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146 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
differences in the design, mechanical attributes, quality, reproducibility, and overall finish
of 3D-printed hydrogels. To reduce end-product variability in quality, a quality-by-design
(QbD) approach is needed to optimise quality control through understanding the critical
material attributes (CMAs), critical process parameters (CPPs), as well as in-process and
finished product testing parameters for assuring quality consistency [46].
7.6.3 Limitations and Future Direction
The main limitations in 3D printing of hydrogels are the low printing speeds and low print-
ing resolution to facilitate the on-demand printing of complex biomimetic tissues and
devices for clinical applications. The current hydrogel-based 3D-bioprinting systems can-
not fully replicate the finer architectures, complexities, and functionalities of natural tis-
sues and organs [47]. The low printing speed will lead to time constraints in fabricating
products of complex designs, refined finishes, and high reproducibility [44, 45, 48].
Printing technology capable of printing with multiple compositions of hydrogel inks and
bioinks will advance 3D-printed tissue engineering applications. The growing emergence
of bioprinting companies indicates positive prospects for newer and improved printing
technologies for biomaterials, hydrogel inks, and pharmaceutical active ingredients. The
use of multiple materials within a single construct will improve the biomimetic properties
and range of functionalities of 3D-printed structures [47]. To achieve the clinical transla-
tion of hydrogel-based 3D printing, proper technological setups, training of personnel to
identify product defects and quality, and regulations overseeing the production process is
required. To assist with in-house quality control measures, non-destructive spectroscopic
analytical methods (such as near infrared and Raman spectroscopy) could be used to con-
firm solid-state characteristics, composition, and drug distribution of 3D-printed hydro-
gels, whereas textural analysis could ensure appropriate mechanical properties, before
dispensing the product to the patient [11, 45].
7.7 Conclusions
The combination of selecting a hydrogel printing technique, the design of hydrogel inks and
bioinks, and the process of crosslinking determines the success of printing viable 3D hydro-
gel constructs for tissue engineering applications, wound healing dressings, and pharmaceu-
tical dosage forms. An important aspect for achieving high printability is proper filament
formation for the precise deposition of hydrogel ink and the production of defined structures
of excellent shape fidelity. Printability is largely dependent on the composition and rheolog-
ical properties of the hydrogel ink to improve its compatibility and cell processing abilities
with the currently available array of 3D-printing techniques and equipment. This chapter
overviewed the various printing techniques and the factors affecting printability of hydrogel
inks and outlined the main limitations to scale-up manufacturing and clinical translation.
Large-scale manufacture of 3D-printed hydrogels may not be possible yet, but the prospect
of small-scale on-demand 3D printing of hydrogels for customised wound dressings and
paediatric-friendly or geriatric-friendly dosage forms is likely. To fully exploit the potential
of this unique fabrication technique, regulations and guidelines need be devised to oversee
product quality, safety, and efficacy of 3D printing in clinical practice. In addition, regula-
tory agencies need to be prepared in terms of understanding the technological details and
pathways for product review and approval for commercialisation [46].
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3D Printing of Hydrogels 147
Copyright © 2019 Tamay, Dursun Usal, Alagoz, Yucel, Hasirci, and Hasirci. This is an
open-access article distributed under the terms of the CreativeCommonsAttributionLice
ns e (CCBY). The use, distribution or reproduction in other forums is permitted, provided
the original author(s) and the copyright owner(s) are credited and that the original publica-
tion in this journal is cited, in accordance with accepted academic practice. No use, distri-
bution or reproduction is permitted which does not comply with these terms.
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3D Printing of Hydrogels 149
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3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside, First Edition.
Edited by Dimitrios A. Lamprou, Dennis Douroumis and Sheng Qi.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
8
Analytical Characterisation of
3D-Printed Medicines
Ana Luiza Lima
1
, Lívia L. Sá-Barreto
2
and Marcilio Cunha-Filho
1
1
Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences,
University of Brasilia, Bras
ília, Brazil
2
Faculty of Ceilandia, University of Brasilia (UnB), Brasília, Brazil
8.1 Introduction
Since the industrial revolution of the eighteenth century, no technological advance has
caused as much anticipation in the pharmaceutical sector as the use of additive manufactur-
ing to produce medicines. At the time, the jump in the production scale resulted in unex-
pected stability problems and quality deviations that could only be overcome with
sophisticated analytical instrumentation that notably emerged in the 1950s, based on spec-
troscopy and chromatography [1].
In less than a decade, additive manufacturing, also called 3D printing, has demonstrated
that it can revolutionise the pharmaceutical segment by producing personalised medicines
for various delivery routes with different drug dosages and release characteristics, in addi-
tion to benefits in cost and easy operation [2, 3]. In particular, such technology makes it
possible to unlimitedly expand the existing types of dosage forms, which were constrained
by the limitations of conventional industrial production [4]. However, for this prediction to
be fulfilled and the full potential of 3D technology to be properly exploited, it is necessary,
once again, to resort to cutting-edge analytical techniques that can guarantee the quality
parameters expected for a pharmaceutical product.
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152 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
In this innovative scenario, it is crucial to consider that additive manufacturing encom-
passes a wide variety of technologies in which new materials and processing conditions,
including stress sources, such as high temperature, light, and shear [5], challenge the
pharmaceutical quality standards in place. According to the American Society for Testing
and Materials (ASTM), the most promising techniques for pharmaceuticals are listed in
Figure8.1, along with the most common materials and the processing stress source [6, 7].
Thus, to guide the development of 3D pharmaceuticals, it is important to properly oper-
ate, interpret, and apply appropriate analytical techniques considering each personalised
drug product. More than ever, the quality of pharmaceutical products made by 3D printing
needs to be built through clear analytical protocols, from the choice of materials that will
constitute the printed dosage form by preformulation studies, through in-process controls
that adequately measure the intermediate products generated from the still partial produc-
tion process, and finally, the use of analytical characterisations adapted to the final products
that can be of an unimaginable number [8–10]. Figure 8.2 illustrates the characterisation
strategy required for the design and production of 3D pharmaceuticals.
Hence, in the current stage of still preliminary development of 3D printing of pharma-
ceuticals, one of the main challenges is to ingeniously combine the conventional analytical
tools used in pharmaceutical production with the instrumentation typically used in
Figure 8.1 3D-printing categories and the respective technologies most used to develop
pharmaceuticals, along with the most explored materials and the processing stress source.
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Analytical Characterisation of 3D-Printed Medicines 153
evaluating 3D objects in different areas. Notably, the developers should keep in mind the
necessary adaptation to the printing technology and the drug product to be developed.
8.2 Preformulation
Preformulation studies are the first stage for pharmaceuticals development. At this phase,
an in-depth evaluation of the drug–excipient interactions is performed to assess their com-
patibility and feasibility [11]. An adequate choice of formulation components at this early
stage can be decisive in obtaining a drug product that meets the expected performance and
health agencies’ requirements. For this, instrumentation capable of measuring the physical-
chemical aspects of the samples must be used. Especially in the case of 3D products,
analytical techniques sensitive to changes in certain physical properties can provide
valuable insights into the miscibility of materials and even their printability.
8.2.1 Thermal Analysis
Thermal analysis includes several techniques in which an analytical signal is measured as
a function of a controlled temperature programme. According to the thermal events
observed, it is possible to monitor physico-chemical interactions and potential instabilities
between drug and excipients, which will guide formulations’ components screening [12].
The most common analytical instrumentation responsible for thermal analysis in a pre-
formulation protocol includes differential scanning calorimetry (DSC), differential thermal
analysis (DTA), and thermogravimetric analysis (TGA) [13, 14]. DSC and DTA are based
on the measurement of the samples’ heat flow and can identify physical transitions such as
melting, crystallisation, and glass transition (Figure 8.3A). Such analyses are of particular
interest for materials used in 3D printing, in most cases, polymers and resins used to form
the 3D matrix [15].
The DSC allows more accurate measurements than DTA, as it works with independent
heating systems between the test sample and the reference [16, 17]. The greater precision
of this instrument can be particularly decisive in the evaluation of drug–polymer interac-
tions in 3D-printed systems. In fact, depending on the printing conditions and the propor-
tion of the components, subliminal variations in the glass transition perceived by the DSC
could lead to important repercussions on printability.
Moreover, the crystallinity of the drug evaluated in the presence of each excipient
obtained by the DSC can also play an important role in preformulation evaluations
Figure 8.2 Schematic illustration for designing and developing 3D pharmaceutical devices,
including the steps of preformulation, in-process control, and final product characterisation.
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154 3D Printing of Pharmaceutical and Drug Delivery Devices: Progress from Bench to Bedside
involving materials for 3D printing. Thereby, the changes observed in the drug’s melting
peak are related to some interaction degree between the components. Particularly, anticipa-
tion or decrease in the melting peak is related to its interaction with the formulation
components, which may occur due to partial or total solubilisation of the drug in the
pharmaceutical vehicle, as schematically represented in Figure 8.3B [18, 19].
Most 3D pharmaceutical products are designed with few excipients and a considerable
amount of an organic matrix; thus, monitoring drug solubilisation is essential to ensure a
final product with adequate pharmaceutical performance [20]. Additionally, in 3D tech-
niques that explore curing or high temperatures (e.g., vat photopolymerisation, material
jetting, a material extrusion), changes in polymer’s glass transition must be monitored in
polymer–drug mixtures in order to assist not only the choice of the material but also the
processing conditions.
TGA, in turn, is a technique used to assess the decomposition profile of the drug and
excipients based on accurate mass loss measurements during such deleterious events. The
decomposition profile of a compound under certain analysis conditions occurs according to
reproducible events. Consequently, changes in these weight loss patterns, which anticipate
or intensify decomposition kinetics, can suggest loss of stability and incompatibilities.
Indeed, as observed in DSC, changes in the TGA curve are associated with component
interaction. Both thermal responses can indicate some sign of incompatibility or may
Figure 8.3 Hypothetical DSC curves illustrating: (A) the possible thermal events that can be
measured in this analytical technique, such as glass transition (T
g
), a kinetic phenomenon in
which the amorphous regions change from a hard glassy state with limited molecular motion
to a flexible soft state with intense molecular motion at a given temperature region; crystallisation
temperature (T
c
), thermal zone in which heat is released from the sample and the molecular
chains have sufficient energy to form ordered arrangements and create a crystal structure;
melting temperature (T
m
), thermal zone in which heat is absorved from the sample to liquefy
the solid structure; degradation temperature (T
d
), thermal zone in which heat is used to
permanently break chemical bonds, destructuring the original molecule. (B) Some of the
responses that can be found in a preformulation test for drug–polymer mixtures, wherein
physical mixture 1 represents no change in melting peak or polymer T
g
, indicating no interaction
between components (18); physical mixture 2 exemplifies anticipation and decrease in melting
enthalpy along with the reduction in polymer T
g
, indicating a partial dispersion of the drug
(19); physical mixture 3 represents the disappearance of the melting event and the reduction
in polymer T
g
, indicating total drug solubilisation (18).
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Analytical Characterisation of 3D-Printed Medicines 155
produce unstable 3D products. The thermal simulations of such analyses are especially
realistic for 3D-printing technologies that exploit high temperatures, such as Fused deposi-
tion modelling (FDM), Stereolithography (SLA), and Digital light processing (DLP) [21,
22]. Establishing analysis programmes that can accurately simulate the particular printing
conditions can be the key to better taking advantage of these analytical tools.
Figure 8.4 shows hypothetical TGA curves and their first derivative, which enables the
visualisation of all decomposition phases. Therefore, an adequate response for a preformu-
lation study of 3D pharmaceuticals would be the alteration of the decomposition profile,
indicative of interaction but without degradation in the heat zone chosen for processing.
The chart highlights the usual temperature range for 3D printing by extrusion material
(150–250 °C) [23].
In fact, small percentages of mass loss in slow decomposition kinetics are acceptable
(physical mixture 1 and 2; Figure 8.4). As TGA promotes an accelerated degradation, a
conventional exposure to the sample’s initial decomposition temperature will not necessar-
ily compromise the material’s thermal stability, mainly in cases of slow kinetic degradation
and reduced processing time, as in 3D printing. On the other hand, interactions that lead to
intense mass loss at lower temperatures are not stable to fit the thermal energy power
source required in additive manufacturing (physical mixture 3; Figure 8.4) [10, 24].
Figure 8.4 Hypothetical TGA curves illustrating (A) possible decomposition profiles and (B)
its first derivative (DTG) showing the peaks corresponding to the different phases of drugs’
decomposition and three different physical mixtures. The shaded area indicates the highest
temperatures used in 3D printing (3DP). Physical mixture 1 represents two decomposition
phases, in which the sum of two degradation events is observed, indicating little interaction
between the components or interactions that do not affect the thermal degradation profile.
Physical mixture 2 exemplifies several decomposition steps, showing that the drug–excipient
interaction modified the materials degradation kinetics. Physical mixture 3 represents an
interaction between the components capable of drastically modifying the decomposition
profile of the materials, anticipating and accelerating their degradation.
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