Drug Delivery Trends: Volume 3:

Expectations and Realities of

Multifunctional Drug Delivery Systems
1st Edition Ranjita Shegokar (Editor)
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DRUG DELIVERY TRENDS
EXPECTATIONS AND REALITIES OF
MULTIFUNCTIONAL DRUG
DELIVERY SYSTEMS
VOLUME 3
Edited by

RANJITA SHEGOKAR, PhD

Capnomed GmbH, Zimmern, Germany
Elsevier
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 Contributors
Salvana Costa Universidade Tiradentes (UNIT),
Aracaju, Sergipe, Brazil
J. Dias-Ferreira Department of Pharmaceutical
Technology, Faculty of Pharmacy, University of
Coimbra (FFUC), P
olo das Ciências da Sa
ude,
Azinhaga de Santa Comba, Coimbra, Portugal
A.R. Fernandes Department of Pharmaceutical
Technology, Faculty of Pharmacy, University of
Coimbra (FFUC), P
olo das Ciências da Sa
ude,
Azinhaga de Santa Comba, Coimbra, Portugal
Rohit C. Ghan Aurobindo Pharmaceuticals USA
Inc., Dayton, NJ, United States
Randeep Kaur University Institute of Pharma-
ceutical Sciences, Panjab University, Chandigarh,
India
Matthias M. Knopp Department of Pharmacy,
University of Copenhagen, Copenhagen, Denmark
A. K€onigsrainer National Center for Pleura and
Peritoneum, University of T€
ubingen, T€ubingen,
Germany
Korbinian L€ obmann Department of Pharmacy,
University of Copenhagen, Copenhagen, Denmark
Conrado Marques Universidade Federal de Sergipe
(UFS), Campus Lagarto, Departamento de Medic-
ina, Sergipe, Largarto, Brazil
Muhaned Al-Hindawi OnTarget Pharma Consul-
tancy Limited, New Malden, Surrey, United
Kingdom
Luciana Nalone Universidade Tiradentes (UNIT),
Aracaju, Sergipe, Brazil; Instituto de Tecnologia e
Pesquisa (ITP), Aracaju, Sergipe, Brazil
Adam Procopio Merck & Co., Inc., Kenilworth, NJ,
United States
vii
Saeed A. Qureshi Pharmacomechanics, Ottawa,
ON, Canada
Vivek Ranjan Sinha University Institute of Pharma-
ceutical Sciences, Panjab University, Chandigarh,
India
M.A. Reymond National Center for Pleura and Peri-
toneum, University of T€
ubingen, T€
ubingen, Germany
Patrícia Severino Universidade Tiradentes (UNIT),
Aracaju, Sergipe, Brazil; Instituto de Tecnologia e
Pesquisa (ITP), Aracaju, Sergipe, Brazil
Ranjita Shegokar Capnomed GmbH, Zimmern,
Germany
A.A.M. Shimojo Department of Materials Engineer-
ing and Bioprocesses, School of Chemical Engineer-
ing, State University of Campinas (UNICAMP),
Cidade Universit
aria Zeferino Vaz e Bar~ ao
Geraldo, Campinas, S~ ao Paulo, Brazil
A.M. Silva Department of Biology and Environ-
ment, School of Life and Environmental Sciences,
University of Tr
as-os-Montes and Alto Douro,
Vila Real, Portugal; Centre for the Research and
Technology of Agro-Environmental and Biological
Sciences, University of Tr
as-os-Montes and Alto
Douro, Vila Real, Portugal
Eliana B. Souto Department of Pharmaceutical
Technology, Faculty of Pharmacy, University of
Coimbra (FFUC), P

olo das Ciências da Sa

ude, Azin-
haga de Santa Comba, Coimbra, Portugal; CEB e
Centre of Biological Engineering, University of
Minho, Campus de Gualtar, Braga, Portugal
M.C. Teixeira Department of Pharmaceutical Tech-
nology, Faculty of Pharmacy, University of Coim-
bra (FFUC), P
olo das Ciências da Sa
ude,
Azinhaga de Santa Comba, Coimbra, Portugal
viii Contributors

Divya Tewari Noramco Inc., Wilmington, DE, Akif Emre T€ €

United States
Pramil Tiwari Department of Pharmacy Practice,
National Institute of Pharmaceutical Education &
Research (NIPER), S.A.S. Nagar, Punjab, India
Nazende G€ unday T€ ureli MJR PharmJet GmbH,
€
Uberherrn, Saarland, Germany
ureli MJR PharmJet GmbH, Uberherrn,
Saarland, Germany
Danillo F.M.C. Veloso Department of Pharmacy,
University of Copenhagen, Copenhagen, Denmark
Venkat Tumuluri Novartis Healthcare Pvt. Ltd.,
Hyderbad, India
 Preface

The book series titled Expectations and
Realities of Multifunctional Drug Delivery
Systems covers several important topics on
drug-delivery systems, regulatory requirements,
clinical studies, intellectual properties trends,
new advances, manufacturing challenges, etc.
written by leading industry and academic
experts. Overall, the chapters published in this
series reflect the broadness of nanopharma-
ceuticals, microparticles, other drug carriers, and
the importance of respective quality, regulatory,
clinical, GMP scale-up, and regulatory
registration aspects.
This series is destined to fill the knowledge
gap through information sharing and with orga-
nized research compilation between diverse
areas of pharma, medicine, clinical, regulatory
practices, and academics.
Expectations and Realities of Multifunctional
Drug Delivery Systems is divided into four
volumes:
Volume 1: Nanopharmaceuticals
Volume 2: Delivery of Drugs
Volume 3: Drug Delivery Trends
Volume 4: Drug Delivery Aspects
The specific objectives of this book series
are to:
1. provide a platform to discuss opportunities
and challenges in development of nano
medicine and other drug-delivery systems;
2. discuss current and future market trends;
3. facilitate insight sharing within various areas
of expertise; and
4. establish collaborations between academic
scientists, and industrial and clinical
researchers.
Innovative cutting-edge developments in
micro-nanotechnology offer new ways of
preventing and treating diseases like cancer,
malaria, HIV/AIDS, tuberculosis, and many
more. The applications of micro-nanoparticles
in drug delivery, diagnostics, and imaging are
vast. Hence, Volume 3: Drug Delivery Trends
in the book series mainly reviews advances in
drug delivery areas via targeted therapy with
improved drug efficiency at a lower dose, trans-
portation of the drug across physiological
barriers, as well as reduced drug-related toxicity.
The contribution by Fernandes et al.
(Chapter 1) discusses new trends in drug
delivery areas via bioactive hybrid nanowires.
Nanowires offer multifunctionality and the pros-
pect of biofunctionalization, thereby reducing
toxicity and side effects. This synergistic approach
overcomes the challenges associated with conven-
tional nanomedicines and exhibits better perfor-
mance. The authors review the potential of
nanowires in this chapter.
The chapter by Procopio and Tewari (Chapter
2) highlights another industry trenddi.e., 3D
printing. This is a fascinating topic recently
adopted by industry. The Food and Drug
Administration has already approved the first
product: Spritam (levetiracetam), a 3D printed
tablet (Aprecia Pharmaceuticals). A thorough
overview of material requirements, types of

ix
x Preface
polymer, available 3D printing techniques, and
regulatory aspects is provided. Finally, the au-
thors present case studies from industry on
tunable release technology and paste gel
extrusion in tableting.
The contribution by Al-Hindawi (Chapter 3)
describes marketing authorization and licensing
of medicinal products in the European Union.
The main aim of this chapter is to provide
readers with a generalized overview of the steps
and criteria while applying licenses in the
European Union. The author also highlights
various directives, extension requests, protection
periods, and legal requirements guidance to
industry and researchers. On the other hand,
preclinical understanding is key to proposing
products for particular indications.
The chapter by Tiwari et al. (Chapter 4)
reviews preclinical considerations on micro-
and nanodrug delivery, which will lead to the
proper positioning of products for market
authorization.
The work by Ghan (Chapter 5) is aimed at dis-
cussing synergistic delivery of nanoparticles
using traditional approaches like tableting or
other forms. The author reviews various nano-
particulate treatments for oral delivery to
improve bioavailability, target specific regions
in the gastrointestinal tract, improve physiolog-
ical stability in the gut environment, and
modulate release when needed. Drug delivery
systems like solid lipid nanoparticles, polymeric
nanoparticles, nanomicelles, and nanosus-
pension are also reviewed.
The chapter by Tumuluri (Chapter 6)
highlights opportunities and challenges in
formulating minitablets. This is another trend
in oral drug delivery systems besides nano-oral
and 3D printed dosage forms. The author
describes in detail technological potential, indus-
trial advantages, technological availability, and
the limitations of minitablets.
The topic presented by Nalone et al.
(Chapter 7) describes the potential of liquid crys-
talline systems in drug delivery. This chapter
discusses in detail the mechanism of formation
of liquid crystalline systems, types of structure
formed, factors affecting formation of liquid crys-
talline systems, compositions, advantages, and
limitations of these forms of drug delivery
systems.
The chapter by Veloso et al. (Chapter 8)
reviews opportunities and challenges in amor-
phous drug stabilization using mesoporous
materials. The team of authors highlights key
points like the role of mesoporous materials,
structural characterizations of such systems,
physical forms of drug loading, and physical
performance of mesoporous particles. Mesopo-
rous particles have huge potential in pharmaceu-
ticals as a drug delivery system, in cosmetics, in
nutraceuticals, and in fast-moving consumer
goods (detergent, oral care), and is a highly
explored trend in the market.
Quality is an important aspect in regulatory
which makes sure patients receive “quality”
products. Newer trends in pharmaceuticals like
nanomedicines, drug device combinations,
nanoparticulate-based tablets, etc. require
special techniques and an understanding of
quality. The chapter by Qureshi (Chapter 9)
asks questions like “what is quality?”, “do we
evaluate quality as per a regulatory definition?”,
and “is there a need to change the definition of
quality when a product is altered?” The main
theme of this chapter is to underline basic
concepts of “quality” and discuss them with
regard to current practices. The author provides
his views on further modifications of current
testing methodologies to assure “real quality.”
The work by Reymond and K€ onigsrainer
(Chapter 10) is aimed at discussing the potential
of pressurized intraperitoneal aerosol chemo-
therapy (PIPAC). The authors review various
chemotherapeutic systems currently used
in vitro/ex vivo models and the success of
clinical trials to date. This generalized overview
of PIPAC technology provides readers with
updates from another innovative trend in
medical practice.
 Preface
The last contribution by T€ ureli and T€ ureli
(Chapter 11) describes industrial challenges of
upscaling and good manufacturing practice in
the production of pharmaceutical drug delivery
systems. The authors highlight the current regu-
latory status of approved nanomedicines and
manufacturing limitations and initiatives.
In summary, I am sure this book volume and
the complete book series will provide you great
xi
insights in areas of micro-nanomedicines, drug
delivery sciences, new trends, and regulatory
aspects.
All the efforts of experts, scientists, and au-
thors are highly acknowledged for sharing their
knowledge, ideas, and insights about the topic.
Ranjita Shegokar, PhD
Editor
 C H A P T E R

1
Bioactive hybrid nanowires: a new in
trend for site-specific drug delivery and
targeting
A.R. Fernandes1, J. Dias-Ferreira1, M.C. Teixeira1,
A.A.M. Shimojo2, Patrícia Severino3,4, A.M. Silva5,6,
Ranjita Shegokar7, Eliana B. Souto1,8
1
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P
olo
ude, Azinhaga de Santa Comba, Coimbra, Portugal; 2Department of Materials
das Ci^encias da Sa

Engineering and Bioprocesses, School of Chemical Engineering, State University of Campinas
(UNICAMP), Cidade Universit
aria Zeferino Vaz e Bar~ao Geraldo, Campinas, S~ao Paulo, Brazil;
3
Universidade Tiradentes (UNIT), Aracaju, Sergipe, Brazil; 4Instituto de Tecnologia e Pesquisa (ITP),
Aracaju, Sergipe, Brazil; 5Department of Biology and Environment, School of Life and Environmental
Sciences, University of Tr
as-os-Montes and Alto Douro, Vila Real, Portugal; 6Centre for the Research
and Technology of Agro-Environmental and Biological Sciences, University of Tr
as-os-Montes and Alto
Douro, Vila Real, Portugal; 7Capnomed GmbH, Zimmern, Germany; 8CEB e Centre of Biological
Engineering, University of Minho, Campus de Gualtar, Braga, Portugal

1. Introduction can be terminated at temperatures ranging

Hyperthermia (“hyper” and “therme”, mean-
ing “rise” and “heat”) is a therapeutic approach
to cancer treatment. Some researchers have
related that a sarcoma disappeared after a very
high fever. This finding is due to the reaction
of immune systems with bacterial infection [1].
Cancer cells are recognized as being vulnerable
to high temperatures. The growth of these cells
from 41 to 46
C or below 47
C for at least
20e60 min [2,3]. Hyperthermia is therefore
used locally to prevent disease by exposing the
whole body to high temperatures to overcome
adverse side effects and to increase treatment ef-
ficiency [4].
The introduction of magnetic nanoparticles
in cancer hyperthermia has been developed
and grown significantly during the last decade.

Drug Delivery Trends

https://doi.org/10.1016/B978-0-12-817870-6.00001-8 1 © 2020 Elsevier Inc. All rights reserved.
2 1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting
The special features of these particles are related
to their capacity to efficiently accumulate at the
tumor cells through the increased permeability
of the tumor vessels and by cancer-specific bind-
ing agents, making the treatment more selective
and effective [5]. The application of an alter-
nating magnetic field (AMF) with the introduc-
tion of magnetic nanoparticles generates local
heat in the tissues that contain these nanopar-
ticles due to magnetic relaxation and hysteresis
loss [6]. Particle characteristics such as size distri-
bution, shape, crystal structure, particle mag-
netic anisotropy and its temperature
dependence on magnetization, fluid viscosity,
amplitude and frequency of the AMF directly
affect the generation of heat, which in turn de-
pends on the absorption efficiency of the mag-
netic particles [1,7].
A significant number of magnetic nanopar-
ticles have been studied over the last few de-
cades. Examples of well-known hyperthermic
agents include iron oxide-based nanomaterials
such as magnetite (Fe3O4) and maghemite (g-
Fe2O), which continue attracting attention due
to their lack of toxicity and excellent biocompat-
ibility [8]. Ferrite nanoparticles (XFe2O4, where
X can be Co, Mn, Ni, Li, or mixes of these
metals), metallic nanoparticles, such as Mn, Co,
Ni, Zn, Gd, Mg, and their oxides, or metal alloys
(FeCo, CoPd, FePt, NiPd, NiPt, NiCu) have also
been studied as possible candidates for hyper-
thermia treatments [9e11].
There are new designs of magnetic nanomate-
rials based on a core/shell approach that have
started to gain prominence due to their versatility
to tailor properties of both core and shell and to
offer multifunctionality, such as core protection,
biofunctionalization platform, toxicity reduction,
and increase in biocompatibility. Examples of
these particles are gold- or silica-coated ferromag-
netic particles [12]. Magnetic nanoparticles also
hold great promise for drug delivery by heating
the tissues. The drug can be released using two
strategies. In the first approach, the drug mole-
cules are attached to the particles through a
linker, which breaks with the heat generated by
the presence of AMF, with the consequent release
of the drug. In the second approach, the release of
drugs takes place from a polymeric matrix with
magnetic material [5,13]. The heat created by
the magnetic field produces crevices or cracks in-
side the polymeric matrix, which releases the
encapsulated drugs [5].
Nanowires, nanowhiskers, nanofibers, nano-
tubes, and other one-dimensional nanostructures
have demonstrated huge abilities for improving
the electrical, optical, thermal, and mechanical
properties of a broad range of functional mate-
rials and composites [14]. These enhancements
substantially exceed those offered by micro- or
nanosized particles. Most of the methods used
for their synthesis are relatively expensive and
difficult to scale up [15]. The underlying princi-
ples for the synthesis of one-dimensional mate-
rials offer significant challenges in the control of
diameter, structure, and composition in the axial
and radial coordinates, which are essential for
the synthesis of materials with designed and
tunable functionality [16].
Nanowires, besides their magnetic perfor-
mance, also have aso an interest in developing
intrinsic mobility triggered by a photochemical
reaction. Examples of applications of magnetic
segmented nanowires are:
1. Magnetic alignment and wireless manipula-
tion (Au/polypyrrole/Ni) [17]
2. Magnetic field sensors and spintronic nano-
devices (Co/Cu and FeCoNi/Cu) [18]
3. Photochemical conversion and hydrogen
generation (Ag/ZnO) [19]
4. Detection of DNA molecules (CdTe/Au/
CdTe) [20]
5. Magnetic control of biomolecule desorption
(FeCo/Cu) [21]
6. Exchange-coupled patterned media (Ni/
CoPt) [22]
7. Nanosensors (Au/Co) [23]
8. Catalytic activities (Pt/Ni) [24]
9. Higher oxygen reduction reaction activity
(Co/Pt) [25,26]
10. Drug delivery
 3. Production methods
Magnetic nanoparticles (including nanowires)
are recognized as nanoparticles with unique
physicochemical properties and are mostly
different from those of conventional materials,
specifically the electromagnetic properties. Mag-
netic nanoparticles show good magnetic orienta-
tion, small size, biodegradability, and reactive
functional groups [27]. The biocompatibility of
magnetic nanoparticles can be improved by
combining them with a variety of functional
molecules such as enzymes, antibodies, cells,
DNA, or RNA. The coating of other materials
such as polyethylene glycol (PEG), chitosan,
lipids, and proteins with good biocompatibility
can stabilize magnetic nanoparticles in physio-
logical fluids and provide chemical functionality
for additional modifications [28].
2. Types of nanowires
In the last few years, magnetic hybrid nano-
wires have been intensively studied for many
applications, such as optics and medicine. There
are two types of morphologies in hybrid
nanowires:
1. Radial structures (core/shell type); and
2. Axial structures (segmented or layered type).
The nanowires that present a core/shell struc-
ture explain many physical characteristics in the
magnetism of the nanoparticles. The hard/soft
core/shell nanoparticles have been studied and
reveal interesting magnetic properties, i.e.,
reversible tuning of the blocking temperature
[29], improved microwave absorption [30], opti-
mized hyperthermia [31], and enhanced coer-
civity [32]. The magnetic segmented nanowires
have multifunctional and structural advantages
compared to their counterparts, single-
component nanowires. The literature reports
that magnetic segmented nanowires are
3
composed of alternating structures of ferromag-
netic/ferromagnetic or ferromagnetic/nonmag-
netic materials, such as Ni/Cu [33], Ni/Au [34],
Co/Cu [35], NiFe/Cu [36], CoNi/Cu [37],
FeCoNi/Cu [38], FeGa/Cu [39], Co/Pt [40],
NiFe/Pt [41], and NiCoCu/Cu [42], among
others.
3. Production methods
The properties of many systems are basically
dependent of the material type used in produc-
tion; however, in the case of nanowires the
material geometry is also important. Thus to
produce and maximize all the properties of
nanowires requires reliable and controlled syn-
theses. The synthesis methods can be grouped
into two categories: (1) top-down and (2)
bottom-up synthesis.
3.1 Top-down method
The most conventional top-down method in
the fabrication of nanowires is lithography.
Lithography is based on the deposition of a resis-
tant material, for example, poly(methylmetha-
crylate), that has the function to act as a
photographic film for the production of a pattern
after exposure and development using a
patterned mask. The resolution of this technique
is dependent on the wavelength of light used in
photolithography and sometimes is not suitable
for small nanowires [43]. To obtain patterns
with a higher resolution, normally electron-
beam lithography is the method used, which
does not use a mask and has direct-write expo-
sure [44]. Thus nanowires can be obtained by
etching the extraneous material from the wafer.
Resistance can be applied directly because the
etch mask can serve as the template for the depo-
sition of a much more stable mask material, for
example, gold. Material that can be used to
4 1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting
etch a pattern is, for example, potassium hydrox-
ide (a wet chemical etchant) or another electro-
chemical etchant. With these materials it is
possible to produce tapered cylindrical wires
once the etching is underneath the mask [45].
One way to obtain cylindrical vertical wires is
to change the wet chemical etch with a highly
anisotropic deep reactive ion etch [46]. Nano-
sphere lithography is another approach that
promises higher resolution by combining the
self-assembly of a monolayer of nanospheres of
polystyrene, for example, onto a substrate in a
close-packed lattice [47]. The nanospheres serve
as a model for the deposition of a metal or
another material and are removed after deposi-
tion. Nanoscale patterns can be produced by me-
chanical transfer using nanoimprint lithography
[48,49].
3.2 Bottom-up method
In contrast to top-down techniques, bottom-
up synthesis offers the opportunity to control
nanowire composition during growth.
In this technique of the production of nano-
wires, the anisotropic growth of nanowires is
normally done using nanoparticle catalysts and
gas-phase precursors. The most used method of
production is vapor/liquid/solid growth. In
this method, gaseous precursors are used to
obtain the desired nanowires and these precur-
sors are dissolved into a liquid-metal catalyst,
for example, in the case of silicon nanowires
the precursor used is SiCl4. After the catalyst is
supersaturated, solid nanowire crystallization
from the liquid catalyst begins [50,51]. In this
process, the metal should form a droplet in the
liquid state that will serve as the catalyst. This
droplet, in some cases, will melt at a lower tem-
perature when compared to pure metal, due to
its eutectic composition. In the case of the syn-
thesis of binary or ternary compounds, which
are metals with low melting points, the vapor/
liquid/solid system can be self-catalyzed [52].
The solution/liquid/solid method is another
technique of nanowire production similar to
the vapor/liquid/solid method; however, in
this case nanowire precursors are dissolved in
a high-boiling liquid and the catalysts are sus-
pended in this liquid [53]. Substrates, such as
anodic aluminum oxide, can be used as template
solution for nanowire growth, using electro-
chemical deposition and after filling the channels
in the template [54]. Control of growth along the
axes of nanowires is necessary for the introduc-
tion of surfactants capable of changing the sur-
face energy of crystal facets, for example,
hexadecyltrimethylammonium bromide.
Anisotropy of nanowires is easy to achieve by
the control of surface chemistry [55] (Tables 1.1
and 1.2 and Fig. 1.1).
4. Applications of nanowires
Nanowire biosensors consist of typical field-
effect transistor-based devices, made up of three
electrodes that are very sensitive to the variation
in the charge density that promotes changes in
the electric field at the external surface of the
nanowires [64].
Nanowires have a high surface-to-volume ra-
tio and well-defined geometry; they have high
sensitivity and short response time. These char-
acteristics offer applications in biology and
chemistry. Applications of nanowires can be
categorized into two methodologies: electrical
detection and optical detection [49].
4.1 Nanowires in bioanalytical chemistry
One of the bioapplications of nanowires is
biomolecule analysis. This application includes
the study of mechanical cell lysis. Cellular lysis
is a fundamental process in the study of intracel-
lular components. There are a number of well-
established methods that can analyze the cell
components, such as chemical, electrical, and
mechanical methods. In the case of chemical
cell lysis many steps are necessary and it is an
expensive process, consuming many reagents
aimed at the purification of biomolecule sam-
ples. Another disadvantage is the high probabil-
ity of the occurrence of harmful effects on
 4. Applications of nanowires 5

FIGURE 1.1 Scanning electron microscopy images of CuS nanowires: (A) array; (B) copper oxide (CuO) nanotubes;
(C) array; (D) fabrication using anodic aluminum oxide template. Image copied from Mu C, He J, Confined conversion of CuS nano-
wires to CuO nanotubes by annealing-induced diffusion in nanochannels. vol. 6. 2011. p. 150. Available via license: CC BY 2.0 (https://
creativecommons.org/licenses/by/2.0/).

TABLE 1.1 Advantages and disadvantages of top-down and bottom-up methods [56e58].

Methods Advantages Disadvantages

Top-down Easy to construct order arrays of nanowires. The applicability of the photolithography method decreases as
This order facilitates electrical contact with the the desired length scale diminishes, which requires the use of
nanowires and their integration into large-scale more advanced methods, for example, extreme ultraviolet
devices lithography, electron-beam and scanning probe lithographies

Compatibility of production methods with
standard microelectronics industry processes.
Easy scale-up
Bottom-up Provides the opportunity for the control of the
composition of nanowires during growth, which
permits the production of complex superlattice
structures
Nanowires formed by top-down methods frequently lack
complex electronic characteristics. All the codifications after
growth greatly increase the material cost of nanowire
The major challenge of these methods is their integration into
large-scale devices

microorganisms [65,66]. The solution to this low throughput [67]. The ultimate discovery
problems is the use of electrical cell lysis, which was the use of nanowires because of their small
is less harmful than the aforementioned method; size (smaller than the cells) and the critical advan-
however, it still an expensive method and has a tage is that the nanowire tip can penetrate and
6 1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting

TABLE 1.2 Drugs incorporated in nanowires.

Active pharmaceutical Production

ingredient (API) Type of system Aim methods References

Paclitaxel Cu nanowires To target the spleen Bottom up [59]

Dexamethasone Polypyrrole For ulcerations, deep bone injuries, Bottom up [60]
nanowires or tumors; avoids the side effects of
systemic treatment with
steroids or chemotherapy
Curcumin Silver nanowires Cancer treatment Bottom up [61]

Doxorubicin Silver nanowires Cancer treatment Bottom up [62]

Cerebrolysin Hydrogen titanate Reduction of brain edema Top down [63]
nanowires

disrupt the function of cellular membranes [68]. used for biomedical applications. Major chal-
Nanowires eliminate microorganisms in cells lenges include
much faster than the previously described
1. advanced techniques and easy methods
methods.
(needed to increase the sensitivity of nanowire-
In analytical and biological processes, the
based electrochemical cytosensors in signal
development of biomolecule separation and
amplification),
analysis is essential. In the separation of long
2. further research into nanowires to promote
DNA molecules, conventional gel electropho-
cell adhesion, sensitivity, and selectivity,
resis has a disadvantage: it is necessary to
3. more specialized coatings to decrease non-
analyze biomolecules for several hours. The
specific bonding,
combination of nanostructures produced by
4. protocols and further experiments to deter-
top-down approaches and microfluidic systems
mine the exact nature of the nanotoxicity of
is usually proposed to overcome the problem.
nanowires and their constituents,
However, difficulty in their production using
5. innovative solutions to reduce fabrication and
an electron-beam lithography process makes it
running costs of nanowire-based micro/nano-
a very expensive and sophisticated system
fluidic devices to make them economically
[69,70]. On the other hand, nanostructures pro-
viable,
duced by bottom-up approaches offer easy fabri-
6. with every emerging technology, standards to
cation and separation of biomolecules; however,
avoid doubts about the lack of reproducibility,
size limitation causes difficulty in their develop-
repeatability, and compatibility across plat-
ment. To overcome all these problems, self-
forms and laboratories, and
assembled nanowire structures of metal oxides
7. an opportunity for further advances and de-
have been investigated due to their rigidity and
velopments of cytosensing devices based on
the possibility of reusability [49] (Table 1.3).
electrochemical methods [73].
Circulating tumor cells play an essential role
4.2 Nanowires as biosensors in medical in cancer metastasis, and knowledge of their
diagnosis presence in blood samples of cancer patients is
There are many challenges ahead that must be needed to understand more about the type of
addressed before nanowires can be successfully cancer. Hosokawa et al. have shown an array
 4. Applications of nanowires 7
TABLE 1.3 Nanowires in bioanalytical analyses.

Nanowire type Production method Results References

Mechanical ZnO nanowires Method of low- Higher extraction efficiency for nucleic acids [71]
cell lysis (diameter: 100 nm) temperature and proteins than using chemical cell lysis
on the surface of a hydrothermal methods
pillar array in a reaction
microchannel
ZnO nanowires were Method of low- Easy and rapid mechanical cell lysis [72]
synthesized on the Si temperature Higher extraction efficiency for proteins and
membrane (average hydrothermal reaction nucleic acids than that obtained for
pore diameter: 75 nm) commercially available kits

Biomolecule SnO2 nanowires Photolithography Nanowire structure controlled the pore [49]
separation produced into process and vapor/ size (20e400 nm) by varying the number of
and filtration fused silica liquid/solid technique nanowire growth times
microchannels Highly dense nanowires, used as a
molecular filter, could provide high-throughput
filtration of DNA molecules

of microcavities to perform size-selective capture
of circulating tumor cells [74]. Another study re-
ported that a herringbone chip captured and iso-
lated clusters of circulating tumor cells from the
patient’s blood, which had a capture efficiency of
more than 80% [75]. Tseng et al. developed sili-
con nanowires, which they called a NanoVelcro
chip, to capture and release circulating tumor
cells from blood samples with high selectivity
[76,77]. Si nanowires were produced based on
substrates by a standard photolithography and
chemical wet etching process, and they were
then bonded to a chaotic mixture of microfluidic
channels to fabricate the NanoVelcro chip. This
procedure of surface modification with cell sur-
face markers of anti-EpCAM increased the
capturing efficiency of circulating tumor cells
or of anti-CD45-depleted white blood cells on
the nanowires [78,79]. The NanoVelcro chip
with nanowires has been developed for single-
circulating tumor cell isolation by depositing
thermoresponsive polymer brushes, poly(N-iso-
propylacrylamide), on silicon nanowires [78].
NanoVelcro chips are promising tools in
diagnosis, because they capture and purify circu-
lating tumor cells rapidly prior to circulating tu-
mor cell molecular analysis [49,76].
A silicon nanowire-based electrical cell
impedance sensor has been developed for the
detection of cancerous cultured living lung cells
by monitoring their spreading state at which
the cells stretched and became extended on
nanowires [80]. The diagnosis was carried out
by penetration into the extended membrane of
malignant cells with respect to healthy cells.
Silicon nanowire biosensors have advantages
in molecular detection because of their high
sensitivity and fast response. A polycrystalline
silicon nanowire field-effect transistor device
was developed to achieve specific and ultrasen-
sitive detection of microRNAs without labeling
and amplification, showing that the diagnostic
and prognostic value of microRNAs in a variety
of diseases is promising. Thus the polysilicon
nanowire biosensor device is promising for
microRNA detection [81].
In short, semiconductor nanowires are
emerging as promising biosensors enabling
8 1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting
TABLE 1.4 List of biosensors in the literature based on nanowires.
Type of biosensor
Silicon nanowire field-effect transistors
NanoVelcro chip with nanowires
Silicon nanowire-based electrical cell impedance
sensor
Nanowire-based field-effect sensor devices (which
can be modified with specific surface receptors)
direct electrical detection of various biomole-
cules. A comparative analysis of bio-
functionalization strategies needs to be
discussed to design and develop optimum mem-
ristive biosensors to be implemented in label-free
sensing applications. The surface of the device is
modified with a specific antigeneantibody via:
(1) direct adsorption on the device surface, (2) a
bioaffinity approach using the appropriate
combination, and (3) the optimum memristive
biosensor, which is defined via the calibration
and comparative study of biosensors’ electrical
response under controlled environmental condi-
tions, such as humidity and temperature, aiming
to maximize the performance of the biosensor.
This modified system shows potential for gen-
eral application in molecular diagnostics, and,
in particular, for the early detection of cancer,
namely, prostate [82] (Table 1.4).
Some investigators of the University of San
Diego have been developing nanowires with
the purpose of recording the electrical activity
of neurons in fine detail. The ambition of the
group is that one day this new nanowire technol-
ogy could serve as a method to screen drugs
used specifically in neurological diseases, which
could help researchers to understand the mecha-
nism of how single cells can communicate in
complex neuronal networks. The main objective
is to allow the scientific community to delve
deeper into how the brain works. In the future,
the goal of researchers is to implant this new
nanowire technology into the brain [85].
Aim References
Detection of proteins, DNA sequences, small molecules, [83]
cancer biomarkers, and viruses
Developed for single-circulating tumor cell isolation [78]
Detection of cancerous cultured living lung cells [80]
Used as a powerful detection device for a broad range of [84]
biological and chemical species in solution
4.3 Nanowires for delivery of
chemotherapeutics
Sharma et al. developed noncytotoxic, mag-
netic, Arg-Gly-Asp (RGD)-functionalized nickel
nanowires (RGD nanowires) that could trigger
specific cellular responses via integrin trans-
membrane receptors, resulting in the dispersal
of nanowires [86]. Their results showed that
dispersal of 3 mm long nanowires increased
considerably with functionalization by RGD
when compared to PEG, through integrin-
specific binding, internalization, and prolifera-
tion in osteosarcoma cells. Additional results
showed that a 35.5% increase in cell density
was observed in the presence of RGD nanowires
when compared to an increase of only 15.6%
with PEG nanowires. These results are very
promising to advance applications of magnetic
nanoparticles in drug delivery, hyperthermia,
and cell separation where uniformity and high
efficiency in cell targeting are desirable.
Contreras et al. showed that magnetic nano-
wires with weak magnetic fields and low
frequencies could induce cell death via a mecha-
nism that does not involve heat production [87].
The low-power field exerted a force on the mag-
netic nanowires, causing a mechanical distur-
bance to the cells. In their results, cell viability
studies showed that the magnetic field and the
nanowires had separately decreased deleterious
effects on the cells. On the other hand, when
combined, the magnetic field and nanowires
 4. Applications of nanowires
caused cell viability values to drop by up to 39%,
depending on the strength of the magnetic field
and the concentration of the nanowires. Cell
membrane leakage experiments showed mem-
brane leakage of 20%, which proved that cell
death mechanisms induced by nanowires and
magnetic fields involve cell membrane rupture.
Thus these results suggested that magnetic nano-
wires can kill cancer cells. The advantages of this
process are the use of simple and low-cost equip-
ment with exposure to only very weak magnetic
fields for brief time periods.
Another alternative is ultrasound-powered
nanowire motors based on nanoporous gold seg-
ments that are developed for increasing drug
loading capacity. These nanowire porous motors
are characterized by a tunable pore size, high
surface area, and high capacity for the drug
payload. These highly porous nanomotors are
prepared by template membrane deposition of
a silver/gold alloy segment followed by dealloy-
ing the silver component. The chemotherapeutic
drug doxorubicin was loaded within the nano-
pores via electrostatic interactions with an
anionic polymeric coating. The nanoporous
gold structure facilitates near-infrared light-
controlled release of the drug through photo-
thermal effects, which is a great advantage.
Incorporation of the nanoporous gold segment
leads to a nearly 20-fold increase in the active
surface area compared to common gold nano-
wire motors [88].
The latter work offers very important infor-
mation for the treatment of cancer patients at a
patient-specific level based on specific drug re-
sponses of circulating tumor cells. So, platforms
for high capture efficiency of circulating tumor
cells are essential for clinical evaluation of
patient-specific drug responses of circulating tu-
mor cells. Recently, nanostructure-based plat-
forms have been developed. In the Kim et al.
study, the breast carcinoma cell-line with an ul-
tralow abundance range was captured by
streptavidin-functionalized silicon nanowire
platforms for evaluation of capture efficiency
9
[89]. In this case, a capture efficiency of more
than 90% was achieved. Specific drug responses
of breast carcinoma cell-line cells captured on
these platforms were analyzed using tamoxifen
or docetaxel as a function of incubation time
and dose. In addition, circulating tumor cells
were successfully captured, and this study sug-
gests that this platform is adaptable for clinical
use in the evaluation of circulating tumor cells
and drug response tests.
Magnetic silica core/shell nanovehicles pre-
senting atherosclerotic plaque-specific peptide-1
as a targeting ligand have been prepared
through a double-emulsion method and surface
modification with magnetic iron oxide (Fe3O4)
nanoparticles. The results demonstrated that un-
der a high-frequency magnetic field, magnetic
carriers incorporating the anticancer drug doxo-
rubicin collapsed, releasing approximately 80%
of the drug payload, due to the heat generated
by the rapidly rotating Fe3O4 nanoparticles,
thereby realizing rapid and accurate controlled
drug release. At the same time, the magnetic
Fe3O4 could also kill the tumor cells through a
hyperthermia effect, i.e., inductive heating. The
combination of remote control, targeted dosing,
drug-loading flexibility, and thermotherapy
and chemotherapy suggests that these magnetic
nanovehicles have great potential for application
in cancer therapy [90].
Another study showed that an electrorespon-
sive drug release system based on polypyrrole
nanowires was developed to induce the local de-
livery of the anticancer drug doxorubicin, ac-
cording to the applied electric field. These
nanowires were initially prepared by electro-
chemical deposition of a mixture of pyrrole
monomers and biotin as dopants in the anodic
alumina oxide membrane as a sacrificial tem-
plate. Additionally, the antitumor efficacy of
doxorubicin released from these nanowires in
response to the external electric field using two
kinds of cancer cell lines, human oral squamous
carcinoma cells and human breast cancer cells,
was investigated. An advantage of these
10 1. Bioactive hybrid nanowires: a new in trend for site-specific drug delivery and targeting
particles is the strong photothermal effect as a
result of the near-infrared absorbing ability of
polypyrrole synergistically that, as a conse-
quence, maximizes chemotherapeutic efficacy,
which is very promising for many therapeutic
applications, including cancer [91].
To detect specific mRNA sequences, essential
in the treatment of cancer, molecular beacons
have been widely employed as sensing probes.
Kim et al. developed a nanowire-incorporated
and pneumatic pressure-driven microdevice for
rapid, high-throughput, and direct molecular
beacon delivery to human breast cancer MCF-7
cells to monitor survivin mRNA expression
[92]. This microdevice is composed of three
layers: (1) a pump-associated glass manifold
layer, (2) a monolithic polydimethylsiloxane
membrane, and (3) a ZnO nanowire-patterned
microchannel layer. The molecular beacons are
immobilized using the ZnO nanowires by disul-
fide bonding, and the glass manifold and mono-
lithic polydimethylsiloxane membrane serve as a
microvalve. The cellular attachment and detach-
ment on the molecular beacon-coated nanowire
array can be easily manipulated. All these pro-
cedures enable the transfer of molecular beacons
into the cells in a controllable way with high cell
viability and are useful to detect survivin mRNA
expression quantitatively after docetaxel treat-
ment [92].
Combination therapy is a promising cancer
treatment strategy that is usually based on the
utilization of complex nanostructures with mul-
tiple components. Ultrathin tungsten oxide
nanowires (W18O49) were synthesized using a
solvothermal approach and were examined as
a multifunctional theragnostic nanoplatform
[93]. In vitro and in vivo analyses demonstrated
that these nanowires could induce extensive
heat- and singlet oxygen-mediated damage to
cancer cells under 980 nm near-infrared laser
excitation. The comparison of near infrared-
induced photothermal therapy/photodynamic
therapy and radiation therapy alone showed
that W18O49-based synergistic trimodal therapy
eradicated xenograft tumors, and no recurrence
was observed. In conclusion, these nanowires
have shown significant potential for cancer ther-
apy with inherent image guidance and synergis-
tic effects from phototherapy and radiation
therapy, which warrants further investigation
[94].
5. Conclusions
This chapter summarizes the critical results ob-
tained using nanowire structures as a platform
useful in bioanalytical chemistry and medical di-
agnostics. Nowadays, there are various technical
approaches to develop nanowires for bio-
applications in molecular to cellular levels. Nano-
wires have been integrated with microchannels,
providing a novel pathway from the macroscale
to the nanoscale that will allow researchers to
observe and analyze target molecules such as
DNA, RNA, proteins, and circulating tumor cells.
Another benefit of nanowires is their very small
diameter size with high aspect ratio; this can
allow researchers to use nanowires as a probe
tip to stimulate and record changes in electrical
signals in living cells. Nanowires were also used
as biological optical sensors. These improvements
in nanowire structures will allow the develop-
ment of new bioanalytical chemistry and medical
diagnostics tools that will open a new age of
nanotechnology with the widespread use of
nanowires for bioapplications.
Acknowledgments
The authors acknowledge the financial support received from
the Portuguese Science and Technology Foundation (FCT/
MCT) and from European Funds (PRODER/COMPETE) un-
der the project reference M-ERA-NET/0004/2015-PAIRED,
cofinanced by FEDER, under the Partnership Agreement
PT2020.
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 C H A P T E R
2
Opportunities and challenges of
3D-printed pharmaceutical dosage forms
Adam Procopio1, Divya Tewari2
1
Merck & Co., Inc., Kenilworth, NJ, United States; 2Noramco Inc., Wilmington, DE, United States
1. Introduction
Drug product development can be a long and
complex process. On average, it is estimated
that it takes about 10 years and costs
US$2.5e5 billion for a new drug product to
get to the market [1,1a]. Given this significant
investment, and the knowledge that any delay
in getting the drug product to the market re-
duces exclusivity, there is a desire to reduce
this development timeline providing an overall
benefit to patients and the industry. 3D printing
(3DP) can allow for a robust, flexible, and cost-
effective approach to drug development in
which drug release profiles may be tailored to
a particular outcome using a single
manufacturing method. Moreover, 3DP allows
for custom designs and dosing amounts such
that the dosage forms may be tailored to a spe-
cific patient population. Due to longer and com-
plex formulation processes, development of
delayed or extended release formulations is
typically even more prolonged as well as
requiring expensive and propriety drug release
technology. To date there is only one approved
Drug Delivery Trends
https://doi.org/10.1016/B978-0-12-817870-6.00002-X 15
product (Spritam) that uses a 3DP technology
based on powder layering launched by Aprecia
Pharmaceuticals. There are existing examples of
implementing 3DP technology to rapidly proto-
type release rates using different strategies,
largely focused on maintaining a similar mate-
rial feedstock and using creative printing pa-
rameters to generate various releases. With
these examples, at least one solid filament mate-
rial is preprocessed to contain active pharma-
ceutical ingredients (APIs). Modifications to
what is called the “infill” parameters of the
printed tablet can manipulate release rates
[1be3]. During a fused deposition modeling
(FDM) printing process, the print head will
print an outer shell in the shape of the part,
and the inside of the shell is largely hollow.
The material that is printed on the inside of
the shell is called the infill and can be controlled
through software by taking into account
what percentage of the shell is hollow and the
geometric design of the infill (honeycomb,
rectilinear, etc.). Other published work involves
the changing of the active dosage form’s overall
shape, size, and surface area, which has
© 2020 Elsevier Inc. All rights reserved.
16 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms
shown to modify the release rate [4e7].
Manufacturing of drug product dosage forms
that combine a shell-based approach to be
described in detail in a later section have
demonstrated a unique ability to generate
distinct release rates. Such core/shell tablets
have been manufactured by using a second
API-containing material [8] or a placebo mate-
rial with the intent to mimic enteric-coated tab-
lets [9,10] and have demonstrated the agility of
3DP to change the onset of the release of the core
of the dosage form.
While these approaches have demonstrated
an ability to use software for tuning drug
release rate while maintaining a constant mate-
rial feedstock, they are reliant on a successful
hot melt extrusion (HME) formulation of a
printable filament for each API. Developing
process conditions to incorporate API into an
excipient-based solid filament is not trivial
[11e14], and these filament processing develop-
ments add to the product development burden,
reducing the rapid prototyping advantage 3DP
brings to the table for early drug screenings. A
major hurdle the pharmaceutical 3DP field has
yet to overcome is providing a wide, distinct
range of dosage forms using a universal set of
starting print-ready materials to accommodate
any API without filament formulation burden,
and has even a greater hurdle on aligning
manufacturing partners to generate good
manufacturing-processed pharmaceutical ma-
terials that are printer ready.
2. Materials
Pharmaceutical dosage form design begins
with material selection. Because the materials
are altered during the 3DP process, it is
imperative to understand the source, purity
and associated material chemistry changes of
the chosen material. Material properties have
wide-ranging impact, from influencing the
preferred route of manufacturing to the phys-
ical properties of the dosage form to its pharma-
codynamic fate in the body. A wide range of
materials are used as substrates in 3DP; howev-
er, because of their origin in industrial prototyp-
ing, most 3DP techniques lack availability of
suitable developed materials [15].
The successful design and printability of the
3D-printed dosage forms is dictated by the phys-
ical, chemical, thermal, and mechanical proper-
ties of the chosen material. Additional
considerations should be given to ease of avail-
ability and the regulatory status of the materials.
In the absence of the standard test methods a
specifically designed method to characterize
the material properties of the additives can be
used, and we have compiled current test proced-
ures employed by various researchers and high-
lighted some of the standard utilized ASTM
methods.
The range of polymers used in 3DP include
thermoplastics, thermosets, elastomers, hydro-
gels, functional polymers, polymer blends, com-
posites, and biomaterials [16]. Polymeric
materialsdpolymersdconstitute the majority
of materials used in 3DP due to several
advantages such as low cost, biocompatibility,
availability, ease of processing, and physico-
chemical properties. Material selection is
dictated by the choice of the 3DP technology,
e.g., polymeric filaments used by FDM must
have a constant diameter of 1.75 mm, an ideal
melt viscosity to facilitate viscous melt forma-
tion preextrusion and solidification postextru-
sion, and a sufficient elastic modulus-to-melt
viscosity ratio to prevent filament buckling and
shear thinning tendencies in liquid form [17].
Commonly used polymers include aliphatic
polyesters (poly(lactide) [PLA], poly(glycolide),
poly(caprolactone) [PCL]), cellulosic derivatives
 2. Materials
(hydroxypropylcellulose [HPC], hypromellose
[HPMC], HPMC acetate succinate [HPMCAS],
cellulose acetate, and cellulose acetate phthalate),
vinyl polymers (polyvinylpyrrolidone [PVP] and
copovidone), polyethylene oxide, polyethylene
glycol (PEG), and acrylic polymers (Eudragit).
Table 2.1 provides an overview of 3DP tech-
nologies and desired material properties
required for successful development of 3D-
printed dosage forms.
17
2.1 Aliphatic polyesters
Aliphatic polyesters are synthetic homopoly-
mers or copolymers of lactic acid, glycolic acid,
lactide, glycolide, and 6-hydroxycaproic acid.
Typically, the molecular weights of homopoly-
mers and copolymers range from 2000 to
>100,000 Da. The representative chemical struc-
tures are provided in Fig. 2.1 and a brief sum-
mary of their physical, chemical, and
mechanical properties is outlined in Tables 2.1
and 2.2.

TABLE 2.1 Summary of material properties and test methods commonly employed.

Material properties Key properties Testing methods commonly employed

Powder physical properties
Mechanical properties
Thermal properties
Optical properties
Rheological properties
Particle shape, particle size distribution,
bulk and tap densities, crystallinity,
moisture content
Yield strength, elasticity, modulus,
elongation at break
Melting point, glass transition temperature,
degradation temperature
Ultraviolet absorption, laser power
Viscosity of the solution, binderepowder
interaction, melt viscosity, melt index,
surface tension
Laser light diffraction, densitometry,
powder X-ray diffraction, differential
scanning
calorimetry, Karl Fischer, flow index
ASTM D638, D3039, D882, ISO 527-2,
three-point bend test
Thermogravimetric analysis
AERS-G2 rheometers, viscometers (USP
911), ASTM D1238

FIGURE 2.1 Representative chemical structures of the aliphatic polyesters.

18 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.2 Typical chemical names and trade names of the representative aliphatic polyesters.

Composition

Generic name Lactide Glycolide Caprolactone Trade name Manufacturer

Poly(L-lactide) 100 0 0 Lactel L-PLA Durect

100L Lakeshore
Resomer L206 S, 207S, Boehringer
209 S, 210 and 201 S Ingelheim
Poly(DL-lactide) 100 0 0 Lactel DL-PLA Durect
Purasorb PDL 02A, 02, 04, 05 Purac
Resomer R 202 S, 202 H, 203 S, Boehringer
203 H Ingelheim

Poly(L-lactide-co-glycolide) 85 15 0 Resomer LG 855 S, 857 S Lakeshore

Boehringer
Ingelheim
Poly-ε-caprolactone 0 0 100 Lactel PCL Durect
100 PCL Lakeshore
Poly-(DL-lactide-co- 85 0 15 8515 L/PCL Lakeshore
ε-caprolactone)

Adapted from Handbook of Pharmaceutical Excipients.

Aliphatic polyesters are United States Food
and Drug Administration (FDA) and European
Medicine Agency approved, versatile thermo-
plastic polymers that are used in a number of
3DP technologies such as FDM, selective laser
sintering (SLS), pressure-assisted microsyringes
(PAMs), etc. due to their biocompatibility,
biodegradability, high mechanical strength
and modulus, and processability [18]. Ease of
availability and cost effectiveness make
aliphatic polyesters highly desirable polymers
for 3DP, whereas the main disadvantages are
the appearance of rough surfaces and low
resolution.
PLA is by far the most widely used material
for FDM printing. PLA and its derivatives are
poorly water soluble but have good solubility
in dioxane, acetonitrile, chloroform, methylene
chloride, 1,1,2-trichloroethane, and dichloroace-
tic acid. The thermal and mechanical properties
of PLA are influenced by small amounts of
enantiomeric impurities. Amorphous grades
were reported to have better processability
and a wider processability window but lower
mechanical properties [19] (Table 2.2).
PCL is a hydrophobic polymer with excellent
blend compatibility with many other polymers
such as polyvinyl(acetate), poly(vinylchloride),
poly(styrene-acrylonitrile), and poly(acryloni-
trile butadiene styrene). Its blend compatibility,
biodegradability, low melting point, and solubi-
lity make this polymer suitable for precise
extrusion deposition and FDM techniques. The
only disadvantage of PCL is its hydrophobicity,
which might adversely impact drug dissolution
characteristics.
2.2 Cellulose ethers and esters
Cellulose is the most abundant naturally
occurring polysaccharide. Each polysaccharide
unit is linked by b-1,4-glycosidic bonds. Each
glucose unit has three hydroxyl groups that
can be derivatized and the average substitution
grade cannot exceed three. Alkalization of
 2. Materials
cellulose, followed by etherification reaction at
elevated temperatures and pressures, is used to
convert cellulose molecules into their corre-
sponding ether, such as HPC, HPMC, and
many other semisynthetic cellulosics. Esterifica-
tion of the cellulose ethers could be used to
derive molecules such as HPMCAS. At the basic
level, cellulose derivatives are characterized by
their average molecular weight distribution
and average composition. Compositionally,
these polymers are defined by the percent
weight of the functional group attached to the
backbone, the degree of substitution per anhy-
droglucose, or the total molar substitution per
anhydroglucose residue [20]. The representative
chemical structures are provided in Fig. 2.2 and a
summary of their physical, chemical, and
mechanical properties is provided in Table 2.3.
FIGURE 2.2 Representative chemical structures of cellulose ethers and esters.
19
Thermoplastic polymers are typically mate-
rials of choice in 3DP coupled with extrusion
because they can be processed at suitable tem-
peratures without affecting the stability of the
APIs [21]. Cellulose esters and ethers have been
tested as carriers or matrices for drugs in FDM
technology with HME [22]. HPMC in either solu-
tion, dispersion, or paste forms has also been
used in PAMs printing technology [23].
2.3 Acrylic polymers
Polymethacrylates are synthetic cationic and
anionic polymers of dimethylaminoethyl meth-
acrylates, methacrylic acid, and methacrylic
acid esters in varying ratios [24]. Eudragit poly-
mers are copolymers derived from esters of
acrylic and methacrylic acid whose
20 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.3 Typical physical and mechanical properties of the aliphatic polyesters.

8515
Properties L-PLAa DL-PLAa PGAa PCLa 85/15 DL-PLGa L/PCLb

Molecular weight (Da) 40,000e100,000 40,000e100,000 >100,000 80,000e150,000 40,000e100,000

Melting point (
C) 173e178 Amorphous 225e230 58e63 Amorphous Amorphous
Glass transition 60e65 50e60 35e40 65 to 60 50e55 20e25b
temperature (
C)
Color White White Light tan White White to light gold
Tensile strength (psi) 8,000e12,000 4,000e6,000 10,000þ 3,000e5,000 6,000e8,000 3,254
Elongation (%) 5e10 3e10 15e20 300e500 3e10 >6.4

Modulus (psi) 4e6  10 5

2e4  10 5
1  10 6
3e5  10 4
2e4  10 5
8.4  104

PCL, Polycaprolactone; PGA, poly(glycolide); PLA, poly(lactide); PLG, poly(lactide-co-glycerol).

a
Specifications from Durect, b Specifications from Lakeshore Biomaterials and process temperature range 140e160
C.
Adapted from Handbook of Pharmaceutical Excipients.

physicochemical properties are determined by members of this product family. PVA is a

functional groups. Several compositional copol-
ymer variants are derived from esters of acrylic
and methacrylic acid, whose physical, chemical,
mechanical, and thermal properties are deter-
mined by the functional groups. The representa-
tive chemical structures and summary of typical
trade names and suppliers is provided in Fig. 2.3
and Tables 2.4e2.6, respectively.
Acrylic polymers have been used for FDM
[11,12], binder jetting additive manufacturing,
and SLS printing technologies [25e28].
2.4 Vinyl polymers
Polyvinyl alcohol (PVA) polymers and PVP
polymers and copolymers are important
FIGURE 2.3 Representative chemical structures of acrylic
polymers.
water-soluble synthetic polymer represented
by the formula (C2H4O)n. It is a synthetic, linear,
semicrystalline polymer produced via the
hydrolysis of polyvinyl acetate in methanol,
ethanol, or a mixture of alcohol and methyl
acetate, using alkalis or mineral acids as cata-
lysts. Unlike other vinyl polymers, it is not pro-
duced via the polymerization of repeating units
of vinyl alcohol because it cannot be obtained in
the quantities and purities required for poly-
merization purposes. It is manufactured by
hydrolysis of polyvinyl acetate and the removal
of acetate groups. It has low solubility in
ethanol and is insoluble in many organic sol-
vents. Its physical properties are dictated by
the degree of polymerization and the degree
of hydrolysis. The pharmaceutical grades are
partially hydrolyzed and available in different
viscosity types.
PVPs or povidone are water-soluble linear
synthetic polymers, manufactured by free
radical polymerization of N-vinylpyrrolidone.
Vinylpyrrolidone-vinylacetate copolymer or
copovidone (PVP/VA) are water-soluble copoly-
mers of the two components in the ratio of 6:4. It
is also produced by free radical polymerization
 2. Materials 21
TABLE 2.4 Typical chemical names and trade names of the representative cellulosic polymers.

Generic name Assay Trade name (grades) Manufacturer

Hydroxypropylcellulose % Hydroxypropoxy Klucel HPC (Klucel EL, LF, GF) Ashland

53.4e80.5a Nisso HPC (Nisso-L) Nippon Soda
Nisso (Seppic)
Hydroxypropylmethylcellulose Type 2910 Methocel HPMC (Methocel E3, DuPont Specialty Solutions
% Hydroxypropoxy E6, E10, K100LV, K4M) (previously Dow Wolff
7.0e12.0 Klucel HPMC (Benecel K100LV Cellulosics)
% Methoxyl PH PRM, Benecel K4M) Ashland
28.0e30.0 ShinEtsu
Type 2208 Lotte Fine Chemical
% Hydroxypropoxy
4.0e12.0
% Methoxyl- 19.0e24.0
Hydroxypropylmethylcellulose % Hydroxypropoxy Aqoat HPMCAS ShinEtsu
acetate succinate 4.0e23.0 (LG, MG, HG) DuPont Specialty
% Methoxyl Affinisol HPMCAS Solutions
12.0e28.0 (LG, MG, HG) Ashland
% Acetate-2.0 16.0 Aquasolve HPMCAS
% Succinate 4.0e28.0 (LG, MG, HG)

Ethylcellulose % Ethoxyl 44.0e51.0 Aqualon ethylcellulose DuPont Specialty

(N types) Solutions (previously Dow
Ethocel ethylcellulose Wolff Cellulosics)
(N types) Ashland
a
Specifications from USP 41-NF 36.

reaction in an organic solvent such as ethanol or
2-propanol [29].
The representative chemical structures, com-
mercial supplier information, and polymer prop-
erties are given in Fig. 2.4 and Tables 2.7 and 2.8,
respectively.
PVA is a thermoplastic, water-soluble excip-
ient that is commonly employed as polymeric
support material for FDM-based 3DP
[5,6,8,30,43,44]. The degree of hydrolysis impacts
the physicochemical, thermal, and mechanical
properties of the resultant PVA grade. Besides
FDM printing, PVA has also been used in inkjet
printing [31].
PVP and PVP/VA polymers are known for
their application in the solubility enhancement
of poorly water-soluble drugs via HME. Due to
the complementarity of HME technology with
FDM, polymers used in HME are frequently
adapted for use in 3DP. Additives, such as plas-
ticizers and fillers, are usually employed to
reduce the Tg of PVP polymers and render
them suitable for FDM printing coupled with
HME. Major et al. examined the material proper-
ties of PVP/VA copovidone copolymers in hot
melt extrusion-based 3DP and encountered diffi-
culties in printing due to brittleness and high
stiffness of the copolymer. Melt blending with
a carrier polymer such as PCL improved flexi-
bility and ductility thereby resolving the print-
ability issue. Polyethylene oxide was also
added to the formulation to reduce the negative
impact of PCL on drug release profiles [32]. Melt
blending PVP/VA with hydrophilic polymers
such as HPMC and HPMCAS resulted in imme-
diate release formulations [33].
22 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.5 Typical physical, mechanical, and thermal properties of the cellulose polymers.

Aqualon
Properties Klucel HPCa Benecel HPMC AquaSolve HPMCAS ethylcellulose

Molecular weight (Da) 40,000e1,150,000 20,000e1,200,000 55,000e93,000d 75,000e215,000f

Melting point (
C) Softens at 130 190e200 156f
Glass transition 0 and 120b 170e180 120e125 129e133e
temperature (
C)
Color White to slightly White to off-white White to off-white White to light
yellow colored powder powder or granuled tan-colored
powdere
Tensile strength (psi) 1450 (Klucel HPC EF) 6816 (Benecel HPMC E6) 5076 (HPMCAS L) 6899
(ASTM D882) 5366 (HPMCAS M)
5802 (HPMCAS H)g
Elongation (%) 12 (Klucel HPC EF) 4 (Benecel HPMC E6) 11 (HPMCAS L) 9
(ASTM D882) 19 (HPMCAS M)
16 (HPMCAS H)g
Modulus (psi) 200,000e630,000c 367,090 (Benecel HPMC E6) 1574 (L) 302,403
(ASTM D882) (grade dependent) 1523 (M)
1494 (H)g,h
a
Adapted from Klucel HPC Physical and Chemical Properties Book (https://www.ashland.com/file_source/Ashland/Product/Documents/Pharmaceutical/
PC_11229_Klucel_HPC.pdf), b Klucel HPC is a special polymer that can show dual Tg because it has a beta transition, c Reference [21], d Handbook of
Pharmaceutical Excipients, Sixth Edition, 330e332, e Handbook of Pharmaceutical Excipients, Sixth Edition, 262e267, f Aqualon Ethylcellulose EC
Physical and Chemical Properties, Product Brochure-PRO 250-42a, g PC-12624 AquaSolve HPMCAS Handbook, h Handbook of Pharmaceutical
Excipients, Sixth Edition, 326e329.

2.4.1 Novel polymers in the market
Melfil is a water-soluble filament of butane-
diol vinyl alcohol copolymer specifically
designed for FDM 3DP. It offers superior water
solubility and printability along with the flexi-
bility to use as a support material or a water-
soluble model (see the Nippon GohseidMelfil
Product Brochure [53]).
Thermoplastic polyurethanes (TPUs) are
elastic and melt processable linear-segmented
block copolymers. TPUs offer a unique advan-
tage over other thermoplastic polymers because
of their extreme material adaptability. This is
due to the flexibility in modifying the molecular
weight, ratio, and chemical composition of soft
(polyether or polyester based) and hard seg-
ments (aliphatic or aromatic based) of the
TPUs [34].
Polyether ether ketone (PEEK) and polyether
imide (PEI, brand name ULTEM) are newer ther-
moplastic semicrystalline materials from the pol-
yaryletherketone (PAEK) family of polymers
currently used in FDM printers [35]. PAEK poly-
mers can withstand high temperatures while
maintaining mechanical strength [36]. PEEK is
a superhigh-performance, biocompatible, chemi-
cally stable, semicrystalline plastic that offers the
advantages of high-temperature resistance
(melting point of 334
C, Tg of 143
C) and excel-
lent mechanical properties, including high
 2. Materials 23
TABLE 2.6 Typical chemical names and trade names of the representative acrylic polymers.

Polymer dry
Generic name weight content (%) Trade name (supply form) Manufacturer

Poly(butyl methacrylate, 98% Eudragit E 100 (granules) Evonik Industries

(2-dimethylaminoethyl) 12.5% Eudragit E 12.5 (organic solution)
methacrylate, methyl methacrylate) 1:2:1 98% Eudragit E PO (powder)
Poly(ethyl acrylate, methyl 97% Eudragit RL 100 (granules) Evonik Industries
methacrylate, trimethylammonioethyl 97% Eudragit RL PO (powder)
methacrylate chloride) 1:2:0.2 30% Eudragit RL 30 D
(aqueous dispersion)
Poly(methacrylic acid, ethyl acrylate) 1:1 95% Acryl-EZE (powder) Colorcon
30% Eudragit L 30 D-55 Evonik Industries
95% (aqueous dispersion) Eastman Chemical
30% Eudragit L 100-55 (powder) BASF Fine
30% Eastacryl 30 D (aqueous dispersion) Chemicals
95% Kollicoat MAE 30 DP
(aqueous dispersion)
Kollicoat MAE 100 P (powder)

Adapted from Handbook of Pharmaceutical Excipients.

FIGURE 2.4 Representative chemical structures of vinyl polymers.

TABLE 2.7 Typical chemical names and trade names of the representative vinyl polymers.

Polymer dry weight

Generic name content (%) Trade name (grades) Manufacturer

Polyvinyl alcohol Degree of hydrolysis Goshenol EG Granules/Powder (EG-03P, Nippon Synthetic

(PVOH/PVA) 86.5e89.0 EG-05P, EG-18P, EG-22P, EG-30P, EG-40P) Chemical Company
Polyvinylpyrrolidones K value- 25-90 Kollidon povidone BASF
(PVP, Povidone) Plasdone povidone Ashland
Polyvinylpyrrolidone: K value - 25.4-34.2a,b Kollidon VA 64 copovidone BASF
vinylacetate 6:4 Plasdone S630 copovidone Ashland
(PVP/VA, Copovidone)
a
http://www.nichigo.co.jp/english/lifechemical/pharma/index.html, b From the Ashland brochure. Adapted from Handbook of Pharmaceutical Excipients.
24 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

TABLE 2.8 Typical physical, mechanical, and thermal properties of the vinyl polymers.

Properties PVA Povidone Copovidonea

Molecular weight (Da) 20,000e200,000b 28,000e1,150,000 45,000e75,000

Melting point (
C) 180e190 for partially Softens at 150
Cc 140
hydrolyzed grades
228 for fully hydrolyzed
grades

Glass transition 85 120e175d 106

temperature (
C)

Color White to cream-colored White to creamy white powderc White to off-white

granular powder free-flowing powder
Tensile strength (psi) 44,961e Films brittle; difficult
e to assess pure film properties
Elongation (%) 2
Modulus (psi) 20,305e

PVA, Polyvinyl alcohol. a Specifications from the Ashland brochure, b Handbook of Pharmaceutical Excipients, Sixth Edition, 564e565, c Handbook of
Pharmaceutical Excipients, Sixth Edition, 581e585, d Ashland Literature PTR-092 Plasticizer compatibility and thermal and theological properties of
Plasdone povidone and copovidone polymers for hot-melt extrusion applications, e Hamied, S.F.A; Abd El-Kader, K.A.M. Preparation of poly (vinyl alcohol)
films with promising physical properties in comparison with commercial polyethylene film.

strength, elastic modulus, and fracture tough- 3. Technology details

ness [37]. PEI was developed by General Elec-
tric’s plastics division in the 1980s (later
acquired by SABIC) and demonstrates superior
thermal properties and mechanical strength
characteristics of the family.
2.4.2 Additives
Plasticizers, fillers, and lubricants are com-
mon additives used to improve printability by
either modifying the melt and mechanical prop-
erties [33] or reducing the friction between the
filament and walls of the printing extruder [10].
Commonly used additives include fillers such
as talc, lactose, microcrystalline cellulose, mag-
nesium stearate, and tricalcium phosphate, or
plasticizers, such as triethyl citrate, triacetin,
PEG 400, Tween 80, etc.
3DP has been gathering significant attention
from both industry and academicians. Research
efforts have spanned the applications of both
novel drug delivery to replacement/supplement
of traditional manufacturing approaches. To
accommodate these various manufacturing
modes, different 3DP approaches are employed.
This section reviews the available technologies
along with their advantages and disadvantages
from a technical point of view. In general, the
technology is built on the principle that matter
is converted from either liquid to solid or un-
dergoes a transition from solid to liquid back to
solid in a layer-by-layer approach either through
chemical means or thermal energy. The contrib-
uting limitations to either print resolution or
print speed are a result of the fundamental
 3. Technology details
mode of the physics used in the print process.
ASTM ascribes seven different 3DP technologies
(ASTM F2792). We discuss here the top three
technologies that are most relevant for the phar-
maceutical industry:
1. Vat photopolymerization
2. Powder-based processes
3. Material extrusion
The aim here is not to describe all of these
technologies in detail but to cover the 3DP
modes that have contemporaneous or direct im-
mediate impact on the biopharmaceutical indus-
try in their application of drug product
prototyping and at-scale manufacture.
3.1 Vat photopolymerization
Vat photopolymerization carries alternative
names with concurrent differing underlying
technologies such as stereolithography appa-
ratus (SLA), digital light processing (DLP), and
continuous liquid interface production (CLIP).
The fundamental principle of operation is that
a liquid photopolymer resin formulation
comprising a monomer, oligomer, and photoini-
tiator is cured through selective exposure to light
using a specified light source (most typically a
450 nm laser) either in a raster mode or as a pro-
jected 2D image (e.g., DLP). The light source is
Vat
SLA Photo
resin
FIGURE 2.5 Principal components of a stereolithography apparatus (SLA) printer.
25
controlled both in terms of energy supplied
and in the amount of time that drives the photo-
polymerization reaction to cross-link the liquid
formulation and convert it to solid polymer pre-
cisely at the regions where the light source is
focused. Vat photopolymerization has the high-
est lateral and vertical print resolution in the
range of 1e10 mm. Lateral resolution is defined
by the positional control of the light source,
whereas vertical resolution is controlled by the
penetration depth of the light source and any
light-absorbing additives that are added to
photochemical resin to control any unwanted
light-scattering events.
3.1.1 Stereolithography apparatus
Fig. 2.5 depicts the principal components of a
typical SLA printer. The platform is precisely
controlled in concert with the position of the
focused laser source and any mirrors used to
direct the light source to sequentially scan or
project the laser light source within a plane on
the surface of the photosensitive resin formula-
tion. The time spent on any individual 2D layer
depends on the chemistry of the resin formula-
tion to successfully complete the cross-linking re-
action and convert the liquid formulation to
solid polymer resin. The lateral (xey) position
of the laser is typically controlled with a pair of
mirrors within servo-controlled galvanometers,
Laser
3D Printed Y plaorm
Object
26 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms
which are electromechanical instruments used to
precisely control the position of the mirror and
hence the position of the laser spot location.
This process is conducted layer by layer whereby
the slicing software converts the 3D image to be
printed into a series of control statements that
ascribe not only the position of the platform po-
sition, but also the laser energy pulse and well as
the tilt angle of the mirrors used to position the
xey position of the spot. A unique feature of
photopolymerization 3D printers is the ability
to resolve fine details by the application of galva-
nometer dithering (or high-frequency move-
ments) to effectively process grayscale images
that prescribe laser energy states between full
on or full off. This technique allows for the crea-
tion of highly resolved surfaces. In general, pho-
topolymerization techniques allow for highly
resolved features and surfaces on the order of
1 mm. Their main disadvantages are extremely
limited for use as a biopharmaceutically accept-
able process in that they are using both toxic
monomer and oligomer materials and usually
have lengthy postprocessing steps to remove
any unreacted monomer and oligomer as well
as completely consume any unreacted free radi-
cals as a result of photochemistry. The materials
available for creating 3DP drug products from
photochemical reactions are limited but research
in this area is evolving.
3.1.2 Digital light processing
DLP is analogous to SLA because both pro-
cesses use a controlled wavelength light source
to selectively drive a photochemical reaction of
a resin formulation. The main difference be-
tween SLA and DLP is that the light source in
SLA acts as an XeY rastering, whereas in DLP
the entire layer to be cured is projected onto
the focal plane at one time. The technology
used with DLP is the same technology used in
overhead projectors, which allows for dithering
as described in the SLA section earlier and for
grayscale image processing and hence higher
resolution features and smoother printed
surfaces. Unlike SLA where the photochemical
reaction is near the liquid/air interface and sub-
ject to oxygen inhibition less direct control of the
photochemical cross-linking reaction, DLP 3D
printers are controlled in the reverse direction
where the reaction layer occurs at a plane
immersed well below the liquid/air interface.
An example of the application of DLP in 3DP is
the work by Kim et al. with precision bioprinting
of silk fibroin bioink for applications in building
complex organ structures [38].
3.1.3 Continuous liquid interface production
The latest variety of vat photopolymerization
is CLIP [39,40]. This technology addresses the
major time-limiting step of both SLA and DLP,
which is the required mechanical separation of
the just-cured material from the vat of unpoly-
merized material. This 3DP technique uses an
oxygen permeable membrane to inhibit poly-
merization at the interface nearest to the ultravi-
olet (UV) light source. This region creates a
10e100 mm “dead zone” where free radical
polymerization does not occur. Just above this
zone, light-catalyzed free radical polymeriza-
tion occurs on the focal plane of the projected
light. This innovation is key to facilitate a faster
3DP process because the need to refresh or
recoat the region between the printed part and
the light source using a mechanically activated
platform is not needed. Using CLIP, this region
is continuously present with uncured formula-
tion and the 3D-printed part appears to
“grow” out of the resin. Resolution of the part
in the vertical direction is improved by
increasing the concentration of the passive light
absorber. This slows down the production
speed because light penetration is in a smaller
volume of the resin. By lowering the concentra-
tion of this additive, deeper penetration of light
can be realized and hence faster production
speeds. Part quality is also improved by
removing the need to mechanically separate
the part from the resin bath. This mechanical
separation that is typical in most SLA 3D
 3. Technology details
printers causes undue stress on the part and can
lead to feature distortion or even failure. CLIP
allows for both high print quality and speeds
and can produce parts with features below
100 mm at growth rates in the range of a vertical
support plate speed of 1000e3000 mm/h.
3.2 Powder bed fusion processes
3.2.1 Selective laser sintering process/laser
sintering process
Generally, laser sintering 3DP allows for
many more materials over other 3DP techniques
from high-performance thermoplastic polymers
to even metal powders.
The operating principle behind powder-based
SLS consists of powder deposition from the feed
chamber to the build chamber by powder trans-
fer and consists of build surface preparation by
rolling and leveling with a scraper, laser raster-
ing and particle melting and sintering, cooling
and solidification, followed by the build cham-
ber being lowered by one-layer thickness to
repeat with a recoating of fresh material from
the feed chamber. During the printing process,
the laser, in most applications a 2 W blue diode
laser (445 nm) light source, is rastered
(w100 mm/s) to match the geometry of the layer
[27]. The light energy from the laser source is
absorbed by the particles at the site of the laser
focal spot, which in turn heats the material
beyond the thermal transition (Tg or Tm) allow-
ing for interparticle contact diffusion and bind-
ing. After removal of the light source the
energy dissipates, and the newly formed
coherent body solidifies. The unprinted material
surrounding the printed material serves as an
intrinsic support material. The fact that the 3D-
printed parts are constantly surrounded by
unprinted support material means that parts
can be effectively stacked and printed together
to make efficient use of the build volume but it
27
also implies that a lengthy and “dirty” postpro-
cessing is required to remove the bulk powder
from the build chamber as well as the powder
that is loosely adhered to the final printed part.
Because of the impact of the heat-affected zone
powder, not all of this unprinted powder can
be reused, and it is good practice to blend virgin
powder with this recycled material.
One key to this technique is for the process to
proceed so that enough thermal mass is present,
such that not only are the particles bonded
within the as-printed 2D layer, but this layer
also softens/melts and binds through the same
diffusional process to the layer(s) just below to
form our 3D-printed part. For thermoplastic ma-
terials, liquid-phase sintering drives capillary in-
teractions between neighboring particles
resulting in bonds due to the diffusion of poly-
mer chains or chemical cross-linking.
One method that ensures a well-formed 3D-
printed part is to keep the entire 3DP chamber
at a temperature just below the softening or
melting point of the material to decrease the pro-
cessing time and reduce thermal gradients
within the part, which can lead to part distor-
tions caused by the relatively large volume
changes in semicrystalline or amorphous poly-
mers. In this method, maintaining an elevated
environment is a key consideration in the pro-
cessing of thermally sensitive materials (e.g.,
oxidation) and would need careful evaluation
depending on the material that is used for print-
ing. To provide the best part quality and mini-
mal part warpage, the build volume is left to
cool gradually over 24e48 h for both safety in
handling and to avoid distortion caused by pre-
mature handling while the parts are in a softened
condition.
One of the more critical criteria for this pro-
cess to be effective is the flow and particle pack-
ing properties of the starting material. Because
the powder deposition process between adja-
cent layers is done by depositing material
28 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms
through a blade and roller recoating process,
the distribution of the particles across the 2D
plane to be printed directly impacts part qual-
ity. If the particles do not flow and fill in the re-
gion in a uniform manner there will be voids in
the final printed part. The size and sphericity of
the particle properties also directly influence the
surface roughness and spatial print resolution
of the manufactured parts. Part resolution on
the order of 100 mm is typical for a printed
part. Compressibility, or volume reduction, un-
der the roller assembly can aid in powder bed
uniformity and this predensification can enable
the printing of higher-density final parts.
Many SLS 3D-printed parts undergo a series
of postprocess finishing operations to provide
more elegant surface properties. In addition,
intrinsic to the type of 3DP, because of the use
of powder as the starting material, final parts
will be porous in nature, which may be consid-
ered as defects from a mechanical strength point
of view or could aid in the disintegration of oral
dosage forms as in traditional compressed tab-
lets. For biomedical applications the porosity
present in these 3D-printed parts could also
serve as a scaffold for cell growth.
Regardless of the material used, the parts
obtained by the powder bed fusion processes
will typically exhibit a certain level of porosity.
The amount of free volume is dependent on par-
ticle size distribution, material choice, and pro-
cess parameters. The pores remaining within a
green part after the additive manufacturing
process represent potential weak points in
models subjected to mechanical load. If high
mechanical strength is required for a given
application, it is therefore common practice to
improve mechanical properties by means of
isostatic pressing, infiltration with suitable
resins, or sintering. On the positive side, SLS-
fabricated parts are light and porosity can be
advantageous in other applications that require
large surface areas, for example, scaffolds for
cell growth in tissue engineering. SLS is appli-
cable to materials with vastly different bulk
properties. Moreover, SLS powders for the
same bulk material can also vary in their
morphology, sintering, and melting behavior.
3.2.2 Powder binding technology
Like the SLS processes, in the first step of
powder binding 3DP a powder layer is depos-
ited using a roller/scraper assembly from a
feeder chamber to the build chamber. Unlike
SLS, which used a thermal method of binding
powder, in liquid-phase powder binding 3DP,
the powder is bound together with the use of a
liquid that is dispensed using an inkjet printing
head. The inkjet head will either contain a sol-
vent (e.g., water) or a solventebinder solution.
In the former, the binder is contained within
the powder formulation whereas if the inject
print head has a solventebinder solution the
binder is dispensed from the print head. The
finished 3D-printed part is then cleaned of any
residual powder using a combination of a vibra-
tory plate and airflow. Much like SLS, the parti-
cle properties drive product quality and final
part resolution, but unlike SLS the inkjet print
head spatial resolution is lower than that of a
laser spot size. This technology offers the ability
to print several materials because of two reasons:
either the powder loaded into the feed chamber
is a blend of multiple materials or the inkjet print
head could also contain a different material such
as an active ingredient or a colorant. This tech-
nology is likely the closest analogy to a tradi-
tional wet granulation process because of the
similarities in materials that are used. In fact,
the powder binding technology is the same
core process that is used by Aprecia Pharmaceu-
ticals to manufacture the Spritam tablet. The
porous nature of the powder bed process creates
a dosage form that instantaneously dissolves
because of the formulation and the intrinsic
capillary wicking action of the dosage form.
 3. Technology details 29

3.3 3D material extrusiondfused extrusion head or build platform moves in z

filament fabrication
3DP extrusion-based processes have seen a
bolster of activity in recent years and cover a
wider range of materials, including thermo-
plastic polymers, pastes, and thermo or UV
curable gels. In this process a nozzle or piston
(e.g., syringe) is fixed to a gantry that moves in
xey space. After a single layer is deposited the
space to complete the next layer. The most com-
mon extrusion-based 3DP is known as fused fila-
ment fabrication (FFF), also known as FDM.
The operating principle is shown in
Figs. 2.6e2.8, where the thermoplastic polymer
filament with a round cross-section of 1.75 or
3.00 mm in diameter is mechanically fed using
a gear-based extruder to a cartridge-heated

Connuous elevaon
Build Support Plate

Photo Dead zone

3D Printed
Resin
Object

Imaging Unit
O2 permeable
window

Mirror

FIGURE 2.6 Schematic of continuous liquid interface production.

Mirror Laser

Roller and scraper

3D printed object Thermoplasc

powder

Build plaorm

Build Chamber Feeder Chamber

FIGURE 2.7 Schematic of selective laser sintering process.

30 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms
Filament
Extruder Gears
3D printed object
Build plaorm
FIGURE 2.8 Operating principle of extrusion-based 3D printing process.
nozzle assembly. Process temperature is
defined by the thermal properties of the poly-
mer filament, which for amorphous polymers
is above the glass transition temperature and
for semicrystalline polymers is above the
melting point. The melted filament forms a
molten bead upon exit from the small nozzle
orifice (0.1e1 mm diameter) and begins solidifi-
cation at the location from which it was
extruded. The resolution of an FFF-printed
part is often defined by the diameter of the
nozzle. Generally, a smaller nozzle results in a
surface that more closely follows the profile of
the 3D geometry; however, this results in an in-
crease in print time because of the requirements
of more nozzle traces to completely define the
geometry as well as often slowing the print
speed because of the increase in nozzle melt
pressure as a result of the smaller diameter.
The rheology of viscous thermoplastic polymer
Material
Spool
Heater
Element
Nozzle
Molten Bead
is often the limiting factor for this 3DP tech-
nique. Processing not only needs to consider
the speed for appropriate bead deposition but
also the temperature and time required for
fusion of the deposited beads onto the adjacent
layers that were previously printed.
Often in 3DP for a new polymer the impact of
several parameters is often experimentally
derived such as filament extrusion feed rate,
temperature and thermal gradients, nozzle
design, die swelling, polymer melt rheology,
quench rate using convective air cooling, nozzle
path direction, and part orientation. These
parameters are optimized to improve 3DP
efficiency, surface roughness, dimensional
accuracy, mechanical properties, and isotropy.
Many common thermoplastic materials (e.g.,
PLA, acrylonitrile-butadiene-styrene copoly-
mers, polycarbonate, and polyamides), have
been optimized for fused filament fabrication
 4. Regulatory and quality considerations
3DP, while other more nascent thermoplastic
polymers relevant for the pharmaceutical
industry are still being experimented.
3.3.1 Postprocessing
Across most all 3DP technologies, the final
part requires additional processing steps after
completion of 3DP. Depending on the printing
process these steps involve either mechanical
removal of material used to improve adhesion
to the printing plates, removal of support
material used in the printing process, chemical
and/or thermal treatment of unreacted surface
material, removal of unbound surface powder,
or heat treatment to reduce unwanted part
residual stresses. Careful consideration and
execution of the postprocessing steps is crucial
to ensure that the part does not suffer undue
damage.
4. Regulatory and quality considerations
The FDA recently issued a guidance for
industry entitled “Technical Considerations for
Additive Manufactured Medical Devices.”
Even though medical device and combination
products are regulated by the Center for
Devices and Radiological Health, many ele-
ments discussed in this document highlight
key considerations for additive manufactured
drug products that are regulated by the Center
for Drug Evaluation and Research. This guid-
ance like most offers supplementary regulatory
guidance that covers 3DP-specific recommen-
dations. The device-specific 3DP guidance
document covers (1) design for 3DP, (2)
patient-matched device design, (3) software
workflows, (4) controls over materials used for
3DP, (5) postprocessing considerations, (6) pro-
cess validation and product acceptance testing,
(7) quality, and (8) device testing consider-
ations. It is not the intention of this section to
recount this guidance document but to direct
31
the reader to key recommendations that are
common for drug products. Generally, regu-
lated products must fulfill standard Quality
System requirements. Specific to 3DP of drug
products, manufacturers must validate their
process and establish and maintain procedures
for monitoring and controlling processing
parameters to ensure that the specifications of
the drug product can be met with a high degree
of confidence and the product performs as
intended. There are numerous 3DP technologies
described that can be used to manufacture drug
products and hence there are different process-
ing steps that are implemented to manufacture
a quality drug product. Because of the relative
novelty of 3DP, a higher level of scrutiny should
be expected due to the integration of a novel
manufacturing technique with traditional or
novel materials that have been reprocessed or
adapted to be enabled by 3DP. One unique reg-
ulatory consideration that is atypical from tradi-
tional pharmaceutical manufacturing is the
utilization of software in both the design of
the final product and in the control of the pro-
cess to manufacture the final drug product.
3DP involves a multistep software process that
is used to design and convert 3D dosage form
shapes ranging from simple/traditional to com-
plex (more on these designs will be highlighted
in the sections that follow), into sliced 2D layers
(using “slicer” software). This geometrical 2D
information is then used as input into control
software that then translates this information
into print commands. To enable consistency
across the industry, the FDA guidance proposes
the utilization of a specific file format for addi-
tive manufacturing (ISO/ASTM 52915 “Stan-
dard specification for additive manufacturing
file format”). The intention of this standard is
to create a well-controlled and integrated file
that describes the printed volume, material
information, and the print controls and print
location within the print volume. As will be
highlighted later, and perhaps more unlike
32 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

other traditional pharmaceutical applications, Table 2.9 highlights some of the critical 3DP
software processes are as critical as and, in processing variables and failure modes that
some instances, more critical of final product need to be considered when establishing the
quality compared to traditional pharmaceutical quality system for a drug product.
process hardware/critical process parameters.
Quality that is governed by software is not
only process control over material being 5. Pharmaceutical applications for drug
handled by the printer in terms of temperature delivery
and time as was pointed out earlier, but just as
important is the structure and path for the print- The current advantages of using 3DP for
ing tool that drives the printing of the drug pharmaceutical dosage forms are targeted at
product. dosage form design and patient customization.
Just like other pharmaceutical processes, 3DP Here we detail several published accounts of
often uses environmentally sensitive material as applying 3DP in the production of more tradi-
a matrix and therefore needs to be handled and tional oral dosage forms, customized oral
evaluated similarly. In addition, many physical dosage forms that highlight the ability to tailor
and chemical attributes that govern product doses and release rates to meet patient needs,
quality in traditional processes are just as impor- as well as nonoral dosage forms that aim to pro-
tant in 3DP. For example, particle size for SLS is a vide more patient complaint dosage forms
critical material attribute that defines not only through longer acting drug delivery. Another
final dosage form elegance but also mechanical advantage of 3DP in drug product development
strength and dissolution variability due to defect is the ability to circumvent the long and com-
populations because of broad particle size distri- plex clinical R&D process. This is especially
bution and insufficient sintering at specified true when the work requires: increasing drug
locations because of voids. solubility by converting the active ingredient
from crystalline to amorphous using processes
such as spray drying or HME, protecting the
TABLE 2.9 Examples of fused filament fabrication active ingredient from a specific region of the
process critical process variables and gut, or altering the drug release profile to over-
failure modes. come pharmacokinetic-related adverse events.
3DP can allow for production of dosage forms
Process variables Failure modes
that overcome these common R&D challenges
Hardware/software Voids between layers in a cost-effective and rapid approach in a
input/output Incomplete layer print single-step process.
Extrusion rate Interlayer adhesion
Retraction settings Plateepill adhesion
Nozzle temperature Stringing
Nozzle size Temperature excursions 5.1 Tunable release technologies
Nozzleeplatform gap Thermal degradation
Platform surface type
Currently, there are limited pharmaceutically
Platform surface roughness acceptable materials available in filament form,
Platform temperature which is the raw material feedstock for FDM
Flow rate printers. Many traditional polymer excipients
Print Speed do not have the appropriate thermal and
 5. Pharmaceutical applications for drug delivery
mechanical properties for filament processing
or the physical properties are altered when
drug is incorporated in the filaments. To have
a robust filament the polymer must be suffi-
ciently rigid to maintain its form as it is pushed
from the compression gear through the hot end
nozzle orifice of the printer. The polymer
should be sufficiently tough so the extruder
gear of the FDM printer can gently depress
and grip the filament to generate an extrusion
force greater than the resistance from the
molten polymer flow out of the nozzle. In addi-
tion, the melting temperature or glass transition
temperature must be significantly higher than
the temperature inside the printing enclosure
to allow forced air cooling to rapidly quench
the extrudate. The melting temperature should
also be below 250
C, which is the maximum
temperature allowed in most commercially
available FDM printers. Finally, to maintain
proper molten flow, the thermoplastic material
must not degrade while it is held at elevated
temperatures during the printing process for
extended periods of time, usually on the order
of minutes. Once a filament is extruded, X-ray
computed tomography can be used as a quality
check for surface or volumetric defects
[40a,40b]. Diameter variations in the filament
tend to strongly correlate with the quality of
the final print as most commercial printers do
not dynamically change the extrusion rate
based on the filament’s instantaneous diameter.
Typically, pharmaceutically acceptable poly-
mers have been experimented with varying suc-
cess. HPC has been used to print drug-free
capsules that are manually filled and assembled
postprinting [41]. Additional work has high-
lighted the difficulties and limitations of using
FDM for printing PVA capsules where the
dosage forms were printed for hand filling
with placebo liquids, followed by manual as-
sembly and sealing, and external and internal
33
surface roughness of the printed capsule walls
were investigated. Typically, however, the fila-
ment that is loaded into the FDM 3D printer is
preprocessed using extrusion to incorporate
active ingredients, which are then used to print
the final dosage form. PVP [10,41a,41b] mixed
with drug in an HME process has been used
with FDM to construct oral dosage forms.
PVA has been most commonly used due to its
beneficial mechanical and thermal properties
aiding the FDM process [6,8,30,40b,42e44].
Recent work on manufacturing filaments for
3DP examined the use of Eudragit EPO, a
cationic acrylic polymer with dimethylamine-
containing side chains, which is a polymer typi-
cally unsuitable for FDM due to its brittle prop-
erties [14]. This study showed that Eudragit
EPO could be compounded with a plasticizer,
triethyl citrate, and a nonmelting filler, trical-
cium phosphate, to optimize the hardness and
flexibility properties to enable printing of the
filament. The same research group
demonstrated the feasibility of printing an
enteric-coated 3D-printed caplet using the
same plasticizer and filler approach with PVP
and drug-free Eudragit EPO [10]. Other
extruded materials, where quinine was mixed
individually with Eudragit RS, PCL, PLA, and
ethyl cellulose at a 5 wt% drug loading, demon-
strated viability for use as FDM filaments for
preparing 3D-printed implants [44a]. It has
also been demonstrated that soaking filaments
in a poor or nonsolvent solution containing
drug can result in diffusion of drug into the
filament, although drug loading is intrinsically
lower than extrusion methods [42]. To date,
there are limited successful piloting examples
of pharmaceutically acceptable filaments, and
the surface quality of these printed dosage
forms indicates more optimization is required
before widespread adoption can be realized.
34 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

As of 2019, there are numerous examples of
applying 3DP to produce dosage forms in a rapid
prototyping method with variable and tunable
release rates within the same manufacturing
step. Several examples rely on incorporating an
API into the filament used in extrusion-based
3DP using a typical HME process
[1,2,5,9,10,41,43,45e48] or solvent-based diffu-
sional processes [26,42]. The primary limitation
with these approaches is the limited amount of
drug that can be incorporated into the filament
and hence the final 3D-printed dosage form
with typical drug loadings in the 1e30 wt%
range. The release rates of dosage forms made
by this approach are governed by either diffusion
or erosion for which the volume and geometry of
the final dosage form play are key role. An advan-
tage of this approach of manufacturing dosage
forms directly from drug-loaded filament is that
the final dosage forms are generally robust
enough to be used immediately after printing.
Figs. 2.9 and 2.10 highlights a well-known study
by Ref. [5,8,43,44] where the dosage form surface
area, surface area/volume, or mass were
discretely controlled and thereby directly
impacted the dissolution rate without changes
to the formulation.
Another degree of freedom in 3DP is the
modification of the infill parameters of the
printed tablet, which can manipulate diffu-
sional length scales as well as the dosage form
buoyancy and hence the release rates [1e3].

FIGURE 2.9 3D-printed dosage forms of various geometries using poly(lactide) as the primary matrix for tunable release
rates at constant (A) surface area, (B) surface area/volume ratio, and (C) mass (scale bar in cm). Adapted from Goyanes A, Chang
H, Sedoug HD, Hatton GB, Wang J, Buanz A, Gaisford S, Basit AW. Fabrication of controlled-release budesonide tablets via desktop
(FDM) 3D printing. Int J Pharm 2015b;496:414e420; Goyanes A, Martinez PR, Buanz A, Basit AW, Gaisford S. Effect of geometry
on drug release from 3D printed tablets. Int J Pharm 2015c;494:657e663; Goyanes A, Buanz AB, Hatton GB, Gaisford S, Basit AW.
3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm Biopharm 2015a;89:157e162; Goyanes A,
Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S, Basit AW. 3D printing of medicines: engineering novel oral devices
with unique design and drug release characteristics. Mol Pharm 2015d;12:4077e4084.
 5. Pharmaceutical applications for drug delivery 35

FIGURE 2.10 Paracetamol dissolution profiles from 3DP solid dosage with surface area/volume ratio 1 in phosphate
buffer (pH 6.8). Adapted from Goyanes A, Chang H, Sedoug HD, Hatton GB, Wang J, Buanz A, Gaisford S, Basit AW. Fabrication
of controlled-release budesonide tablets via desktop (FDM) 3D printing. Int J Pharm 2015b;496:414e420; Goyanes A, Martinez PR,
Buanz A, Basit AW, Gaisford S. Effect of geometry on drug release from 3D printed tablets. Int J Pharm 2015c;494:657e663; Goyanes
A, Buanz AB, Hatton GB, Gaisford S, Basit AW. 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. Eur J Pharm
Biopharm 2015a;89:157e162; Goyanes A, Wang J, Buanz A, Martínez-Pacheco R, Telford R, Gaisford S, Basit AW. 3D printing of
medicines: engineering novel oral devices with unique design and drug release characteristics. Mol Pharm 2015d;12:4077e4084.

Infill is the process by which the print head will
print an outer shell of the shape of the part and
the inside of this shell is filled in with a partic-
ular pattern to accommodate a predefined vol-
ume percentage. The material that is printing
between the outer shell is termed “infill” and
can be controlled through software to define
both the geometry of the infill material as well
as the amount of infill.
In addition to their use in solid filament as the
starting material for extrusion-based 3DP,
viscous pastes and UV curable polymers have
been shown to be viable feedstocks for
extrusion-based 3DP of active dosage forms
[46,47,49]. Preparing these starting materials as
shown in Fig. 2.11 requires less process develop-
ment as compared to an extrusion-based
approach; however, these dosage forms typically
require postprocessing, such as drying or active
thermal curing, and the mechanical properties
for the resulting dosage product have not been
investigated thoroughly. With both of these ap-
proaches, API chemical and/or physical stability
may be compromised. These paste formulations
have been printed using similar equipment to an
FDM printer, except the hot end is replaced with
a closed shot canister. Using this approach,
HPMC and polyacrylic acid (Carbopol 974P)
[46], HPMC and lactose [47], and HPMC hydro-
alcoholic gels [49] have been printed. Notably,
this approach has been used for polypills
[47,49], which are single oral dosage forms that
contain three or more isolated volumes each con-
taining a different active ingredient. While paste
formulations open doors to more material
choices, this approach typically requires
36 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

FIGURE 2.11 (i) Schematic diagrams of (A) the dispersion technique of hypromellose (HPMC) 2910 powder and
(B) formulation of HPMC hydroalcoholic gel [46]. (ii) Photograph of a RegenHU 3D printer (left) RegenHU Switzerland
(regnhu,com), and image of a multiactive tablet (right) (10.45 mm [height], 6 mm [radius]) composed of a captopril osmotic
pump compartment (bottom), and nifedipine (hole I) and glipizide (hole II) sustained release compartments (top) and joining
layer (middle).

subsequent steps such as overnight drying of the
print to remove any solvent or water from the
dosage form for long-term physical stability,
and it is unclear at this time how the mechanical
robustness of paste-printed dosage forms will
endure secondary packaging and user handling.
These are existing examples of implementing
3DP technology into rapid prototype release
rates using different strategies, largely focused
on maintaining a similar material feedstock
and using creative printing parameters to
generate various releases. With all the following
examples, at least one solid filament material is
preprocessed to contain API. The extrusion of
filaments or pastes has been used to manufac-
ture what are termed core/shell tablets, where
 5. Pharmaceutical applications for drug delivery
the outer shell’s thickness is varied, and has
demonstrated the generation of distinct release
rates. Core/shell tablets have been manufac-
tured by using a second API-containing mate-
rial [8] or a placebo material with the intent to
mimic enteric-coated tablets [9,10], and have
demonstrated the agility of 3DP to change the
onset of the release of the core of the dosage
form by as much as 2 h in vitro using the same
material feedstock. While these strategies have
been demonstrated to provide a software tun-
ing knob for release rate manipulation while
maintaining a constant material feedstock, all
of these strategies rely on HME formulation of
a printable filament for each API. Developing
process conditions to incorporate API into an
excipient-based solid filament is usually not
trivial [11e14], and these filament processing
developments add to the product development
burden, reducing the rapid prototyping advan-
tage 3DP brings to the table for early drug
screenings.
Fina et al. [52] presented the first published
work to utilize SLS for the production of oral
dosage forms using two thermoplastic
pharmaceutical-grade polymers, Kollicoat IR
(75% polyvinyl alcohol and 25% PEG
copolymer) and Eudragit L100-55 (50% metha-
crylic acid and 50% ethyl acrylate copolymer),
with immediate and modified release char-
acteristics. For this process to achieve print-
ability and aid in the sintering process,
pharmaceutical-grade silicate and oxide-based
pigments are added to improve laser energy
absorption and dissipation. In general, SLS-
printed dosage forms have poorer surface qual-
ity and higher porosity as shown in the example
from [52] (Fig. 2.12A). Control of the release rate
of the SLS dosage forms based on the research
thus far is governed more by the thermoplastic
material than by the printing conditions as
seen in Fig. 2.12B.
37
5.2 Paste/gel extrusion-based
technologies
A unique approach that attempts to incorpo-
rate both filament-based and paste/gel
extrusion-based technologies has been devel-
oped by Smith et al. [50,51]. The aim of their
work was to take advantage of the printability
of pharmaceutically acceptable polymers like
PLA and PVA while limiting the processing of
API to similar approaches shown earlier for
paste, liquids, and gel-based formulations.
They developed a single-step FDM 3DP process
to manufacture thin-walled drug-free capsules,
which can be filled with dry or liquid drug prod-
uct formulations. Drug release from these sys-
tems is governed by the combined dissolution
of the FDM capsule “shell” and the dosage
form encapsulated in these shells. To prepare
the shells, the 3D printer files (extension
“.gcode”) were modified by creating discrete
zones, so-called “zoning process,” with individ-
ual print parameters. Their work clearly shows
several unique aspects of the difficulty in 3DP
quality dosage forms that are elegant and water
tight. The geometry of the dosage form requires
a design that is specific to the 3DP process,
breaking from the more traditional shapes to
account for the physics of 3DP. In their work
they highlight the need to redesign the shape
with different angles (so-called zoning) using
software that is commonly available to the pub-
lic. Fig. 2.13 shows different colors within the
dosage form to show where FDM thermal and
mechanical process conditions are purposely
changed to improve the quality of the final
printed dosage form.
It is well known that the speed of FDM 3D
printers is not particularly fast as compared to
traditional dosage form manufacturing where a
rotary tablet press can accommodate on the
order of 1,000,000 tablets per hour. A 3D printer
38 2. Opportunities and challenges of 3D-printed pharmaceutical dosage forms

FIGURE 2.12 (A): Scanning electron microscopy images of the selective laser sintering of printlet vertical sections. On the
top from left to right, Kollicoat IR K5, K20, and K35. On the bottom from left to right, Eudragit L100-55 E5, E20, and E35, where
5, 20, and 35 represent the wt% of paracetamol used as a model active pharmaceutical ingredient. (B) Drug dissolution from
Eudragit SLS printlets. Adapted from Fina F, Goyanes A, Gaisford S, Basit AW. Selective laser sintering (SLS) 3D printing of medicines.
Int J Pharm 2017;529:285e293.
Another random document with
no related content on Scribd:
 “Robespierre has triumphed over the others, and he has
had Hébert, Vincent, etc., arrested and guillotined.
Robespierre had declared himself anxious to stop the flow of
blood ...; he had spoken up for the prisoners in the Temple.
Fresh letters are arriving here. It is certain, I think, that my
wife has not yet been charged with anything, or even
suspected of anything in regard to the prisoners.”
The event was inopportune. Cormier had just decided to leave
London for the coast, where he was to receive certain information
and to take counsel with his agents. Now his plans were all upset.
He would have to postpone the journey and redouble his
precautions.
At the end of five days there was ground for taking a hopeful view
of things. There was every reason to believe that Mme. Cormier’s
arrest would not have any grave results.
“What annoys me most,” writes Cormier to Lady Atkyns on
March 28, “is the fact that the news had got back to Paris,
with commentaries which may do harm both to my wife and to
our affairs.”
As a matter of fact, Peltier and d’Auerweck hastened, on hearing
of what had happened, to convey their sympathy to their friend, and,
like true journalists, spread the tidings in every direction, thus
intensifying Cormier’s uneasiness.
“But I must only try and put aside this anxiety,” he
continues, “as I have so many others. I have not yet started; I
shall not start before Monday or Tuesday, because I must wait
for replies from Dieppe, which cannot arrive before Sunday or
Monday. Have no fears; my courage will not fail me—indeed,
at present it is taking the shape of a feeling of rage, which I
am trying to keep down. You will have learnt from the public
prints that the statement has gone out that the King has been
carried off to the army of the Prince of Saxe-Coburg. This
false report has troubled me a good deal. I don’t want
attention to be directed that way just now, especially as
something has happened which would increase our
 confidence—something which I cannot at present confide to
paper. Do not exert yourself too much, madame; do not
measure your efforts by your courage. Your friends beg this of
you.”
In all these letters of the Breton magistrate there is a real ring of
sincerity. The admiration he feels for this interesting woman resolves
itself into a whole-hearted devotion to her cause, and if, later, her
large fortune and her generosity seem to have too large a part in
Cormier’s thoughts and too great an influence upon his actions, at
least he must be credited with absolute frankness throughout.
The death of Sir Edward Atkyns on March 27, 1794, gave Cormier
an opportunity for expressing his sympathy with the widow, and of
enlarging still further upon his feelings. The scant mention made of
Sir Edward, indeed, in the correspondence of this little circle
suggests that the relations between husband and wife must have
become perceptibly colder of late. It is probable that the baronet
looked with disfavour upon his wife’s schemes and the heavy outlay
they entailed.
“A score of times,” writes Cormier, “I have taken pen in
hand this morning to express to you the intense interest with
which I have learnt of the sad event which occurred, and as
often my courage has failed me. Truly you have been the
victim of many misfortunes. Will the Fates never have done
pursuing you? You must only make use of the great qualities
Providence has given you to bear up against what has
befallen. Your courage is exceptional. Make the most of a
quality which is rare with men, but rarer still in women. As for
me, I vow I shall not give in under my misfortune, and shall
not be put off by any perils.... I have not started yet, and shall
not start to-morrow, not having yet received the letters I was
expecting. If they come to-morrow, I shall start on Thursday.
So that this delay may not cause you anxiety, I may mention
that in the last letters which have come to me, he who left last
... asks me not to start until I heard again from him. He has
not been beyond D(ieppe), and the others have returned from
P(aris) to take counsel with him—I don’t know on what.”
 These last words show that something was already happening on
the Breton coast, and that it was desired to send news of interest to
Cormier. But the departure postponed so often was still
impracticable, and Cormier began to lose patience.
“I am still kept here,” he writes. “It is becoming incensing. I
feel as though I were being chained up, but prudence and
common sense keep me quiet. I get news regularly from
D(ieppe). I have just received a third letter enjoining me to
make no movement until they give me the word, and insisting
that the success of our project and the safety of him who is so
precious to us depend upon this. I don’t understand, however,
their not telling us why and how.... I have lost patience, and
have sent one of these gentlemen.[72] (That is not the same
as myself.) I am afraid that Hamelin may really have been
killed; I can’t make it out at all.”
Who was Hamelin? It is difficult to guess. It is difficult to identify a
great many of the individuals of whom there is question in these
letters, and who are designated by borrowed names. The most
elementary prudence called for absolute secrecy concerning the
names of the agents who were working for our committee, and
although the messages were carried by the most trustworthy
emissaries, it was always possible that one of them might be
arrested en route. This doubles our difficulty in clearing up the
imbroglio, and enhances a mystery already sufficiently troublesome.
Failing Mme. Cormier, who was still under arrest, and whose
absence had been making itself felt more and more, another
arrangement had been made for securing news from Paris. At what
expense? Heaven knows! But once again money had set tongues
going and procured the needed help. Cormier, coming back to the
question of his departure, writes again (April 14, 1794) to his friend
to tell her of the messages he has sent from England:—
“I shall not start until this evening,” he tells her. “You can
guess why. I have just despatched two messengers. Things
are moving, but very slowly. However, let us not lose heart. If
we go slowly we go all the more surely, and every day
 achieve something which helps to advance our schemes and
to keep us in security. Therefore do not be impatient.”
The weeks passed by, and that fateful day “9th Thermidor,” which
was to bring with it such a bouleversement in Paris, was drawing
nigh. At the Temple there had been no change—the Dauphin was
still sequestrated from the outside world.
On May 11, 1794, Robespierre visited the prison, and had a brief
interview with Marie-Therèse, but we have no information as to what
happened.
The 9th Thermidor arrives and throws the dictator down from his
pedestal, thereby proclaiming the end of his reign of terror. General
Barras, invested with the command of the armed forces within the
city, begins to take an important part in the management of affairs.
One of his first acts, it will be remembered, after he had triumphed
over Robespierre’s party, was to go to the prison of the Temple, on
July the 28th, accompanied by his brilliant staff, bedecked with gold.
The miserable aspect of the child after being shut up for months
caused the general to take immediate steps, and by his order of July
29, 1794, a special guardian, chosen by himself, named Laurent, a
native of Martinique, was brought to the prison, there to be entrusted
with the sole care for nearly five months of the young Capet.
A careful study of the documents bearing upon this period of the
captivity of the Dauphin makes it quite clear that in the hands of his
new guardian he was looked after in a fashion which contrasted
strongly with the previous neglect, and that he soon became
attached to Laurent, who proved himself good-natured, kind, and
even affectionate in his attitude towards his charge. If strange things
came about in the Temple at that time, we may be certain that
Laurent knew about them, and we may assume that Barras was the
prime mover in all that happened.
It is impossible, as we have said before, to recapitulate all the
arguments which tend to bring home to the general some complicity
in the fate of Louis XVII., and which implicate a large number of
persons, most of them people of influence in the world of the
Convention. Other writers, notably M. Henri Provins,[73] have done
this so conscientiously and thoroughly that there is no need for us to
attempt it. We may content ourselves with making public a series of
documents and newly ascertained matters, the gist of which bears
out exactly all that we knew already of Laurent’s conduct at the
Temple. Lady Atkyns and her friends could not have done without
him. It is true that his name never appears in their communications,
for reasons already given, but the striking connection between the
events within the prison walls and their effects in London upon the
Royalist Committee proves beyond doubt the relations subsisting
between them. Between the lines of these documents we get to
understand what Cormier meant by “new combinations.” Lady
Atkyns has been at pains to say it herself in one of her notes which
she used to make upon her correspondence, and which often serve
to explain her actions.
In his anxiety about the future, did Cormier entertain fears lest all
remembrance of his heroine’s devotion would vanish with her if by
some mischance her enterprise should fail, or if she herself should
lose her life? Who knows? However that may be, it is the case that
on August 1, 1794, he had two statements drawn up (the text of
which, unluckily, is not forthcoming), in which Lady Atkyns recorded
all that she had achieved down to that date for the safety of those
who were so dear to her.
“These records are to my knowledge the absolute truth,”
attested Cormier at the foot of the deposition, “and I declare
that ever since I first knew Lady Atkyns, she has always
shown the same purity of principles, and that all she has here
stated is true in every particular.”
These documents were to have been handed over for
preservation, with a number of others, to a solicitor or some
trustworthy person in London.
Meanwhile, renewed efforts were being made to bring about a
good service of news to the Continent and Paris. As time passed,
Lady Atkyns’ friends realized more and more that it would have been
madness to proceed with a regular attempt at a sudden rescue in the
actual conditions of things. In truth, the calm which had followed the
9th Thermidor, and which gave Paris time to take breath, was
making itself felt within the Temple. Laurent’s nomination was
evidence of this. Any attempt to act at once would have been sheer
folly. What was to be done was to “get at” those who had any kind of
influence within the Temple or without, whilst taking care not to let
too many people into the secret of the enterprise. Here, again,
unluckily, the wise secretiveness of all their papers prevents us from
ascertaining any names. Those who were tempted by Lady Atkyns’
gold to compromise themselves in any way, took too many
precautions against being found out.
Lady Atkyns, however, was not idle. Two sailing vessels were
continually plying between different points on the French coast. A
third, which she had recently purchased, had orders to keep close to
land between Nantes and La Rochelle, ready at any moment to
receive the Dauphin.[74]
The cost of keeping these three ships was considerable, and Lady
Atkyns had great difficulty in providing the money. She was in the
hands of agents whose services, indispensable to her, could be
depended upon only so long as the sums they demanded were
forthcoming. We can imagine the feelings of anxiety and
despondency with which she must have read the following letter from
Cormier. What answer was she to make to him? (The person to
whom she had applied for financial help appears on several
occasions in their correspondence under the designation of “le diable
noir.”)
“Your diable noir’s reply is very little consolation to me,”
writes Cormier; “he has promised and postponed so often.
For Heaven’s sake, see to it that he does not promise us this
time also to no purpose!... I gather that you were to have two
definite replies to-day—I shall be in Purgatory until five
o’clock. Mon Dieu! Mon Dieu! I wonder what you will send me,
or rather what you will be able to send me? Our own courage
alone does not suffice—we have to keep up the courage of
others, and they are losing heart. Worst of all, there is that
avaricious Jew of a captain! We are absolutely dependent
upon him. If we lost him where should we get another to take
 his place? I beg of you, in the name of the one you know, to
do all you possibly can, to exert all your resources, to prevent
his having to leave me empty-handed.”
And to excuse the ultimatum-like tone of his letter, Cormier adds—
“Forgive the urgent persistent style in which I write! But
when one is writing about business matters and matters of
this importance, one has to forget one is writing to a woman—
especially when it is a question of a Lady Atkyns, who is
different from the rest of her sex.”
The occasions for entering into communication with their agents
on the Continent are more propitious now than ever, but many efforts
are frustrated owing to the sharp watch which is kept along the
coast.
“They have tried eleven times to land since Saturday last,”
writes Cormier, “and failed every time. There were always
either people in sight or else there were transports sailing
from Havre to Dieppe or from Dieppe to Saint-Valery, etc., etc.
There has been a lot going on evidently, for signals have
been given on fifteen or twenty different occasions. That
shows how important it is to effect a landing. They returned
simply to make this fact known to me, and went back again
without coming on shore—except the captain, who came for
an hour and who is positive they have something to hand over
to him. I believe this myself, for I learn also this morning that
the Government boat which plies along the coast of Brittany
has made thirty vain attempts during the last three weeks.”
We can imagine the mental condition of poor Lady Atkyns on
receiving letter after letter in this strain. She no longer goes away
from London at this period, feeling too remote in the country from the
centre of news. She stays either at the Royal Hotel or else with
friends at 17, Park Lane. Here it is that she receives Cormier, Frotté,
Peltier. When there is a long interval between their visits her fears
grow apace. What would she not give to take an active part herself in
the enterprise! “No messenger arrived—no news, therefore, from
France,” that is the message that comes to her only too often. And
Cormier writes, full of excuses for his persistent appeals—
“Forgive my tone,” he writes. “I apologize a thousand times
for being such a worry to you, but I can’t help it in regard to so
important a matter, calling for so much energy and hurry. You
have voluntarily abandoned the position ensured you by your
sex and great advantages in order to play the rôle of a great
and high-minded statesman. There are discomforts and
disadvantages attached to this new estate, and it is my
misfortune to have to bring this home to you. I can but
console myself with the thought of your goodness and of the
great cause which we have embraced and which is the
subject of all our anxieties. May God prosper it, and may it
bring you glory and me happiness!”
In the mouth of any one but Cormier these protestations would
arouse one’s distrust; but what we already know of him, and what we
are to learn presently of his later conduct, serve to reassure us in
regard to him.
In spite of all his good will, however, Cormier is constantly being
interrupted in his work. Now it is the health of his son, Achille, which
disquiets him, now he is a prey to terrible attacks of gout which will
give him no rest.
“I have been bent double for two nights and a day,” he
writes to his friend on September 1, 1794, “without being able
to change my position. It takes four persons to move this
great body of mine. I am a little more free from pain at
present, and I take up my pen at the earliest possible moment
to send you this explanation of my silence.”
It is at this moment that Louis de Frotté, who has been a little in
the background, comes again to the front of the stage. Since his
arrival in London, the young officer, without neglecting the society of
the Royalist Committee, has been spending most of his time in the
offices of the English Government, endeavouring to impress upon
Windham “the desirability of carrying out his ideas, and the ease with
which they may be brought to fruit, as he has made up his mind to
devote himself to them.” One project he has specially at heart, that of
receiving some kind of official mission from the Government which
will enable him to land in Normandy with adequate powers and to
give new life there to the Royalist insurrection. Should he succeed,
the help he “would thus obtain would lead to the execution of our
cherished plans,” he writes to Lady Atkyns, and she will reap at last
“all the honour that will be due to the generous sacrifices that she
has made.”
But in his interview with the Minister he does not think it necessary
to speak of their relations with the Temple. This secret is too
important for him to confide it to any one. “Too many people know it
already.” These words, hinting a delicate reproach, are meant,
perhaps, to put his fair friend upon her guard. Perhaps they mean
more than that. Read in the light of subsequent letters from the
young émigré, they serve as a key to his private feelings—to his
dislike at having to share her confidence with so many others, and to
his jealousy later of the man who has so large a place in her heart.
These feelings, still slight, soon become more marked, and presently
we find that they are reciprocated.
For the time being, however, both Frotté and Cormier worked with
the same ardour at their allotted tasks. Frotté, proceeding with his
negotiation with Windham, counted now upon support from Puisaye,
his famous compatriot recently come to England. Cormier writes to
her to report that, despite apparent dilatoriness, their agents have
not been inactive.
“I have received letters through the captain,” he tells her on
October 1, 1794, “which satisfy me, brief as they are. Here is
what they have to tell me: ‘Be at ease in your mind; they
imagine they are working for themselves, and really they are
working for us, and we shall have the profit. Be patient and
don’t lose trust.’ The captain had orders to return at once to-
day, but he will not start until to-night or to-morrow morning,
and we have news by the packet-boats meanwhile that order
reigns in Paris.”
 Day after day passed by, bringing new reports, none of them
positive, of the death of the little Dauphin. Lady Atkyns knew not
what to make of the situation. Presently—eight days after the last—
there came another letter from Cormier, to reassure her.
“I have great faith in your judgment,” he declares, “and your
presentiments are almost always right, but I really do not think
that you have ground for disquiet now. Three agents of ours
at the Temple are either at work silently or else they are in
hiding. All we know for certain is that they have not been
guillotined, as they have not been mentioned in any of the
lists.”
His wife was still unfortunately detained, but there was prospect of
her being shortly at liberty, and then she would write to him. If the
agents had taken it upon themselves to modify their project—the one
thing that was to be feared—they could not possibly have succeeded
in sending particulars yet of this. But an explanation of the mystery
was soon to be forthcoming.
“The Dauphin is not to be got out by main force or in a balloon,”
Cormier had once written. Any attempt at carrying him off under the
very nose of his warders and of the delegates of the Commune
would have been madness. All idea of such a rescue had long been
put aside. How, then, was the matter to be dealt with? By such
means as circumstances might dictate—by finding a substitute for
the young prisoner, a mute who should play the rôle until an
occasion should offer for smuggling away the real Dauphin,
concealed meanwhile somewhere in the upper chambers of the
Tower. Mme. Atkyns did not herself approve of this plan.
“I was strongly opposed to it,” she notes at the foot of a
letter from Cormier dated June 3, 1795, “as I pointed out to
my friends that it might have an undesirable result, and that
those who were being entrusted with the carrying off of the
Dauphin, after getting the money, might declare afterwards
that he had not been got out of the Temple.”
She saw reason to fear that at the last moment she would be done
out of the recompense of all her efforts, and that the Royal child
would not be entrusted to her care.
However, it was clear that once the plan was agreed upon it was
necessary in order to carry it out to secure the help of the gaoler
Laurent, who had had the Dauphin under his charge during the last
four months. Laurent’s complicity may be traced through the
documents bearing upon the whole episode.
Let us examine first of all Laurent’s own famous letters, the first of
which, dated November 7, 1794, synchronizes with the events we
have been following.
It is well known that only copies of these letters are in existence—
the originals have never been discovered. They were published first
in a book which appeared in 1835, Le Véritable Duc de Normandie,
the work of an adherent of the pretender, Nauendorff, Bourbon-
Leblanc, whose real name was Gabriel de Bourbon-Russet, dit
Leblanc. From the fact of the originals being missing, the authenticity
of these letters has long been a matter for debate. A close
examination of them, side by side with all the other documents upon
which we have come in the course of our researches, results, we
think, in justifying our belief in their genuineness.
Cormier, then, was not mistaken in supposing that his agents had
modified their plan. The letter in which he confided his suspicion to
Lady Atkyns was dated October 8, 1794. On the last day of the same
month he wrote to her again:—
“I have to thank you cordially for your kind letter of
yesterday. I have had no time to answer it properly, not
because of the gout, for that has left me. In fact, my mind is
so fully occupied that I have no time to trouble about any kind
of malady, and am, in fact, at my wits’ end with excitement.
However, I must just send you this brief note in haste (for it is
just post time) to bid you not merely be at rest but to rejoice! I
am able to assure you positively that the Master and his
belongings are saved! There is no doubt about it. But say
nothing of this, keep it absolutely secret, do not let it be
suspected even by your bearing. Moreover, nothing will
happen to-day, or to-morrow, or the day after, nor for more
 than a month, but I am quite sure of what I say, and I was
never more at my ease in my own mind. I can give you no
details now, and can only tell you all when we meet; but you
can share my feeling of security. I am glad to say I have good
news of my wife, but I must continue to keep a sharp look out
all round me.”
This letter evidently alludes to what had happened at the Temple.
The young Dauphin, we may conclude, was halfway on his road to
liberty. Lodged in the garrets of the Temple tower, and with the little
mute as his substitute down below, he was not yet out of peril. But
an important step had been taken towards the ultimate goal.
It seemed clear that Laurent, l’homme de Barras, was having a
share in this, and had at least rendered possible the execution of the
project. The letter which he wrote eight days later to a general,
whose identity has never been established, bore out exactly what
Cormier had said; here it is:—
“General,
“Your letter of the 6th came too late, for your first plan had
been carried out already—there was no time to lose. To-
morrow a new warder is to enter upon his duties—a
Republican named Gommier, a good fellow from what B——
tells me, but I have no confidence in such people. I shall find it
very difficult to convey food to our P——. But I shall take care
of him; you need not be anxious. The assassins have been
duped, and the new municipal people have no idea that the
little mute has been substituted for the Dauphin. The thing to
be done now is to get him out of this cursed tower—but how?
B—— tells me he cannot do anything on account of the way
he is watched. If there were to be a long delay I should be
uneasy about his health, for there is not much air in his
oubliette—the bon Dieu would not find him there if he were
not almighty! He has promised me to die rather than betray
himself, and I have reason to believe that he would. His sister
knows nothing; I thought it prudent to pass the little mute off
on her as her real brother. Meanwhile, this poor little fellow
 seems quite happy, and plays his part so well, all
unconsciously, that the new guard is convinced that he is
merely refusing to speak. So there is no danger. Please send
back our faithful messenger to me, as I have need of your
help. Follow the advice he will convey to you orally, for that is
the only way to our success.
“The Temple Tower, November 7, 1794.”
The contents of this letter, taken together with its date, accord in a
remarkable way with Cormier’s communication to Lady Atkyns.
There is another striking argument in favour of the authenticity of
Laurent’s letters. When they were produced by the pretender
Nauendorff, they were for the most part in complete contradiction to
all that was known of the Dauphin’s captivity and the testimonies of
those connected with it. Certain facts to which they made allusion
were known to nobody. Thus Laurent states clearly on November 7
that a new warder—whom he calls Gommier instead of Gomin—is to
come to the Temple next day and to be associated with him. Now, in
1835, when this letter was published, what was known of Gomin?
Next to nothing, and the little that was known did not tally with
Laurent’s statements. Simeon Despreaux, author of a book entitled
“Louis XVIII.,” published in 1817, did not even know of Gomin’s
existence. Gomin himself made a formal declaration before the
magistrates that he entered the Temple about July 27, 1794, before
Laurent was there at all. Many years later it was found, on examining
all the documents referring to the Temple that were kept in the
National Archives, that Laurent’s statements were quite correct.
Some days after this letter to Lady Atkyns, Cormier informed
Frotté of the great news, in the course of a visit paid him by the
latter.
“I know all about it,” he said, according to Frotté’s account
of the interview afterwards in a letter to Lady Atkyns,
“because they could do nothing without me; but everything is
now ready, and I give you my word that the King and France
are saved. All the necessary steps have been taken. I can tell
you no more.... Do not question me, don’t try to go further into
 the matter. Already I have told you more than I had any right
to, and from Mr. Pitt down to myself there is now no one who
knows more about it than you do. So I beg of you to keep it
absolutely to yourself.”
From November 8, then, Laurent is no longer sole guardian of the
young Prince. His duties are henceforth shared with Gomin. What
kind of relations subsisted between the two? It is hard to say, for it is
even more difficult to find out the truth about the Temple during the
subsequent months than during those which went before.
We find one innovation introduced during these months which is
worth noting. It is no longer the delegates of the Commune who have
to pay the daily visit to the prison, but the representatives of the
Comités Civils of the forty-eight divisions of Paris. Now, among all
those who visited the Dauphin none left any record, with one
exception, to which we shall come presently. All that we can learn
from Gomin’s own statements, so often contradictory, is that
throughout the period the child placed under his care uttered no
word. The warder takes no further notice of this strange conduct,
Laurent having satisfied him that if the Dauphin will not open his
mouth it is because of the infamous deposition against his mother
that he was made to sign. It is unnecessary to point out how
improbable was this explanation, the Dauphin’s examination having
taken place on October 6, 1793, and Laurent not having come to the
Temple until July 29, 1794. Gomin, however, asked no further
questions, and Laurent experiencing no further anxiety in regard to
him, sought what means he could of bringing about the desired end.
Six weeks pass, however, without further progress, and then on
November 5 Laurent hears, to his great satisfaction, that his master
has become a member of the Committee of Public Safety. This new
office would surely enable the general to carry out his plan and
relieve the anxious guardian from the heavy responsibility lying on
his shoulders.
It was, therefore, not without surprise that on December 19
Laurent and Gomin saw three Commissioners of the Committee of
Public Safety make their way into the prison and up the stairway of
the Tower to the Dauphin’s cell. These three visitors—Harmand la
Meuse, Matthieu, and Reverchon—asked to see the Dauphin, so
that they might question him and satisfy themselves as to the way in
which he was kept under supervision. At a time when there were so
many rumours current about the Temple, and when rescues were
openly talked about, when every day brought forth some new
sensational report, it was only natural that the Convention, in order to
silence these rumours and calm public opinion, should institute an
official inspection of the prison in this way.
In a work which he published twenty years later, Harmand de la
Meuse tells us all that we know of this visit, and of the impression
made upon the delegates by the little mute ushered into their
presence. Suffice it here to record that this narrative (written with an
eye to the good graces of Louis XVIII.) makes it quite clear that it
was a mute whom they saw, and that all efforts to extract replies
were quite in vain.
Harmand repeats the explanation of this persistent silence which
had been furnished by Laurent. He ignores the fact that the Dauphin
had talked with the Simons, had been interviewed by Barras, and
had been heard to speak on several other occasions.
Assuredly, Harmand and his colleagues—his narrative allows it to
be seen on every page—very soon realized that they were not in the
presence of the Dauphin. This is proved by the fact that, despite the
very distinct terms of the resolution of the Committee entrusting them
with this mission, and the object of which was to dispel the rumours
current in Paris, “they decided they would make no public report, but
would confine themselves to a secret record of their experience to
the Committee itself.”
However natural and intelligible all this may have been to those
who knew what was in the mind of the Convention and the
exigencies of the situation at this period, to Laurent it was a matter of
stupefaction. Barras had sent him no warning, and his position was
getting more and more difficult, for his colleague, who had, of
course, to be taken into his confidence, was beginning to be nervous
about participating any further in the intrigue, and might betray him
any day. At last he loses patience, and expresses himself as follows
to his friend the unknown general:—
“I have just received your letter. Alas, your request is
impossible. It was easy enough to get the ‘victim’ upstairs, but
to get him down again is for the moment impossible, for so
sharp a watch is being kept and I am afraid of being betrayed.
The Committee of Public Safety sent those monsters Matthieu
and Reverchon, as you know, to establish the fact that our
mute is really the son of Louis XVI. General, what does it all
mean? I don’t know what to make of B——’s conduct. He
talks now of getting rid of our mute and replacing him by
another boy who is ill. Were you aware of this? Is it not a trap
of some kind. I am getting very much alarmed, for great care
is being taken not to let any one into the prison of our mute,
lest the substitution should become known, for if any one
examined him they would discover that he was deaf from
birth, and in consequence naturally mute. But to substitute
some one else for him! The new substitute will talk, and will
do both for our half-rescued P—— and for myself with him.
Please send back our messenger at once with your written
reply.
“The Temple Tower, February 5, 1795.”
Let us note the date of this letter—February 5. Therefore the visit
referred to must have taken place before February 5. Now, Eckard,
one of the earliest biographers of the Dauphin, having in the first
edition of his book made the date December 2, 1794, altered it
afterwards to February 13, 1795. De Beauchesne makes it February
27. Chantelauze, February 26.
On referring to the original documents at our disposal, however,
we find that Laurent’s letter is borne out. In his book, Le dernier roi
legitime de France, M. Provins shows that the visit must have taken
place between November 5, 1794, and January 4, 1795, as it was
only during this period that the three delegates were all members of
the Committee. A recent discovery of documents in the National
Archives establishes the fact that it took place on December 19,
1794.

FOOTNOTES:
[66] G. Lenôtre, Vielles Maisons, Vieux Papiers, 2nd series.
[67] A curious plan of this house is to be found at the
Bibliothèque Nationale, Print Department, Paris topography, the
Madeleine quarter.
[68] The decree of divorce of Marie-Anne-Suzanne-Rosalie
Butler, forty-nine years old, born at La Rochelle, resident in Paris,
Rue Basse, section des Piques, daughter of Jean-Baptiste Butler
and of Suzanne Bonfils; and Yves-Jean-François-Marie Cormier,
aged fifty-six, born at Rennes, department d’Ile-et-Vilaine, son of
the late Yves-Gilles Cormier and of Marie-Anne-Françoise
Egasse.
[69] V. Delaporte, article already quoted, Études, October,
1893, p. 265.
[70] Unpublished Papers of Lady Atkyns.
[71] Note in Lady Atkyns’ own handwriting at the end of a letter
of Cormier’s, dated March 24, 1794.
[72] M. M. de Corbin (note on the letter in Lady Atkyns’
handwriting).
[73] Henri Provins, Le dernier roi légitime de France, Paris,
1889, 2 vols.
[74] Note in Lady Atkyns’ handwriting at the foot of a letter from
Cormier, dated June 3, 1795.
 CHAPTER V
THE MYSTERY OF THE TEMPLE (continued)

Meanwhile the feelings of jealousy and suspicion which had

sprung up between Cormier, still Lady Atkyns’s principal lieutenant
and confidant, and the Chevalier de Frotté were becoming more and
more marked. At the beginning of October, 1794, Cormier learns of a
correspondence in progress between Lady Atkyns and a person
whom he imagines to be his rival (but who turns out to be merely the
“little baron”), and his ill-humour breaks out in the form of
reproaches.
“Chance has willed that I should become acquainted with
the fact that some one has been getting up a correspondence
with you,” he writes to Lady Atkyns, “in such a way as to
prevent me from hearing of it.... You will admit that I am
justified in assuming there are reasons why this
correspondence is being kept secret from me.”
But he proceeds to assure Lady Atkyns that she still retains all his
admiration and respect, and to protest that he only acquaints her
with the discovery that he has made because of his attachment to
her. Filled with mistrust of Frotté, Cormier withholds from him
particulars as to the progress of affairs at the Temple, and only
vouchsafes his information now and again in vague terms. “I refused
to give Frotté the names of the agents,” he wrote to Lady Atkyns
some months later. “Please remember that. I shall always be proud
of that.”
It is not astonishing that Frotté should show some surprise at the
way in which he was being treated, though he was prevented by
other causes of annoyance—his failure to get any satisfaction out of
the British Government and the repeated postponements of his
departure—from taking his position in this respect too much to heart.
 Lady Atkyns herself was keeping him at a distance at this time and
avoiding him when she came to London. When he asks for an
interview, she refuses on the pretext of her widowed state and public
opinion.
“I wished to avoid seeing or writing M. de Frotté,” she
herself records at a later period, “as I was not in a position to
talk to him about the means being taken for the rescue of the
King.”
However, on the eve of setting out from England into the unknown,
the Chevalier makes one more effort to see her.
“You do not write to me,” he begins his letter (December 27,
1794), “and I should be angry with you if I could be angry with
any one, now that I have all my wishes fulfilled. In three days
everything has changed, and I have nothing more to ask for in
England. The longed-for moment has come. P[uisaye] wants
me. I go with him, and all my requests are granted. We start
on Thursday at latest. It is important that I should see you. I
beg of you to set out at once and spend twenty-four hours
here, but without any one knowing of your journey, lest its
object should be suspected. Try to be here by Monday
evening, and let me know where I could see you.”
This time the appeal was too strong to be resisted. It was in the
depths of winter, and the letter arrived at Ketteringham in the
evening; but Lady Atkyns hired a post-chaise at once, and set out a
few hours later, and travelled all night in stormy weather to London,
arriving there in the morning. She seems, however, to have resisted
the temptation to let Frotté into the secret of the Temple doings.
Perhaps she had a presentiment that the Chevalier, for all his
protestations of fidelity now, would fall away later and pass into the
camp of some other pretendant to the throne.
We have spoken already of the endless intrigues which were
being hatched round the British Government by the hordes of
émigrés and broken-down exiles from the Continent. For these
gentry, mostly penniless and forced to beg their livelihood, no
resource was too base by which they could get into favour with the
Ministers. Besides scheming in a thousand different fashions against
the common enemy, the Revolution, they stuck at nothing in their
efforts to throw suspicion upon each other. The little court which had
gathered round the Comte D’Artois on the Continent was also a
hotbed of plots and schemes, the influence of which made itself felt
in London. Every one spied on every one else.
In the midst of this world of intruders a sort of industrial association
came into being in the course of the year 1794, for the purpose of
inundating France with false paper-money. It was hoped that in this
way a severe blow would be dealt at the hated Jacobins and their
friends. These nefarious proceedings soon became known, and
called forth the indignation of some of the better class of émigrés,
among them the honest Cormier.
His position among his compatriots was not at this time of the
best. They had no love for this man of firm character, faithful to his
principles and incapable of lending his countenance to such doings.
He himself soon came to realize this.
“One doesn’t know whom to trust,” he wrote to Lady Atkyns.
“I am sure some one has furnished the Government with a
long report upon my projects. I am on the track of the man
who I think is guilty. There is no reason for you to be anxious
on the subject. I shall soon know what has been done, and
both the traitor and the Government shall be outwitted.”
About this time a flood of memorials of all sorts poured in by
mysterious channels upon the British Government, maintaining that
“the general desire of the French was for a change in the ruling
family.” Cormier discovered that they all were traceable to the same
source, and we find him declaring energetically that “the
blasphemous scoundrels” who were responsible for them all
belonged to one clique.
His indignation, in which he found few sympathizers, made him a
number of enemies, and the disfavour with which he was already
regarded in French circles soon changed into downright hatred. The
fact that he denounced the false paper-money to the British
Government—and not in vain—was a cause of special bitterness