Development of a Simple Mechanical Screening Method for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament
Pharm Res
D e v e l o p m e n t o f a S i m p l e M e c h a n i c a l S c r e e n i n g M e t h o d for Predicting the Feedability of a Pharmaceutical FDM 3D Printing Filament
Jehad M. Nasereddin 0 1 2 3 4
Nikolaus Wellner 0 1 2 3 4
Muqdad Alhijjaj 0 1 2 3 4
Peter Belton 0 1 2 3 4
Sheng Qi 0 1 2 3 4
Guest Editor: Dennis Douroumis 0 1 2 3 4
0 Department of Pharmaceutics, College of Pharmacy, University of Basrah , Basrah , Iraq
1 Norwich Research Park, Quadram Institute Bioscience , Colney Norwich, Norfolk NR4 7UA , UK
2 School of Pharmacy, University of East Anglia , Norwich, Norfolk NR4 7TJ , UK
3 ABBREVIATIONS 3DP 3D printing ABS Acrylonitrile butadiene styrene ATR-FTIR Attenuated Total Reflectance Fourier Transform Infrared CPP Critical processing parameters DSC Differential Scanning Calorimetry FDA Food and Drug Administration FDM Fused Deposition Modeling HME Hot-Melt Extrusion HPC hydroxypropyl cellulose HPMCAS Hypromellose acetate succinate PAC Paracetamol PCA Principal Component Analysis PEG Polyethylene glycol PEO Polyethylene glycol PLA Polylactic acid PVA Polyvinyl alcohol PXRD Powder X-Ray Diffraction TA Texture Analysis
4 School of Chemistry, University of East Anglia , Norwich, Norfolk NR4 7TJ , UK
Purpose The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM. Methods A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments. Results Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts.
feedability screening; fused deposition modeling 3D printing; hot melt extrusion; plasticization; printability; solid dispersions
INTRODUCTION
In recent years, there has been a rise in interest in utilizing 3D
printing (3DP) as means to manufacture pharmaceutical
dosage forms due to its ability to produce bespoke objects
possessing high geometrical complexity quickly with high
precision and accuracy. This gives 3DP the potential for the
manufacturing of personalized dosage forms (
1,2
). FDM is a
variant of 3DP that utilizes filament-shaped thermoplastic
polymers as the building material. The mechanical assembly
of a FDM printing head consists of the feeding rollers, heating
zone, and the nozzle (
3–5
). The filament is fed into the printer
by the action of the two counter-rotating feeding rollers, as
illustrated in Fig. 1a. The filament is fed to a heating zone
where the filament is melted and extruded through the
printing nozzle onto the build plate layer-wise to form the desired
object.
For pharmaceutical applications of FDM, the
incorporation of a drug substance into the filament is achieved by two
methods, impregnation and hot melt extrusion (HME) (
2
).
Impregnation is done by immersing the filament in an organic
solution of the drug. This method often yields low levels of
drug loading (
6–8
). Preparation of FDM filaments by HME is
the more attractive method for pharmaceutical applications as
it allows for higher drug loading than the impregnation
method, and allows for the use of pharmaceutical-grade polymers
(
9–11
). Most hot melt extrudable pharmaceutical grade
polymers, however, do not possess the required properties to allow
for good quality FDM printing. This has been recognized as a
significant technical barrier for further developing the
pharmaceutical applications of FDM printing (
10
).
Critical process parameters (CPPs) which govern FDM are
categorised into three types of parameters: machine-specific,
operation-specific, and material-specific parameters (
12
).
Machine-specific parameters are parameters relating to the make
and model of the printer, operation-specific parameters are
parameters relating to the processing conditions during the printing
run, and material-specific parameters are parameters relating to
the physiochemical properties of the material being printed.
Most studies reported in the literature utilize commercially
available, hobbyist application printers which do not allow for control
of the machine-specific parameters. While such printers allow
control over operation-specific parameters such as printing speed
and temperature, restrictions imposed by polymer melt rheology
and the printer feeding mechanism generally result most
pharmaceutical polymers being unsuitable for FDM applications.
Although the CPPs of FDM have been identified and are
relatively well understood, there exists, to the best of our knowledge,
no preformulation tools have been developed to allow for a quick
and rational design of pharmaceutical FDM formulations. Most
formulations reported in the literature employed a
trial-anderror approach for development.
To achieve a continuous, high-throughput FDM printing
operation, the filament needs to be firstly feedable through
the feeding zone of the printer, and must also possess suitable
melt flow properties to be printable once is transferred into the
heating zone of the printing head. The filament-based feeding
mechanism employed by FDM printers utilizes mechanical
gearing arrangements to push the filament into the heating
zone (Fig. 1a) (
4
). In order to accurately control the feeding rate,
the filament has to be held tightly (pinched) between the two
rollers (
13
), leaving it effectively under compression throughout
the feeding process. In situations where the filament is brittle,
this is likely to cause the filament to fracture, discontinuing the
forward propulsion of the filament, causing a blockage in the
printing head, as illustrated in Fig. 1a. Blockages in the printing
head are very problematic; broken pieces of filaments inside the
printing head can contaminate the machine, compromising the
purity of any dosage forms one wishes to fabricate. Blockages in
the printing head are also difficult to clean, often requiring
disassembly of the entire printing head to be cleared.
Therefore, there is a need for screening the mechanical
suitability of the filament before attempting to feed the filament into a
printer.
For the scope of this article, the term feedability is used to
describe the mechanical suitability of a filament for FDM, with
non-feedable filaments being filaments that can cause a block
in the printing head of an FDM printer, regardless of whether
their melt flow rheology is within acceptable limits for FDM.
This study describes the development of a new formulation
screening tool for the predetermination of the feedability of
FDM filaments fabricated by HME from pharmaceutically
relevant polymers. This tool was built based on the understanding
of the relationship between the mechanical properties of some
pharmaceutical polymer blends and how they correlate with
their suitability for FDM. A number of simple in-house filaments,
commercial filaments, as well as a printable complex
pharmaceutical filament previously reported in the literature (the
material was a placebo filament containing Eudragit EPO,
Tween 80, PEG and PEO named as EUD was used in this study)
(
10
) were prepared and attempted to be fed into an unmodified,
commercial 3D printer to determine their feedability. A
custommade texture analyzer rig was used to test the filament response
in a compress-and-release cycle, yielding a plot of force (exerted
by the filament as resistance to deformation) vs. distance
compressed plot. The texture analysis experiments were used to
quantify the mechanical properties of the filaments and to
ascertain whether it is possible to predetermine the feedability of a
filament without having to compromise the printing head.
Using the force/distance plots (hereinafter referred to as the
flexibility profile) produced by commercial filaments as a control,
correlation analysis and principle component analysis (PCA)
were used to determine whether there exists a statistically
significant correlation between the flexibility profiles of different
filaments and their feedability (and subsequently printability). This
allows one to predetermine if hot melt extruded filament
possesses adequate mechanical properties to be feedable. A test
which can be used as a performulation tool to minimize
trialand-error when developing pharmaceutical formulations for
FDM. The relationship between the formulation composition
and the feedability of the filaments investigated in this study
can bring new insights into the development of principles in
rationalization of FDM formulation design.
MATERIALS AND METHODS
Materials
Acrylonitrile butadiene styrene (ABS) and Makerbot®
Dissolvable Filament commercial filaments were purchased from
Makerbot (Makerbot Industries LLC., New York, United
States). Polylactic acid (PLA) commercial 3D printing filaments
were purchased from XYZprinting (XYZprinting Inc.,
California, United States). All three commercial filaments were
used as purchased. Pre-plasticized polyvinyl alcohol
(otherwise known as Mowiflex®) C-17 grade pellets were graciously
donated by Kurary (Kurary GmbH, Frankfurt, Germany).
Hypromellose acetate succinate (HPMCAS, low-fine grade)
was graciously donated by Shin Etsu (Shin Etsu Inc., Tokyo,
Japan). Polysorbate (Tween® 80) was purchased from Acros
Organics (Acros Organics, Geel, Belgium). Polyethylene oxide
N-10 grade (PEO; molecular weight = 100,000) was graciously
donated by Colorcon (Colorcon Ltd., Dartford, United
Kingdom). Eudragit® EPO was graciously donated by Evonik
industries (Evonik, Darmstadt,Germany). Soluplus® and
Kollidon® vinyl acetate 64 (polyvinyl pyrrolidone vinyl acetate
64) were graciously donated by BASF (BASF inc., Ludwigshafen,
Germany). Polyethylene glycol 4000 (PEG; molecular weight =
4000) and paracetamol (PAC) were purchased from Sigma
Aldrich (Sigma Aldrich, Salisbury, United Kingdom).
Preparation of In-House Filaments
In-house filaments were prepared by HME, using a Haake
Minilab II hot melt compounder (Thermo Fisher Scientific,
Karlsruhe, Germany) equipped with a 1.75mm circular die. A
list of prepared formulations and their key extrusion parameters
can be found in Table I. All multi-component formulations were
cycled in the extruder for 5 min at a screw speed of 100 RPM to
ensure homogenous mixing (
10
). Following extrusion, filaments
with diameters of 1.75mm ± 0.05 mm were collected for further
testing.
Filament Characterization
Differential Scanning Calorimetry (DSC)
DSC was conducted using a Q20 differential scanning
calorimeter (TA Instruments, Newcastle, United States). All
inhouse prepared filaments were tested using a
heat-coolreheat cycle with a temperature range of 20°C to 185°C at
10°C/min. All samples were tested as fresh samples
immediately after extrusion. All tests were done in triplicates.
Attenuated Total Reflectance Fourier Transform
Infrared Spectroscopy (ATR-FTIR)
FTIR was conducted using a Vertex 70 FTIR spectrometer
(Bruker Optics Ltd., United Kingdom), equipped with a
M I R a c l e ™ s i n g l e r e f l e c t i o n A T R a c c e s s o r y ( P i k e
Technologies, United States) fitted with a diamond internal
reflection element. ATR-FTIR spectra were acquired in
absorbance mode, using a resolution of 2 cm−1, 32 scans for each
sample, within the range of wavenumbers from 4000 to
550 cm−1. Spectra analysis was conducted using OPUS
version 7.8 (Bruker Optics Ltd., United Kingdom). All
measurements were done in triplicate.
Powder X-Ray Diffraction (PXRD)
A Thermo ARL Xtra X-ray diffractometer (Thermo
Scientific, Switzerland) equipped with a copper X-ray Tube
(k = 1.540562 Å) was used to detect the presence of drug
crystals (if any) in the extruded filaments. A scanning range of 3°
< 2θ < 30°, using a step scan mode with step width of 0.01°
and scan speed of 1 s/step was used to conduct all
measurements.
Feedability of the extruded filaments was tested by feeding into a
standard Makerbot® Replicator 2X commercial FDM 3D
printer (Makerbot Industries LLC., New York, United States).
Successful extrusion of the polymer through the nozzle tip was
regarded as successful feeding, making the filament feedable. It
should be highlighted that the printing quality was not assessed
and is out of the scope of this study. All filaments were fed at the
printer’s default printing temperature of 230°C.
Texture Analysis (TA) Screening Test
Compression tests that simulate the feeding process of the
filament through the printing head were performed using a
TA.XT2 Plus Texture Analyzer (Stable Micro Systems,
Godalming, United Kingdom) equipped with an in-house rig
(Fig. 1b) and a 5 kg Load cell. Filaments were compressed axially
with a compression speed of 3.15 mm/sec, corresponding to the
roller movement speed of a Makerbot® Replicator 2X
(determined by feeding an accurately cut 10 cm filament into the
printer head and measuring the time needed for the filament
to pass through the printing head). 5 cm long filament pieces
were held standing in conical end caps to allow bending and to
avoid fracturing them with the clamps. The compression
distance was set to 15 mm with a trigger force of 0.05 N and data
was collected during both compression and release. TA tests were
done in triplicate for all tested filaments.
TA Data Manipulation and Statistical Analysis
Since the materials tested were of varying hardness, the scaling of
the flexibility profile (force (N) vs. distance (mm)) plots was not
directly comparable without data range normalization.
Therefore, data range normalization was performed using the
equation
Y nNormalized ¼ ΣY
Y n
where Yn is the nth point on the Y-axis (force). Correlation
analysis of the flexibility profiles of the pharmaceutical filaments with
those of the commercial filaments was conducted using
Microsoft® Excel 2016 expanded with the Data Analysis
addon. PCA was conducted using IBM® SPSS Statistical Analysis
Suite (version 25), with the Varimax rotation method, 25
iterations for convergence, extracting components possessing an
eigenvalue ≥1. The loadings of the three components with an
eigenvalue at or above 1 are reported in Table S1 in the
Supplementary Materials.
ð1Þ
RESULTS
Filament Characterization
There are 3 categories of pharmaceutical filaments produced
and tested in this study; pure pharmaceutical polymers which
are hot melt extrudable (HPMCAS, PEO, PVPVA 64, Soluplus,
Eudragit EPO), polymer-plasticizer blends (HPMCAS-PEO,
EUD, Soluplus-PEG, Soluplus-Tween), and drug loaded
filaments (HPMCAS-PAC, HPMCAS-PEO-PAC). The rationale
of including these different categories of the pharmaceutical
filaments is to test a broad range of pharmaceutical materials to
validate the screening method and develop understandings of
the effects of additives and drugs on the feedability and
printability of the pharmaceutical polymers. Figure 2 shows the DSC
thermograms of the physical mixes and extruded filaments of
HPMCAS based filaments. The DSC results of the rest of the
filaments are available in the Supplementary Materials Fig. S1
and the Tg of the filaments that were detectable by DSC are
summarized in Table II. Melting endotherms corresponding to
the Tm of PEO at ~60°C and Tg of HPMCAS at ~120°C were
seen in all physical mixes of the placebo and drug loaded
HPMCAS-PEO blends. For drug loaded physical mixes, a small
melting endotherm at ~169°C can be seen corresponding to the
melting of PAC form I (monoclinic form) (
14
). For placebo HP
filaments, the melting of PEO is absent in the low-loading
formulations (HP10, HP20, and HP30), but is clearly seen in
formulations with PEO content above 30% w/w (HP40, HP70 and
HP90). This result indicates that with 10–30% PEO loading,
Tg (°C)
124
−60
108
70
45
83
42
*The Tg of the rest of the in-house filaments
were not clearly identified using DSC
HPMCAS mixed well with PEO after extrusion and the
significant amount of HPMCAS was sufficient to prevent PEO from
recrystallization. When increasing the PEO content to above
30%, clear phase separation of crystallised PEO and
HPMCAS-PEO phase can be identified. Using the melting
enthalpy values of the PEO melting in the HP filaments and the
enthalpy value of the pure PEO (obtained from the DSC results
of pure PEO), it is possible to estimate the degree of crystallinity
of PEO in the filaments. HP90 and HP70 have 56.3 and 51.5%
crystallinity, respectively, which is much higher than the 30.8%
for HP40. This indicates that in high PEO content filaments
(HP70 and HP90) the continuous phase is the semi-crystalline
PEO. This contrasts with low PEO content filaments (HP10–30)
that has the HPMCAS as the continuous phase. For HP40, as
the contents of HPMCAS and PEO are close, it is reasonable to
expect that there is no one polymer dominates as a continuous
phase, which would contribute to the significant mechanical
property difference observed later in the texture analysis tests.
For drug loaded HP30D a small melting endotherm of PEO
was detected indicating the semi-crystalline nature of PEO in this
drug-loaded filament. The Tm of PAC was not seen in any of the
drug-loaded filaments, suggesting no crystalline PAC in the
filaments. The Tg values of the HP placebo and drug-loaded
filaments could not be clearly identified.
ATR-FTIR and PXRD were carried out to further confirm
the amorphous nature of the filaments and investigate any
possible molecular interactions between the polymers and additives.
Figure 3a shows the ATR-FTIR spectra of PEO and HPMCAS,
as well as mixture filaments. The spectra of HP10 and HP20
closely resemble that of HPMCAS. The C-H stretching peaks of
semi-crystalline PEO, occurring at 2876 cm−1 can be seen
slightly more defined in HP30, At higher PEO concentrations the
sharp PEO bands are dominating, nearly resembling the raw
PEO material, and indicating significantly increased crystallinity
of PEO in these filaments. In the spectra of HP70 and HP90 the
PEO peaks at 1341 and 1077 cm−1, corresponding to C-H and
O-H bending, are visibly unchanged in the placebo filaments
indicating no specific interactions between HPMCAS and
PEO. Figure 3b shows the ATR-FTIR spectra of PAC loaded
filaments. Across the whole spectrum, the sharp bands of
crystalline PAC are absent and a broad peak at 3321 cm−1, which
corresponds to the N-H stretching of PAC in its amorphous state,
can be seen in all drug-loaded filaments. In the drug containing
samples, there was no observable change in the carbonyl peak of
HPMCAS indicating the no significant hydrogen bonding
interactions with the drug. The PXRD patterns of the
filaments shown in Fig. 3c confirm the fully amorphous nature
of all drug-loaded filaments, as neither PEO nor PAC signals
are found in the diffraction patterns of HP10D, HP20D, and
HP30D filaments.
Filament Feedability Tests
Pure polymer filaments Eudragit® EPO, HPMCAS, PVP/
VA 64, and Soluplus® were found to be too brittle and would
fracture inside the printing head whenever feeding was
attempted. With the addition of low levels (10% w/w) of drug
(PAC) or plasticiser (PEG), HD and SP could still not be fed
through the FDM printer. Increasing the degree of the
plasticization (Tween 80 20% for ST and PEO 40% for HP40) in
the filaments led to over-plasticization. The ST and HP40
filaments were found to be overly flexible and coiled up inside
the feeding zone and would not thread through into the
melting zone of the printing head. The rest of the
pharmaceutical filaments were successfully fed through the FDM printer.
The feedability test results are summarized in Table III.
TA Screening Tests
TA tests were used to obtain the flexibility profiles of the filaments
under axial compression. The areas under the curves were then
normalized and plotted to give the comparisons of stress on the
filament vs. distance travelled by the probe as seen in Figs. 4 and
5. Using the data, it is possible to group their behaviour to
examine the correlation between the flexibility profile and the
feedability of the filaments tested directly using the FDM printer.
The ST and HP40 filaments were too flexible to be placed in the
TA rig (as illustrated in Fig. 4a). The rest of the non-feedable
filaments all shared a characteristic brittle fracture pattern, with
sudden discontinuation of force on the filament after reaching a
peak fracture force, as seen in Fig. 4b. These filaments fractured
immediately at the maximum force, showing no bending, plastic,
or elastic deformation to accommodate the increased strain.
Within the non-feedable filaments, Eudragit EPO, PVPVA64
and Soluplus exhibited much sharper fracture than HPMCAS,
HD and SP. This is evident by the longer travel distance of the
probe before the fracture of the HPMCAS, HD and SP filament,
and by the existence of some minor resistance to deformation by
the filaments after reaching the yielding force.
Despite seeming random at first glance, the flexibility profiles
of the feedable filaments, as seen in Fig. 5, all share a
characteristic bending deformation after the maximum strain bearing
point is reached. When the TA probe was returning to the start
position, the filaments could partially recover and straighten
within the rig even though they had lost some of their stiffness.
Of the feedable filaments, filament HP10 was notable the only
filament to fracture during TA. However, filament HP10 did
exhibit substantial bending after reaching peak tension force
and only fractured after being bent considerably by the texture
analyzer probe. Therefore, its recorded fracture pattern was
found to considerably differ from the sharp brittle fracture
patterns exhibited by non-feedable filaments, mainly HD and SP.
Figure 6 shows an example of a flexibility profile combined with
photographs of the filament at critical points in the profile.
During TA testing, the filament is subjected to axial compression
forces, as the TA probes continue moving towards each other,
the forces born by the filament continuously increase. At the
first critical point, the filament reaches the Euler point (yield
point), above which even the application of an infinitesimal
lateral force will cause bending. This is the bending point
highlighted in Fig. 6. After this, the applied force acts to both compress the
filament and to further bend the filament at the weakened bend
point which leads to the complex TA profile pattern of this stage
of test as seen in Figs. 5 and 6. Notably, this characteristic feature
of bending and maintaining structural integrity above the Euler
point was seen in all feedable filaments as shown in Fig. 5.
Correlation Analysis
The correlations between the flexibility profiles (the
normalized area under the flexibility profile) of each in-house
filaments and each of the three commercial FDM printable
filaments, ABS, dissolvable filament and PLA, were generated
and listed in Table III. This correlation can be treated as the
quantification of the level of similarity between the flexible
profile of the in-house pharmaceutical filaments and the
commercial printable filaments. The higher the correlation
score, the higher the mechanical similarity of the tested
filament to the commercial filaments. As seen in
Table III, for most of the filaments, the correlation
scores to the 3 commercial filaments vary. This is not
surprising as the correlations scores of the flexible
profiles of the 3 commercial filaments also varies indicating
there are some differences in their flexible profiles. The
correlation scores were further analysed by taking the mean of
the three correlation scores per filament using the equation
where Cx is the correlation score with commercial
filament x. Overall, all the in-house filaments that passed
the feedability test had an average correlation score
above 0.5; whereas the filaments that failed the
feedability test all had a correlation score below 0.5.
Furthermore, the correlation scores of plasticized
filaments were higher than those of non-plasticized
filaments indicating that plasticization improves the flexibility
of the filaments.
Principal Component Analysis (PCA)
PCA is a multivariate statistical technique that, from a data
table containing observations describing a multitude of
interrelated variables, can extract key information which is
represented as functions of BPrincipal Components^. Similarities
between the observations can be represented by plotting the
variables on a map referred to as a space plot (
15
). PCA was
performed to further explore the relationship between
flexibility profile of the filaments and their feedability. As the
correlation scores of the Dissolvable filament with the other
commercial filaments are low, the dissolvable filament
was treated as an outlier and was not included in the
PCA. For the PCA, the normalized full force-distance
curves were used the analysis. Principal Component 1
shows an eigenvalue of 10.13, Principal Component 2
shows an eigenvalue of 3.57, Principal Component 3
shows an eigenvalue of 1.51, while all other principal
components show an eigenvalue <1. By applying the
Kaiser Rule, the first three principal components were
extracted and the component loadings are shown in
Supplementary Materials Table S1.
Figure 7a shows the rotated space plot of Principal
Components 1, 2, and 3. The filaments aggregated on the plot
into five clusters. The feedable filaments aggregated into three
clusters, the first containing ABS, PLA, HP10D, HP20D, and
HP30D. The second contains filaments HP10, HP20, HP30,
EUD, and PEO. The third cluster contains filaments
Mowiflex, HP70, and HP90. The three clusters are closely
aggregated together and can be looked at as a single
macrocluster.
The fourth cluster contained filaments SP, HD, and
HPMCAS, which are the filaments that showed some
strainbearing ability in the TA tests but still fractured as the result of
compression (Fig. 4b). This cluster of slightly deformable brittle
filaments is closely positioned to the macro-aggregated cluster
of feedable filaments. Although the filaments in this cluster are
not feedable, they exhibited some potential, such that, with
formulations modification such as adding plastisisers, they can
be possibly be tuned to become feedable. The transformation of
the mechanical properties of HPMCAS upon the addition of a
drug (PAC) and a second polymer (PEO) is an example of such
tuning (Fig. 7b). The fifth cluster contains the highly brittle and
non-feedable filaments Eudragit® EPO, PVPVA 64, and
Soluplus®.
DISCUSSION
Correlation between Mechanical Properties and Feedability
This study is aimed to develop a screening method to speed up
the formulation development of FDM printable solid
formulations. To achieve good printability, the FDM filaments first need
to exhibit good feedability to allow the smooth and continuous
delivery of the filaments to the melting zone of the printing head.
As previously discussed, the feeding mechanism employed by
FDM printers involves mechanical pushing of a filament held
between two counter-rotating gears. In situations where the
filament being fed is too brittle to bear the mechanical strain
generated from the compression and pushing, this is likely to cause
the filament to fracture, discontinuing the force that is propelling
the filament forward, causing a block in the printing head. If it is
too ductile it will deform when begin passed forward and again
block the head.
For developing pharmaceutical FDM filaments, the polymers
firstly must be hot melt extrudable to form the filaments. When
HME is used in the fabrication of traditional solid dosage forms
(i.e. tablets), the extrudates produced often undergo particle size
reduction, to produce powders or granules with a suitable
particle size for pharmaceutical processing (i.e. compression) (
16
).
Unsurprisingly, brittle extrudates are more suitable in that
regard, as brittle materials require less time and energy to be milled
or granulated as opposed to ductile/flexible materials (
17
).
Therefore, most pharmaceutically relevant polymers that are
suitable for HME often yield brittle extrudates that readily
fracture, and while this makes such polymers suitable for traditional
pharmaceutical applications of HME, it renders those polymers
unsuitable for FDM implementation.
TA studies clearly show that there exists two types of
nonfeedable filaments, both highly friable, either with or without any
strain bearing ability. The additions of plasticizers caused an
increase in the strain bearing ability of the filaments. As an
example, pure Soluplus filament exhibited no strain bearing capacity
in the TA test, whereas the addition of 10% PEG (SP) shifted the
flexibility profile to the group exhibiting some strain bearing
capacity, owing to the plastisisation effect of the PEG. The
incorporation of plasticizers also decreases the glass transition, and
improves melt flow properties of thermoplastic polymers, which
are important factors that influence FDM. Among the
plasticizers used in the formulation of pharmaceutical blends for
FDM printing are triethyl citrate, triacetin, various grades of
polyethylene oxides (PEG and PEO), Tween® 80, and glycerol
(
6,8–11
). However when comparing the Tg data in Table II and
Fig. 5 Flexibility profiles of
feedable filaments. (a) the
commercial filaments, (b) the
placebo HP filaments, (c)
PACloaded HP filaments.
the feedability data in Table III, it is clear that the absolute Tg
values of the filament do not directly correlate to their feedability.
Over-plasticization of filaments was observed to also cause a
feeding defect; filaments HP40 and ST were found to coil inside
the printing head when feeding was attempted. Those filaments
possess little-to-no rigidity and would readily deform when any
force is applied, with their texture being more like that of fabrics
than thermoplastic polymers. This indicates that the appropriate
level of plasticization is vitally important. The non-feedability of
the overplasticized filaments is because they readily deform inside
the printing head making them unable to thread through the
melting zone for deposition. This lack of rigidity sits in stark
contrast to feedable filaments which are pliable enough to bend
and deform on handling, but retain their original shape when
force is released.
HPMCAS was selected as the platform polymer for drug
loading and plasticization screening because, although the
filament itself was not feedable, its flexibility profile clearly displayed
some strain-bearing properties comparable to those of plasticized
Soluplus (SP). The addition of 10% PEO was found to readily
transform the filament into a feedable one. Furthermore, the
addition of 10% PAC to the filament significantly changed its
fracture pattern from a brittle fracture to a slightly more ductile
fracture (Fig. 7b). This can be attributed to the plasticization
effect of the drug on the polymer. This is also supported by the
fact that although HP10 did fracture (but was still feedable),
filament HP10D did not, suggesting that the addition of 10%
PAC further increased the strain-bearing ability of the
filament HP10.
Filaments HP10, HP20, HP30, HP20D, and HP30D were all
found to be feedable, suggesting that, at least for HPMCAS,
there is a wide margin available for plasticizer loading without
unduly influencing the mechanical properties. Increasing the
PEO loading to 40% rendered the filament unfeedable
(HP40), which most likely is due to the significant phase
separation of HPMCAS and PEO as indicated by the DSC in Fig. 2.
Conversely, filaments HP70 and HP90 were found to be
feedable. However, the high PEO loading in comparison to
HP10, HP20, and HP30 means that the filaments are most likely
PEO-based with the HPMCAS being the second material in the
matrix. This is further supported by the color difference; HP10,
HP20, and HP30 all had the characteristic pale yellow color of
hot-melt extruded HPMCAS (
18
), while filaments HP70 and
HP90 were colored identically to the PEO filament. Based on
these results, it is reasonable to hypothesize that, in the case of
HPMCAS-PEO blends, the existence of a continuous phase
(either HPMCAS or PEO) as the primary matrix former is
important to maintain the mechanical strength of the filaments.
Using Flexibility Profile towards Screening
In terms of screening, the TA test was designed to simulate the
conditions inside the printing head as closely as possible, the
speed of compression was set to 3.15 mm/s, which matches the
speed of feeding inside the printer. Tested filaments were found
to exist in either one of three categories; brittle filaments,
stringlike filaments, and pliable filaments. Brittle filaments are
filaments that fracture during the analysis. String-like filaments
are filaments could not be tested due to them being too
flexible to maintain a vertically suspended straight beam shape
and would collapse under their own weight. Pliable filaments
are filaments that would deform due to compression by the
texture analyzer, but recover when the force is removed.
It should be noted that the aforementioned categories do not
have clearly defined boundaries, but are rather like a spectrum.
Filaments SP, HD, and HPMCAS, despite being brittle
filaments, did exhibit some pliability before fracturing. Inversely,
filament HP10 did fracture during TA, but the predominating
mechanical property it exhibited was pliability.
High correlation scores between the feedable in-house
filaments and the commercial filaments were observed. All feedable
filaments displayed correlation scores >0.50 with the commercial
filaments, indicating the significance of the relationship between
the flexibility profiles of the filaments and their feedability.
However, no observations were made that indicate feedability
existing as a spectrum property of the filaments (i.e. no filaments
were found to be Bmore feedable than others^). Feedability of
the filaments is a Boolean value, being either true of false. The
TA data is a curve which is then normalized and sorted into
categories by the statistical analysis. The normalisation procedure
used in this removes differences in the absolute values of force
applied. Mowiflex is feedable but notably much stiffer than all
other tested materials, with the minimum required force for
deforming Mowiflex being 120N. The higher stiffness of the
filament does not affect its feedability and indicates that a range
of absolute mechanical properties might lead to feedable
materials provided the shape of the overall flexibility profile falls within
the acceptable range. To further simplify the analysis, rounding
the mean correlation scores of each filament to the nearest
integer (values <0.5 are rounded down to 0, while values >0.5 are
rounded to 1) produces a method (Table III) that simply sorts the
filaments into feedable with a score of 1 (True) and non-feedable
filaments with a score of 0 (False).
PCA was used as a qualitative statistical method to sort the
different filaments using their flexibility profiles into feedable
and non-feedable filaments. As seen in Fig. 7a, three clusters
were observed in the rotated space plot of the filament
flexibility profiles. The feedable and non-feedable filaments are
well separated. Interestingly a cluster containing filaments that
can be easily tuned to become feedable (referred in the Fig. 7a
as ‘tunable’ filament) is also isolated. Using HPMCAS as an
example (Fig. 7b), by adding different types and amounts of
plasticizers, the non-feedable polymer and polymer blend
(HPMCAS and HD) in this cluster can be transferred into
feedable filament (HP10 and HP10D). This data
demonstrates that the flexible profile obtained from TA test
can be correlated to the feedability and used to predict
the potential of the FDM printability of the targeted
materials.
CONCLUSION
Mechanical properties of the HME filaments is an important
property determining the processibility for FDM 3DP. By
measuring the flexibility, one of the most directly relevant
mechanical properties of the HME filaments, this study
described the development of a simple method for screening the
feedability and subsequent printability of HME filament for
FDM printing. A wide range of filaments prepared using
pharmaceutical polymers and excipients were tested to
validate the method. The method described could accurately and
reproducibly separate feedable and non-feedable filaments.
Furthermore, coupled with PCA, more insights were gained
in the aspects of how plasticisation and phase separation could
influence the feedability of the pharmaceutical filaments.
ACKNOWLEDGMENTS AND DISCLOSURES
QIB receives strategic funding from BBSRC. The authors
report no conflicts of interest.
author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made.
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