high
contents of a crystalline drug have also been reported to negatively impact surface
morphology, which might also induce filament feeding issues. Case studies have
been reported about drug crystals on the surface of the filament which accumulated
in the nozzle and caused degradation (Tidau et al.,
drug has been shown to (partly) overcome these issues as can be seen in Fig.
2019). Milling of the crystalline
2.12
(Verstraete et al., 2018). Lastly, the presence of crystalline API in a semi-crystalline
polymer might affect the crystallization kinetics of the polymer, resulting in an
altered solidification behaviour and a different visual quality of the dosage form.
For example, Samaro et al. (
2020) found the presence of metoprolol tartrate in
polycaprolactone accelerated solidification, improving the quality of the resulting
tablet (Samaro et al.,
2020).
An API might also act as a plasticizer by improving the flexibility of the
polymer chains, hence decreasing the glass transition or/and melt temperature and
viscosity profile of the melt. For example, Elbadawi et al. (
2020) discovered that
ciprofloxacine reduced the complete viscosity-over-shear profile of polycaprolactone (Elbadawi et al.,
lowered the viscosity of polyvinyl alcohol (Gottschalk et al.,
(
2018) identified enalapril maleate as a plasticizer for Eudragit EPO (Sadia et al.,
2020), Gottschalk et al. (2022) showed that ketoconazole
2022), Sadia et al.
2018) and Henry et al. (2021a) showed the melt point depression of ibuprofen on
polycaprolactone as illustrated in Fig.
2.13 (Henry et al., 2021a).
68 S. Henry et al.
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Fig. 2.13 Plasticizing effect of ibuprofen as illustrated by melting point depression of polycaprolactone. (Reprinted with permission from Henry et al.
2021a)
2.3.3 Processing Aids
Processing aids are excipients added to the polymer–drug formulation to i mprove
printability. Different classes can be distinguished: plasticizers, dissolution modifiers, inert fillers and specialty excipients.
2.3.3.1 Plasticizer
Plasticizers are a class of materials increasing the free volume and mobility of the
polymer chains, which is noted by a decrease of the glass transition temperature
(Tg). As a result, extrusion can be performed at lower temperatures which might
be beneficial to avoid degradation of the API (Parulski et al.,
2021). Moreover,
plasticizers will also influence the mechanical properties of the filament and
have been reported to increase the elasticity (Oladeji et al.,
2022). Hence the
concentration of plasticizer should be optimized to avoid hyper flexibility and
feeding issues of the filament. Unfortunately, plasticizers have been associated with
a lower stability of the end-product as described by for example Kempin et al. (
2018)
who noticed filament deformations when storing polyvinyl pyrrolidone filaments
containing higher plasticizer fractions (20% triethyl citrate) (Kempin et al.,
Wei et al. (
of the drug in polyvinyl alcohol filaments (Wei et al.,
2020) noticed that the presence of sorbitol initiated rapid r ecrystallization
2020).
2018).
A variety of plasticizers have been investigated and successfully applied like
glycerin (Lima et al.,
2022), PEG (Oladeji et al., 2022), triethylcitrate (Kempin
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 69
et al., 2018; Zhao et al., 2022; Sadia et al., 2018), dibutyl sebacate (Oladeji et al.,
2022), sorbitol (Wei et al., 2020), stearic acid (Giri et al., 2020), d-alpha tocopherol
PEG 1000 succinate (Ilyés et al.,
Windolf et al.,
2022). Water was investigated as a temporary plasticizer, successfully
2019) and mannitol (Kollamaram et al., 2018;
enabling extrusion of polyvinyl alcohol at lower temperatures. A drawback of this
approach is however the potential for hydrolytic degradation (Pereira et al.,
2019).
2.3.3.2 Dissolution Modifier
Immediate release formulations are obtained by the addition of disintegrants, which
accelerate the disintegration process of the 3D-printed tablet by means of swelling
and consequent wicking of the liquid into the tablet. Common disintegrants that
have been successfully tested in FMD 3D-printing are starch (Ehtezazi et al.,
sodium starch glycolate (Than and Titapiwatanakun,
microcrystalline cellulose (Than et al.,
low substituted HPC (Than et al.,
2022), crospovidone (Than et al., 2022),
2022) and croscarmellose sodium (Than et al.,
2021; Ehtezazi et al., 2018),
2018),
2022; Ehtezazi et al., 2018). However, the addition of these disintegrants did not
always effectively accelerate the dissolution process (Henry et al.,
2018).
et al.,
2021b; Sadia
Other materials might be added to create channels within the matrix upon
dissolution, hence altering the drug diffusion rate. Examples are PEG (Elbadawi
et al.,
2020), chitosan (Yang et al., 2022) or mannitol (Omari et al., 2022). It
must be noted that some constituents might serve both as a plasticizer and as a
pore former in a certain formulation. This dual action of for example mannitol
has been exploited by Kollamaram et al. (
simultaneously increasing the release rate of ramipril (Kollamaram et al.,
2018) by plasticizing povidone while
2018).
The addition of surfactants to improve wettability was also successfully tested.
For example, sodium lauryl sulfate accelerated the dissolution kinetics of paracetamol (Ehtezazi et al.,
2018) and Tween 80 enhanced the hydrophilicity of printed
vaginal rings, hence enabling controlled progesterone release as can be seen in
2.14 (Fu et al., 2018).
Fig.
2.3.3.3 Inert Filler
Inert fillers have been added to formulations for either flow stabilization or feedability optimization. In terms of flow stabilization, the addition of fillers was reported to
decrease die swell (Barnes,
2003), although discrepancies were reported in terms of
filler type. Lamellar particles like talc were reported to generate flow stabilization,
while glass beads and fibers were reported to generate flow instabilities (Baldi et al.,
2014). Talc for example has been reported to decrease layer deformation of the
printed object as can be seen in Fig.
solidification (Okwuosa et al.,
consistent melt flow (Sadia et al.,
2.15 (Oladeji et al., 2022) and enable rapid
2016), while tribasic calcium phosphate allowed
2016, 2018). In terms of feedability optimization,
the addition of fillers increased the stiffness of extruded filaments. Oladeji et al.
(
2022) have added talc to a formulation containing HPMCAS to enable feeding. It
must be noted that the dynamic viscosity of polymeric systems in combination with
a filler was generally higher, which could influence processing temperature (Than
et al.,
2022).
70 S. Henry et al.
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Fig. 2.14 Effect of adding a wetting agent (Tween 80) and a pore-former (PEG) on the
dissolution profile of progesterone-loaded 3D-printed vaginal rings consisting of a poly(lactic
acid)/polycaprolactone mixture (8:2). (Reprinted with permission from Fu et al.
2018)
Fig. 2.15 Surface morphology analysis using SEM images. Addition of talc (F5) to HPMCAS
decreased layer deformation, even at higher plasticizer (PEG) concentration. (Reprinted with
permission from Oladeji et al.
2022)
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 71
2.3.3.4 Glidant
Glidants might be added to facilitate the hot-melt extrusion process of poorly
flowing powders. Examples are fumed silica (Windolf et al.,
stearate (Ayyoubi et al., 2021).
2022) or magnesium
2.3.3.5 Specialty Excipient
The addition of lubricating liquids with a high boiling point like castor oil or oleic
acid was effective to prevent filament from sticking to the nozzle wall. The lubricant
was not incorporated into the filament itself but was added by passage through a
lubricating station (Okwuosa et al.,
Certain substituents might be added in very specific cases to enhance the stability
of the drug in the dosage form. The addition of magnesium carbonate, for example,
provided an alkaline environment to avoid degradation and stabilize ACE inhibitors
(Kollamaram et al.,
ensure UV protection (Pereira et al.,
2018). Titanium dioxide can be added to the formulation to
2017).
2019).
2.4 Characterization Techniques
The printed pharmaceutical dosage forms are often investigated using traditional
characterization techniques for oral pharmaceutical dosage forms as mentioned in
the relevant monographs of the pharmacopoeia: friability (Nukala et al., 2019b,a),
diametral hardness tests (Zhang et al.,
time (Omari et al.,
testing (Kempin et al.,
weight variability, dimension analysis (Henry et al.,
and drug content (Giri et al.,
et al.,
2022). However, printed dosage forms differ from traditional, compacted
ones due to the inherent layer-by-layer production technique. Hence additional,
innovative characterization techniques e.g. hardness, topography or solid state might
be appropriate and have been developed.
2022; Ehtezazi et al., 2018; Nukala et al., 2019a), dissolution
2018; Giri et al., 2020; Wei et al., 2020), weight and
2020; Palekar et al., 2022; Wei et al., 2020; Zhao
2019; Henry et al., 2021c), disintegration
2021b,c; Zhao et al., 2022)
2.4.1 Mechanical Resilience
In terms of mechanical resilience of the dosage form, it must be stated that FDM
3D-printed products always display directional anisotropy due to the layer-bylayer printing mechanism (Henry et al.,
manufactured via conventional direct compression mainly depends on the applied
pressure, the hardness of FDM 3D-printed tablets is more dependent on material
properties of the carrier, designed tablet structure and printing method (Zhao et al.,
2022). As a result, an in-depth mechanical analysis of the constructed dosage
form is more informative. Tests described in the literature include for example
vertical hardness testing (Henry et al.,
testing (Henry et al.,
2021c) or the Brazilian test (Tidau et al., 2019). Figure 2.16
2021c). While the hardness of tablets
2021c; Zhao et al., 2022), Brinell hardness
72 S. Henry et al.
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Fig. 2.16 Application of different mechanical tests (Brinell, diametral and vertical strengths) on a
variety of FDM 3D-printed dosage forms. The horizontal line at 1.7 MPa represents the industrial
standard for minimal tensile strength. (Reprinted with permission under the open access CC BY
4.0 license from Henry et al.
2021c)
represents a comparison of different mechanical tests executed on printed tablets.
Specific mechanical tests might be relevant for other dosage forms like suture
retention tests for cardiovascular prostheses (Domínguez-Robles et al.,
folding endurance tests for skin patches (Chaudhari et al.,
(Eleftheriadis et al.,
2020) (Fig. 2.17).
2021) or buccal films
2.4.2 Topography
The surface of produced dosage forms is often rougher than traditional compacts
since the product is constructed freestanding. The resulting morphology might
thus present an interesting quality attribute. Techniques like scanning electron
microscopy (Giri et al.,
microscopy (Domínguez-Robles et al.,
of the topography. Figure
printed tubular grafts analysed through SEM. A higher drug loading was associated
with a rougher surface (Domínguez-Robles et al.,
2020; Ehtezazi et al., 2018) or 3D-surface metrology
2022) might enable detailed visualization
2.18 represents a series of cross-sections and surfaces of
2022).
2022) and
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 73
Fig. 2.17 SEM images of the surface and cross-section of 3D-printed TPU-based tubular grafts
with different concentrations of dipyridamole (DIP). Higher concentrations of DIP are associated
with rougher surfaces. (Reprinted with permission under the open access CC BY 4.0 license from
Domínguez-Robles et al.
2022)
Fig. 2.18 Pore structure analysis of 3D-printed dosage forms from PLA (a–c)orPVA(d–f)
utilizing X
and f represent a y-z cross-section of the structure. (Reprinted with permission under the open
access CC BY 4.0 license from Markl et al.
. μCT. Subfigures b and e represent the pore length distribution (color map), while c
2017)
2.4.3 Solid State and Degradation
FDM 3D-printing is a thermal technique which might influence the solid state of the
API or initiate degradation. Solid state analysis using crystallinity assessment based
on for example wide angle X-ray diffraction (XRD) (Ilyés et al.,
2019; Ehtezazi
74 S. Henry et al.
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et al., 2018), infrared spectroscopy (Ehtezazi et al., 2018) or nuclear magnetic
resonance (Kollamaram et al.,
methods like differential scanning calorimetry (Giri et al.,
or thermogravimetric analysis (Eleftheriadis et al.,
2018) might be interesting. Thermo-analytical
2020; Ilyés et al., 2019)
2020; Domínguez-Robles et al.,
2022) can also help to investigate crystallinity, polymorphism, interactions between
drug and polymer and susceptibility towards degradation.
API degradation through FDM 3D-printing could be investigated by characterization of the degradation pathways and resulting degradants utilizing high-pressure
liquid chromatography (Ilyés et al.,
2019) or mass spectroscopy (Ehtezazi et al.,
2018).
2.4.4 Stability
Intermolecular bonds and interactions between constituents of the 3D-printed end
product might indicate altered stability of the dosage form or dissolution of the drug
within the polymeric carrier. Information of these bonds can be retrieved utilizing
for example Fourier transform infrared spectroscopy (FT-IR) (Zhao et al.,
Omari et al.,
example Karl Fischer titration (Henry et al.,
(Cerda et al.,
2022). The tendency for moisture absorption (determined via for
2021b) or dynamic vapour sorption
2020)) can also be critical to evaluate the stability of the printed
product.
2022;
2.4.5 Porosity
The microstructure or pore architecture of a dosage form often drives its performance in terms of dissolution kinetics or mechanical resilience (Markl et al.,
2018).
In terms of microstructure, FDM 3D-printing is a unique production technique
as it enables the design of a tablets’ microstructure almost independent from its
outer dimensions (Henry et al.,
2021c). Porosity determination and pore structure
characterization hence become a vital quality characteristic of printed dosage forms.
The most widely used technique to characterize total porosity is helium pycnometry
(Henry et al.,
tigating pore structure include terahertz pulsed imaging (Markl et al.,
. μCT (Markl et al., 2017; Sadia et al., 2018).
X
2021b,c). More innovative techniques capable of additionally inves-
2017) and
2.4.6 Dissolution Behaviour
Dissolution behaviour is one of the most critical performance characteristics of
a dosage form and is influenced by the microstructure and wettability of the
dosage form. Microstructure determination of printed dosage forms has been
discussed in the previous section. Wettability can be investigated using contact angle
measurements (Joseph et al.,
2021). In-depth real-time analysis of the dissolution
2 Fused Deposition Modeling (FDM) of Pharmaceuticals 75
behaviour of printed dosage forms can be performed utilizing optical coherence
tomography (OCT) (Stewart et al.,
tomography (X
. μCT) (Gioumouxouzis et al., 2017).
2020) or time-lapsed X-ray micro-computed
2.4.7 Distribution Homogeneity
Distribution homogeneity of the drug can be investigated using for example near
infrared (NIR) chemical imaging (Samaro et al.,
et al.,
2017; Goyanes et al., 2015) or fluorescence microscopy (Kempin et al., 2017).
2021), Raman mapping (Okwuosa
Especially for multi-layered tablets, visualization of the individual, separated layers
containing different drugs could be interesting. This approach also enables solid
state analysis (Goyanes et al.,
2015).
2.4.8 Specific Requirements
Dosage forms for applications other than oral intake might require unique properties. For example, implants are often tested to ensure bio-compatibility and cell
viability (Domínguez-Robles et al.,
developed specifically for bacterial treatment need testing to ensure antimicrobial
efficacy (Domínguez-Robles et al.,
their mucoadhesive properties utilizing mechanical tests (Eleftheriadis et al.,
Skin patches need sufficient folding endurance and a pH compatible with the skin
(Chaudhari et al.,
2021). Paediatric formulations might require additional testing to
confirm taste masking of drugs (Scoutaris et al.,
The flexibility of 3D-printing could enable production of dosage forms onsite. Certain drugs might however display photosensitivity, requiring the need
for appropriate packaging to ensure stability of the drug product (Henry et al.,
2021b; Azizo˘glu and Özer, 2020). Moreover, certain drug products might require
sterilization or aseptic production prior to application for example wound dressings
(Oliveira et al.,
2021) (Fig. 2.19).
2022; Eleftheriadis et al., 2020). Dosage forms
2022). Mucoadhesive formulations are tested for
2020).
2018).
2.5 Pharmaceutical Applications
The flexibility inherent to the 3D-printing technique allows the production of a wide
variety of dosage forms targeting specific applications and containing a multitude
of drugs as can be seen in Fig.
used to construct the dosage form but could also aid in the detection of falsified
medicines by printing binary digits on the surface of printed dosage forms (Windolf
et al.,
2022). Some examples of FMD 3D-printed drug products are enlisted below.
2.19. Moreover, FDM 3D-printing can not only be
76 S. Henry et al.
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Fig. 2.19 An overview of different classes of 3D-printed dosage forms with their administration
routes. (Reprinted with permission from Gioumouxouzis et al.
2019)
2.5.1 Oral Solid Dosage Forms
Oral solid dosage forms remain the most popular treatment strategy, which is
reflected in the number of studies exploiting FDM for oral therapy (Fig.
2.5.1.1 Multi-drug Therapies
The concept of a polypill containing multiple drugs, each in their own personalized
dose, was often investigated as it could increase patient compliance. For example,
2.20).
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