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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5947_Библиотеки_им_академика_М_И_Перельмана
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Editors and Contributors
About the Editor
Subham Banerjee, Ph.D. is an Associate Professor in the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER),
Guwahati, Assam, India. He is also a visiting staff faculty of the University of Texas
(UT) at Austin, Texas, USA. In addition, he is also serving as a coordinator cum
co-principal investigator of the “National Centre of Pharmacoengineering (state-ofthe-art facility)” funded under the Drugs and Pharmaceuticals Research Programme
(DPRP), Department of Science and Technology (DST), Ministry of Science and
Technology, Government of India. He has also served as an Assistant Professor
in the same department at the NIPER, Guwahati. His research area focuses on
pharmacoengineering including pharmaceutical additive manufacturing (AM), drug
delivery engineering, and cutting-edge translational pharmaceutical research.
He is the recipient of several prestigious national and international competitive
awards, notably Gandhian Young Technological Innovation (GYTI) Award (2017)
from Rashtrapati Bhavan (President’s Secretariat), New Delhi, India; Innovators
Under-35 (2017) from MIT Technology Review, USA; NASI-Swarna Jayanti
Puraskar (2020), Prayagraj, India, etc. He also bagged the first prize in 2020 for
BIRAC-BRTC Mapping the Changemakers of the Northeast Region of India and
many other prestigious recognitions, including several extramural research funds
from various funding bodies in the Government of India.
He has more than 9.5 years of teaching and research experience. He possesses
3 granted Indian patents, 2 granted Indian design patents, a 3D printed technologyderived product transferred to the industry, and 9 international book chapters and
has published more than 90 research articles in peer-reviewed national/international
journals.
He is an active member/associate/fellow of the leading learned scientific
societies of India and overseas as well. He is a “Member of the National Academy
of Sciences (MNASc),” Prayagraj, India; “Associate of the Indian Academy of
Sciences (IASc),” Bengaluru, India; “Associate of the West Bengal Academy of
Science and Technology (AAScT),” Kolkata, India; “Member of the Royal Society
of Chemistry (MRSC),” United Kingdom (UK); “Fellow of the Indian Chemical
xi
xii Editors and Contributors
Society (FICS),” India; and “Executive Committee Member of the Controlled
Release Society-Indian Local Chapter (CRS-IC),” Mumbai, I ndia.
Contributors
Subham Banerjee Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India
Ruy Carlos Ruver Beck Programa de Pós-Graduação em Ciências Farmacêuticas,
Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre,
Rio Grande do Sul, Brazil
Mahdi Bodaghi Department of Engineering, School of Science and Technology,
Nottingham Trent University, Nottingham, UK
Amedeo Franco Bonatti Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy
Naseem A. Charoo Succor Pharma Solutions, 216-Laboratory Complex, Dubai
Science Park, Dubai, UAE
Centric Compounding LLC, 216-Laboratory Complex, Dubai Science Park, Dubai,
UAE
Bodhisattwa Chaudhuri Department of Pharmaceutical Sciences, University of
Connecticut, Storrs, CT, USA
Department of Chemical and Biomolecular Engineering, University of Connecticut,
Storrs, CT, USA
Institute of Material Sciences, University of Connecticut, Storrs, CT, USA
Irene Chiesa Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy
Atchara Chinnakorn School of Physics, Institute of Science, Suranaree University of Technology (SUT), Nakhon Ratchasima, Thailand
Priyanka Das Department of Pharmaceutics, Polymer-based Medical Devices, and
Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education
and Research Kolkata, Kolkata, India
Pallab Datta Department of Pharmaceutics, Polymer-based Medical Devices, and
Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education
and Research Kolkata, Kolkata, India
Aurora De Acutis Research Center E. Piaggio and Department of Information
Engineering, University of Pisa, Pisa, Italy
Carmelo De Maria Research Center E. Piaggio and Department of Information
Engineering, University of Pisa, Pisa, Italy
Editors and Contributors xiii
Thayse Viana de Oliveira Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto
Alegre, Rio Grande do Sul, Brazil
Mansi Dixit Department of Medical Devices, National Institute of Pharmaceutical
Education and Research Kolkata, Kolkata, India
Gabriele Maria Fortunato Research Center E. Piaggio and Department of Information Engineering, University of Pisa, Pisa, Italy
Nadine Lysyk Funk Programa de Pós-Graduação em Ciências Farmacêuticas,
Faculdade de Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre,
Rio Grande do Sul, Brazil
Silke Henry Laboratory of Pharmaceutical Technology, Ghent University, Ghent,
Belgium
Tukaram Karanwad Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India
Canberk Kayalar Irma Lerma Rangel College of Pharmacy, Texas A&M Health
Science Center, Texas A&M University, College Station, TX, USA
Mansoor A. Khan Irma Lerma Rangel College of Pharmacy, Texas A&M Health
Science Center, Texas A&M University, College Station, TX, USA
Abbas Z. Kouzani School of Engineering, Deakin University, Geelong, VIC,
Australia
Mathew Kuttolamadom College of Engineering, Texas A&M University, College
Station, TX, USA
Júlia Leão Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de
Farmácia, Universidade Federal, do Rio Grande do Sul, Porto Alegre, Rio Grande
do Sul, Brazil
Srushti Lekurwale Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, Assam, India
Eman M. Mohamed Irma Lerma Rangel College of Pharmacy, Texas A&M
Health Science Center, Texas A&M University, College Station, TX, USA
Department of Pharmaceutics, Faculty of Pharmacy, Beni-Suef University, BeniSuef, Egypt
Wiwat Nuansing School of Physics, Institute of Science, Suranaree University of
Technology (SUT), Nakhon Ratchasima, Thailand
Center of Excellent on Advanced Functional Materials (CoE-AFM), Suranaree
University of Technology, Nakhon Ratchasima, Thailand
Koki Ogawa Drug Delivery and Nano Pharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
xiv Editors and Contributors
Tetsuya Ozeki Drug Delivery and Nano Pharmaceutics, Graduate School of
Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
Parimal Patel Department of Mechanical & Aerospace Engineering, University of
Texas at Arlington, Arlington, TX, USA
Ziyaur Rahman Irma Lerma Rangel College of Pharmacy, Texas A&M Health
Science Center, Texas A&M University, College Station, TX, USA
Prashanth Ravi Department of Radiology, University of Cincinnati College of
Medicine, Cincinnati, OH, USA
Koyel Sen Boehringer Ingelheim, Material & Analytical Sciences, Ridgefield, CT,
USA
Nidhi Singh Department of Pharmaceutics, Polymer-based Medical Devices, and
Complex Drug Delivery Laboratory, National Institute of Pharmaceutical Education
and Research Kolkata, Kolkata, India
Tatsuaki Tagami Drug Delivery and Nano Pharmaceutics, Graduate School of
Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi, Japan
Valérie Vanhoorne Laboratory of Pharmaceutical Technology, Ghent University,
Ghent, Belgium
Chris Vervaet Laboratory of Pharmaceutical Technology, Ghent University,
Ghent, Belgium
Giovanni Vozzi Research Center E. Piaggio and Department of Information
Engineering, University of Pisa, Pisa, Italy
Thomas G. West Independent Consultant, Lawrenceville, NJ, USA
Jaedeok Yoo FoundationLayers LLC, Princeton, NJ, USA
Ali Zolfagharian School of Engineering, Deakin University, Geelong, VIC,
Australia
History and Present Scenario of Additive
Manufacturing in Pharmaceuticals
Koyel Sen, Thomas G. West, and Bodhisattwa Chaudhuri
Abstract
Additive manufacturing also called 3D printing has provided a personalization
front to the pharmaceutical industry where dosage development can be patient
centric. If needed, 3D printed dosage form can be formulated with customized
shape, size, and release characteristics on the patient bedside. Hailing from
rapid prototyping and into biomedical field, 3D printing has convincingly
revolutionized pharmaceutical industry and its pace of innovation. 3D printing empowers the formulation design to new directions such as personalized
medicine, controlled released dosage form, organ on a chip, as well as implants.
Even until few years ago, it was implausible to foresee the adoption of 3D
printing to formulation development pipeline such as preformulation to First-inHuman (FIH). And now, 3D printing is being investigated to be used in front
line clinical trial setting to provide personalized service to the trial patients.
Around 30,000 articles in technological literature have already been published
discussing the futuristic application of 3D printing in pharmaceutical field.
The rapid progression of 3D printing in the pharmaceutical field is a result of
an extensive amount of past research, driven by its vast application potential.
1
K. Sen ()
Boehringer Ingelheim, Material & Analytical Sciences, Ridgefield, CT, USA
T. G. West
Independent Consultant, Lawrenceville, NJ, USA
B. Chaudhuri
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA
Department of Chemical and Biomolecular Engineering, University of Connecticut, Storrs, CT,
USA
Institute of Material Sciences, University of Connecticut, Storrs, CT, USA
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
S. Banerjee (ed.), Additive Manufacturing in Pharmaceuticals,
https://doi.org/10.1007/978-981-99-2404-2_1
1
2 K. Sen et al.
Hence, this chapter encapsulates the past and the present status of 3D printing in
pharmaceuticals with an open-ended future application possibility.
Keywords
AM · Additive manufacturing · 3DP · 3D Printing · Pharmaceutical
Sciences · Formulation development · Personalized medicine
1.1 Historical Foundation of AM Technologies for
Pharmaceuticals
Although Additive Manufacturing (AM) is considered a new category of technology
for pharmaceuticals, the underlying foundations of AM are more than four decades
old.
The genesis of modern AM is essentially 1984, when Chuck Hull filed the first
patent application for stereolithography (SLA) (Hull
was followed by the first patent application each for selective laser sintering (SLS)
in 1986 (Deckard
and the powder-liquid process now known as binder jetting in 1989 (Sachs et al.
1993). At the time, and for many years afterward, binder jetting itself was uniquely
referred to as three-dimensional printing, 3D printing, and 3DP before those terms
were adopted more widely across multiple forms of AM. Today 3D printing is a
common umbrella term, sometimes synonymous with AM.
The advent of modern AM was initially unrelated to pharmaceuticals. The
technology was created in order to form physical prototypes quickly from computeraided designs, allowing for rapid design review and iteration without the delay or
cost of creating traditional molds or tooling. Dedicated companies were set up for
this purpose, including 3D Systems for SLA, Desk Top Manufacturing (DTM) Corp.
for SLS, Stratasys for FDM, and Z-Corporation for binder jetting. Over time, DTM
Corp and Z-Corp were acquired by 3D Systems. Other companies and technologies
have since joined the field.
The AM of pharmaceuticals first emerged as part of the binder jetting research
at the Massachusetts Institute of Technology (M.I.T.) and later under licenses
from M.I.T. to startup companies. Initially Therics, Inc. explored pharmaceutical
use of binder jetting from 1993 to 2003 as part of a broader license for medical
applications. Therics ultimately narrowed its license to medical devices, obtaining
its first FDA 510(k) clearance in 2003 for TheriRidge bone substitute, a porous
hydroxyapatite implant made using binder jetting. That clearance represents an early
milestone for use of binder jetting in the manufacture of an FDA-regulated product
for use inside human body. Aprecia Pharmaceuticals was formed later in 2003 and
became the new exclusive licensee of binder jetting for pharmaceuticals, prioritizing
novel equipment designs to enable pharma-specific scale and operations. In 2011,
Aprecia opened its first centralized plant for scaled binder jetting, an essential step
toward regulatory entrée in the pharmaceutical field. In 2015, the FDA-approved
1989), fused deposition modeling (FDM) in 1989 (Crump 1992),
1986). Within 5 years, this
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 3
Aprecia’s 505(b)(2) New Drug Application for Spritam ® , the first ever approval
of a pharmaceutical product manufactured using a form of AM. Following this
milestone, interest in AM of pharmaceuticals accelerated.
Alongside binder jetting, other forms of AM have been applied to pharmaceuticals over time, with principal motivations for dosage form personalization,
point-of-use manufacturing, and on demand manufacturing. Proof of concept
research was performed to fabricate pharmaceutical dosage forms using FDM, SLS,
SSE, SLA, etc. (Fina et al.
2017; Goyanes et al. 2014; Khaled et al. 2014;Wuetal.
2009). In 2014, FabRx Ltd. was formed with interest in multiple forms of AM for
personalized pharmaceuticals. In 2015, Triastek Inc. was formed to commercialize
™
its material extrusion deposition technology, MED
3D, intended for centralized
manufacturing of novel dosage forms. In 2019, FabRx conducted the first clinical
study with personalized pharmaceuticals via AM—chewable tablets made using
semisolid extrusion (SSE).
In 2020, FabRx introduced the first commercial platform for small-scale personalized pharmaceuticals, the M3DIMAKER
sites (Sertoglu
2020). CurifyLabs was formed, aimed at personalized medicine.
™
, which is designed for use at clinical
Merck KGaA and AMCM/EOS announced a partnership for SLS-type AM of
tablets (Schrimpf G Merck KGaA, Darmstadt, Germany and B. Braun Join Forces
in the Development of Bioelectronic Devices
n.d.).
In 2021, Triastek received FDA clearance for their IND on product candidate T19
(Everett
2021;Trieste 2022). Aprecia introduced ZipCup™ (Z-Fill) orodispersible
shells (Pollinger and West 2021).
In 2022, CurifyLabs introduced MiniLab™ platform (SSE 3D printing) for
potential personalized medicine to be used for developing human and veterinary
dosage form (Ebrahim and Fahem
2022; Sjöholm et al. 2022). Triastek obtained
FDA clearance on INDs for candidates T20 and T21. Aprecia introduced its Z-Form
equipment design for binder jetting within blister packages (
https://fi.linkedin.com/
posts/aprecia-pharmaceuticals_aprecia-introduces-z-form-flex-manufacturingactivity-6987723679329656832-D2Jw?trk=public_profile_like_view).
Selected milestones in the AM of pharmaceuticals are illustrated in Fig. 1.1.
1.2 Overview of AM and Process Considerations for Use
in Pharma
The AM technology umbrella is diverse. AM processes differ from one another
in their capabilities for forming unit doses and in the type and extent of process
stress applied to the units made. Likewise, the AM techniques also differ in the
choice of materials that can be used and the types of structures that can be created
most effectively. This section will provide a synopsis of these factors for the main
families of AM applied to pharmaceuticals thus far. It will also mention some
current practitioners for certain technologies.
4 K. Sen et al.
Fig. 1.1 Foundations of AM for pharmaceuticals
1 History and Present Scenario of Additive Manufacturing in Pharmaceuticals 5
1.2.1 Stereolithography (SLA)
SLA uses liquid resin as feedstock material, which undergoes localized photopolymerization when contacted by a directed energy source such as a laser. The printing
process goes on to fabricate printed parts in layer-by-layer fashion onto a build
platform, typically within a vat of resin. The advantage of SLA 3D printing of
medicine is high resolution of the printing process compared to other printing
processes. Thus, it is possible to introduce very fine and complex physical features
into the dosage form. Moreover, due to the use of laser photo-cure mechanism
designed for near room temperature operation, SLA imparts low localized thermal
stress for short periods, which might make this process a candidate for some
thermolabile drugs. API can be directly incorporated in the liquid resin prior to
the printing process and therefore the drug can be entrapped in the printed dosage
form. During SLA printing, the build platform submerges in the liquid resin tank
and a UV laser initiates the cross linking of the liquid resin at the free surface
according to the CAD image file. After each layer is completed, the build platform
submerges further into the vat and the steps repeat until the desired height of the
part is complete. After the part is extracted from the vat, additional post-SLA curing
or other post-processing may be required.
SLA requires a (i) photocrosslinkable polymer, (ii) hydrophilic polymer, (iii)
photoinitiator apart from API for formulation development. However, the available
number of photocrosslinkable polymers available for formulation development
is limited such as Poly(ethylene glycol) diacrylate (PEGDA), poly(propylene
fumarate)/diethyl fumarate (PPF/DEF), poly(ethylene glycol) dimethacrylate
(PEGDMA), and poly(2-hydroxyethyl methacrylate) (pHEMA) (Wang et al.
A photoinitiator goes through photolysis and changes into a primary radical or
cation, thus initiating crosslinking process of the photopolymer and converting resin
to solid. Most initiator used in SLA 3D printing are either monoacylphosphine oxide
(MAPO) or bisacylphosphine oxide (BAPO) [Bao]. The ratio of photocrosslinkable
polymer and hydrophilic polymer can be adjusted to modify the drug release (Bao
et al.
2022; Wang et al. 2016).
Although it is one of the oldest forms of AM, challenges remain in the use of
SLA for pharmaceuticals. Due to the lack of FDA-approved photocrosslinkable
polymer, SLA has more limited options for raw materials when compared to other
AM options (Deshmane et al.
remain active topics for resin selection and design of any post-SLA processing.
2021). Toxicity of residual initiator and monomer
2016).
1.2.2 Fusion Deposition Modeling (FDM)
In its original form, FDM combines a melt extrusion nozzle with X-Y-Z motion
controls to provide for layer-by-layer deposition of the extrudate into a desired
part shape according to preprogrammed machine instructions. Compared to other
forms of AM, the parts produced are not automatically surrounded with support
6 K. Sen et al.
material that requires recycling or disposal, which can be advantageous for material
efficiency. However, support structures can be extruded if a complex shape requires
them.
Classic FDM uses filament as a feedstock for the printing process. As few offthe-shelf FDM filament materials are of pharmaceutical grade (such as ABS, Nylon,
ASA, PETG, etc.), pharmaceutical filament may need to be formed as a precursor
step. Hence, powdered pharmaceutical excipients must be screened for suitable
mechanical and thermal properties for filament formation. To bridge this gap, HME
(or similar processes) have been introduced in combination with FDM, either as
discrete sequential steps having a filament intermediate or as integrated apparatus
that forego a filament stage. Thus, the excipient selection in HME-FDM process is
driven by the processability requirement of HME and FDM.
Apart from the API, and depending on the drug delivery goals, formulation development for FDM (or HME-FDM) typically includes: (i) thermoplastic polymer, (ii)
disintegrant, and (iii) plasticizer.
Thermoplastic polymers consist of polymer chains associated by intermolecular
forces and are thermally shapeable by molding, extrusion, and sintering processes.
The thermoplastic polymer forms the physical matrix of a dosage form in which
the API would be embedded, and therefore has significant influence over drug
release. Pharmaceutical thermoplastic polymers which can be directly used in FDM
or HME-FDM include vinyl pyrrolidone and vinyl acetate copolymer (Kollidon
®
VA64), polyvinyl alcohol (PVAl), poly-lactic acid (PLA), hydroxypropyl cellulose
(HPC), and hydroxypropyl methyl cellulose (HPMC) (Fanous et al.
and Quodbach
2018; Than and Titapiwatanakun 2021). Other thermoplastics such
2021;Korte
as Eudragit based polymers have difficulty forming a flexible filament for FDM
alone and require formulation aids. For example, Sadia et al. (Sadia et al.
2018)
have successfully extruded FDM filament with Eudragit-E by incorporating plasticizer (Triacetin) and filler (tricalcium phosphate). The role of plasticizer in the
formulation is to lower the overall Tg of the formulation during extrusion, leading
to better mixing and lower brittleness in the filaments.
Since 2020, the M3dimaker™ has been available from FabRx (London, United
Kingdom). It is a small-scale FDM-type pharmaceutical compounding machine for
making personalized medicines in a decentralized manner. It can be configured
with specific print heads to perform filament extrusion, direct powder extrusion
(single screw), or semisolid extrusion (SSE) and is positioned for research, drug
development, and clinical practice (Markarian
at individualized dosing for patients. MED
2022). M3dimaker is largely aimed
™
3D (Deng et al. 2019; Zheng et al.
2021) from Triastek (Nanjing, China) is another FDM-type technology that is able
to work directly from API and excipient powders, forming parts with single or
multiple extrusion nozzles. In contrast to FabRx, Triastek currently uses MED 3D
in a centralized manner to develop and manufacture products for itself and its
partners. The technology is primarily positioned to create modular tablet designs
providing customized release profiles and bioavailability enhancement for clinical
differentiation.
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