3D Printing - shaping the future of formulation development

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
3D Printing -
Shaping the future of
formulation development
Thomas Kipping
18th of February 2021, Darmstadt

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1
2
3
Introduction
Overview of 3D printing technologies
Fused deposition modeling (FDM)
Improving filament properties
Novel 3D printing technologies
Advanced melt drop deposition
4
Future potential
Melt based 3D printing technologies

Overview of 3D printing technologies in the pharmaceutical industry
Introduction
2021-02-18 | 3D Printing - Shaping the future of formulation development
5
Powder based systems
▪ Drop on Powder, Binder Jetting (DOP)
▪ Selective Laser Sintering (SLS)
Extrusion based systems
▪ Solid forms: Fused deposition modeling
(FDM)
▪ Semi-solid forms: Pressure assisted
syringe
Liquid based systems
▪ Drop on Drop deposition (DOD)
▪ Stereolithography (SLA)
1
3
3D Printing in the
Pharmaceutical Industry
2
Liquid binder Laser
UV Laser Temperature
Temperature
Graphic modified from Jamróz et al. 3D Printing in Pharmaceutical
and Medical Applications - Recent Achievements and Challenges.
Pharmaceutical research. 2018;35(9):176

Potential future applications for 3D printing
Introduction
6
Rx
Diagnosis
Digital prescription
Design of the tablet
3D printing
Personalized medicine
Targeted therapeutic effect
Concept adapted from Lamichhane et al. Complex
formulations, simple techniques: Can 3D printing
technology be the Midas touch in pharmaceutical
industry? Asian Journal of Pharmaceutical
Sciences. 2019;14(5):465-79.
Pharmaceutical
applications

Future challenges during formulation development
Introduction
8
Permeability
Solubility
BCS
Class I
BCS
Class II
BCS
Class IV
BCS
Class III
35%
30%
25%
10%
5-10%
60 – 70%
5-10%
10-20%
Current distribution of
marketed drug substances
Distribution of drug substances according to their respective BCS
classification modified from Ting et al. Advances in Polymer Design
for Enhancing Oral Drug Solubility and Delivery. Bioconjugate
Chemistry. 2018;29(4):939-52.
Distribution of drug
substances in the pipeline
Bioavailability enhancement is an important topic also for 3D printing applications

Introduction
Types of solid dispersions – an evolution
9
Solid
dispersions First generation Crystalline carriers Urea & sugars
Second generation Polymeric carriers
Known polymers for
HME
Third generation
Mixture of surfactants
& polymers
Surfactants
Novel strategies:
Carriers provide
surfactant activity and/
or self-emulsifying
capabilities
Mixture of polymers
Fourth generation
Controlled release solid
dispersion
Release modifying
polymers
Vasconcelos et al. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today. 2007;12(23):1068-75
Info
Great advantage of polyvinyl
alcohol as a surface active
polymer with potential for
tailoring a broad range of
release kinetics

Product characteristics of Parteck® MXP
Introduction
Product Properties
Bulk density (g/mL) 0.53±0.02
Tapped density (g/mL) 0.74±0.02
Particle size (D50) (μm) 60-80
Loss on drying (%) <3.0
Angle of repose (°) 35
Tg
(by DSC)
Tm
(by DSC)
Td
(by TGA)
40-45 °C 170 °C >250 °C
Temperature
Melt Viscosity
D=200 (s-1)
Melt Viscosity
D=1200 (s-1)
210 °C 702 Pa*s 283 Pa*s
230 °C 345 Pa*s 174 Pa*s
Product Properties
Hydrolysis grade (%) 85-89
Solubility (%) (max. in water) 33
Mass average molar mass approx. 32,000
pH-value (4% / water) 5.0-6.5
10

Hot melt extrusion technology
Introduction
Potential
HME has a high potential to
become one of the most prominent
pharmaceutical formulation
processing technologies of the 21st
century:
➢ Continuous process
➢ Solvent-free
➢ Enhanced process
understanding
➢ Versatile application fields
Twin screw extrusion process involves heating, mixing and melting of an
API together with a polymeric carrier
11

Fused Deposition
Modeling (FDM)

13
Technology overview
Fused deposition modeling
Info
▪ FDM process is based on
extrusion of the molten
material
▪ Drug loaded polymer
filaments can be produced
via hot melt extrusion
▪ Commercial filament
diameters include 1.75 mm
and 2.85 mm
Conveyor belt
Twin screw extruder Winding
(optional)
1st step: Filament creation
2nd step: 3D Printing via FDM

15 2021-02-18 | 3D Printing - Shaping the future of formulation development
175
Target pressure:
~ 40 bar
200
200 200 195
200 190
80
200
200 200 195
200 190
80
Feedrate: ~ 0.3 kg/h, rotation speed: 150 rpm
Feedrate: ~ 0.3 kg/h, rotation speed: 150 rpm
Process evaluation
Twin screw extruder
(Pharma 11) Conveyor belt Laser measurement
Conveyor belt Laser measurement
Melt pump
(extrex® PFS)
190
Twin screw extruder
(Pharma 11)

16
In-process control required to
continuously monitor strand geometry
▪ Optical laser scanning technology
▪ 3 axes can be measured
simultaneously
▪ Very interesting PAT tool for process
monitoring
▪ System can be integrated in the
manufacturing process
Monitoring of filament geometry

17
With melt pump
Standard conveying belt
Without melt pump
In-process control – Placebo filaments
3-axis laser measurements: Continuous monitoring of diameter during filament production

18
With melt pump
Without melt pump
In-process control – drug loaded filaments (ketoconazole 20%)
3-axis laser measurements: Continuous monitoring of diameter during filament production

19
FDM 3D Printing process
Info
▪ Modified 3D printer
▪ Nozzle diameter: 0.4 mm
▪ Geometry: Cylindric shape
(diameter: 10 mm, height: 2.4
mm)
▪ Printing speed: 10 mm/s
▪ Infill density: 100%
▪ Printing temperatures:
▪ Parteck® MXP Placebo: 230°C
▪ Parteck® MXP API 20%: 210°C

Good performance during 3D printing independent of down-stream technology applied
for filament production
Characterization of 3D printed tablets

No major impact of different processing techniques
on dissolution kinetics is observed
Dissolution performed in 900 ml 0.1 N HCl,
37 °C, paddle method, n=3; normalized data
set
Characterization of 3D printed tablets - Dissolution

22
Parteck® MXP Placebo - with melt pump
Parteck® MXP Placebo - without melt pump
Fused deposition modelling
Characterization of 3D printed tablets – SEM images 1/2
SEM images of 3D printed tablets (up: Top view; down: Side view)

23
Parteck® MXP - Ketoconazole 20% - with melt pump
Parteck® MXP - Ketoconazole 20% - without melt pump
Characterization of 3D printed tablets – SEM images 2/2
SEM images of 3D printed tablets (up: Top view; down: Side view)

24
Latest publications
Info
▪ Optimization of a 3D
printing FDM process by
QbD approach
▪ Mechanical properties of
PVA based filaments can
be optimized by addition of
plasticizers (e.g. sorbitol)

26
Short summary
1
2
3
Enhanced process understanding
▪ Integration of latest down-stream technology broadens the process
window and provides solutions for challenging formulations
Polyvinyl alcohol
▪ Simple synthetic polymer with a high thermal stability
▪ Particle characteristics and melt viscosity of Parteck® MXP optimized
for hot melt extrusion resulting in homogenous filaments
Easy integration on existing FDM printers
▪ Due to the broad processing range of the polymer printing
parameters can be easily identified
▪ Mechanical properties can be individually adapted by
addition of plasticizers

28
Principle of Arburg Plastic Freeforming (APF)
Melt drop deposition
Process
1. Polymer is melted in a
heated plasticizer barrel
2. Via screw rotation the
material is transported to
the nozzle tip
3. Pressure generation via
translational movement of
the screw
4. Discharge of droplets
controlled via piezo
actuator
Simplified schematic view of the Arburg Plastic Freeforming process (APF)

29
SEM images of 3D printed tablets
Infos
▪ SEM Images of 3D
printed tablets
▪ Top- and side view
▪ Strands consist of
individual droplets
▪ High homogeneity of the
process

Application for tablet developments
30
Info
▪ Variation of infill
volume can be used
to individually
adjust the porosity
of the tablets
30% Infill 40% Infill 50% Infill 60% Infill
70% Infill 80% Infill 90% Infill 100% Infill
SEM images of 3DP tablets created with Parteck® MXP (variation of infillvolume))

31
Mass distribution
Info
▪ Homogenous mass
distributions can be
achieved
▪ Drug loading affects
homogeneity but still
remains within
targeted limits of
pharmacopoeias
Mass distribution of 3DP tablets (left: Parteck® MXP Placebo,
right: Parteck® MXP caffeine 10%), (n=6)

32
Mechanical stability
Info
▪ Diametral compression
was assessed with a
Texture Analyzer
▪ 3D printed tablets
based on Parteck® MXP
provide a high
mechanical strength
even at low infill
volumes
Mechanical strength of 3DP tablets (n=3)

Individual drug release profiles
33
Info
▪ Modification of
drug release
rates via infill
volume
Drug release from 3DP tablets Parteck® MXP, caffeine 10%; paddle method, 900 ml 0.1N HCl, 37 °C, 75 rpm

34
Short summary
1
2
3
Technology status
▪ Advanced technology already established in plastics industry
▪ Fast expansion in other technological fields expected
Application for pharmaceutical industry
▪ New technology provides a high accuracy for melt based printing systems
▪ High level of material deposition due to exactly defined droplet geometry
Key differentiation to existing FDM technology
▪ Process based on a single melting step direct from powder
▪ Enhanced processing range linked to direct extrusion
▪ Complex forms can be realized due to highly defined material deposition

Melt based 3D printing Technologies
Future Potential
36
Individualization and rapid
prototyping
➢ Personalized medicine will be an
important driver for 3DP technology
development
➢ Other fields of interest are rapid
prototyping and supply of clinical
trial material
Growth potential
➢ 3D Printing is gaining increased
attention in nearly all industrial
sectors
➢ Accelerated development timelines
will require new manufacturing
technologies
Key technologies
➢ Due to its simplicity fused deposition
modeling can serve as an enabling
technology for early formulation
development
➢ Current developments are also targeting
direct extrusion approaches
Polymer requirements
➢ High thermal stability of the
polymer is a key requirement
➢ Mechanical properties are rather
dependent on intermediates as well
as on constructive requirements

Thank you for your attention !

thomas.kipping@emdgroup.com
Dr. Mengyao Zheng
mengyao.zheng@emdgroup.com
Dr. Thomas Kipping

3D Printing - shaping the future of formulation development

3D Printing - shaping the future of formulation development

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