TUGAS DESAIN RISET

ANALISIS REVIEW JURNAL

“ Parameter optimization in a continuous direct compression process of

commercially batch-produced bisoprolol tablets”

APT. OKE SETIAWAN GOSEPA, S. FARM.

2350411016

PROGRAM STUDI MAGISTER FARMASI

FAKULTAS FARMASI
UNIVERSITAS JENDERAL ACHMAD YANI
CIMAHI
2023
 International Journal of Pharmaceutics 628 (2022) 122355

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Parameter optimization in a continuous direct compression process of

commercially batch-produced bisoprolol tablets
Jenna Lyytika¨inen a,*, Pawel Stasiak b, T o m ´a ˇs Kubelka b, Tino Olenius a, Ossi Korhonen a,
Jarkko Ketolainen a, Tuomas Ervasti a
a
School of Pharmacy, PromisLab, University of Eastern Finland, Kuopio, Finland
b
Zentiva, Prague, Czech Republic

A R T I C L E I N F O
A B S T R A C T
Keywords:
Continuous tablet manufacturing is a competitive option to replace the traditional batch manufacturing
Pharmaceutical continuous manufacturing
Tableting
approach. The aim of this study was to evaluate technology transfer from batch-based direct compression of a
Process conversion commercial tablet formulation to continuous direct compression without changes to the composition of the
Multi-tip punches formulation. Some powder studies were conducted with the raw materials and multi-tip punches were utilized
Continuous powder blending in the tableting studies. To lower the high level of tablet weight variability that was evident during
Paddle speed preliminary tests, a process parameter optimization was performed using an experimental design with different
rpm values of force feeder and mixer impeller. By selecting the most appropriate settings of these parameters
for the studied product, the weights of the tablets could be controlled adequately to meet the specification
criteria. The func- tionality of the best-performing parameter settings was investigated with a three-hour-long
tableting run. The tablets were evaluated with the same quality criteria as the commercial batch-produced
tablets, and they passed all the tests performed in this study. Despite the challenging material properties
according to the flowability tests, production of tablets with the desired quality was achieved using the
original composition with continuous direct compression.

1. Introduction
production (de Beer et al., 2011; Saito et al., 2020; Skibsted et al.,
2007) and before the analysis results are finished, the batch stays
Continuous manufacturing of tablets is an innovative way of
quarantined, usually for some weeks. By monitoring and controlling
modernizing manufacturing processes in the pharmaceutical industry
critical quality attributes in real-time with Process Analytical
(Sierra-Vega et al., 2019). In 2021, ICH published a draft version of
Technology (PAT) tools, the full benefits of continuous processing can
guideline Q13 about continuous manufacturing of drug substances and
be achieved (Fonteyne et al., 2015; Pedersen et al., 2021). Monitoring
drug products, which stated that this approach was becoming a good
of critical process pa- rameters makes it possible to adjust certain
option to be adopted by the pharmaceutical industry. Compared to
parameters ensuring that the target properties of the end-product are
batch processing, continuous manufacturing offers many advantages
achieved already during the process which can lead to the possibility
like improved controllability, economic benefits, flexibility and
of real-time release.
accelerated product development (Ierapetritou et al., 2016; Pauli et al.,
Especially continuous direct compression (CDC) has attracted
2019; Srai et al., 2015; Vanarase and Muzzio, 2011). In continuous
widespread interest as it offers many benefits due to the very few unit
manufacturing processes, all the process steps are connected in series
operations in the process (Gohel, 2005). Another notable advantage
to each other, and the charging of raw materials occurs at the same that is gained with the use of CDC is the low amount of material in the
time when the end products are being collected (Pauli et al., 2019;
system at any given time which improves the process’s risk
Roggo et al., 2020; Yu and Kopcha, 2017). Traditionally the quality of
pharmaceutical prod- ucts has been assessed by testing small sets management
(Allenspach et al., 2021). Loss-in-weight (LIW) feeders are able to
of samples after their
monitor weight changes in a hopper that contains a screw-conveying
system for feeding the materials (Destro et al., 2021; Li et al., 2020).

* Corresponding author at: University of Eastern Finland, School of Pharmacy Yliopistoranta 1 C 70210 Kuopio Finland.
E-mail addresses: jenna.lyytikainen@uef.fi (J. Lyytika¨inen), pawel.stasiak@zentiva.com (P. Stasiak), Tomas.Kubelka@zentiva.com (T. Kubelka), tino.olenius@
uef.fi (T. Olenius), ossi.korhonen@uef.fi (O. Korhonen), jarkko.ketolainen@uef.fi (J. Ketolainen), tuomas.ervasti@uef.fi (T. Ervasti).

https://doi.org/10.1016/j.ijpharm.2022.122355
Received 22 August 2022; Received in revised form 24 October 2022; Accepted 25 October 2022
Available online 29 October 2022
0378-5173/© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355

After the material feeding phase, the powders need to be mixed before of multi-tip punches in the
compaction to ensure the formation of a homogeneous blend
(Berthiaux et al., 2008). One advantage of continuous mixers is that
they possess a lower risk of segregation than batch mixers due to the
lack of filling and emptying operations. Continuous horizontal mixers
typically consist of a cylindrical case and a mixing impeller and their
dimensions are signif- icantly smaller than the mixing containers that
are used in the batch processes (Tez˙yk et al., 2015).
Even though at first glance developing a CDC process for a certain
tablet product might appear as a simple task, it is essential to find the
optimal combination of manufacturing equipment and process param-
eters such as feeder types, feeding screws and the correct speed of the
tablet press turret, force feeder and the mixer impeller to fulfill the pre-
defined critical quality attributes of the product. For example, the ac-
curate feeding of the raw materials at given ratios in the process is one
of the key factors ensuring that there will be the correct concentration
of the active pharmaceutical ingredient (API) in the final tablets.
(Bostijn et al., 2019; Engisch and Muzzio, 2015a; Li et al., 2020;
Sacher et al.,
2021). Feeding performance is dependent on many factors such as the
material’s properties i.e. its density, cohesivity and electrostatic prop-
erties which may affect the screw feeding and other unit operations.
Different feeder types have differing ranges of operation regarding the
implementable mass flow rates which introduces some limitations on
the selection of material and feeder type combinations. In addition to
highly potent APIs, some excipients like lubricants and flow aid agents
require feeding at low flow rates to keep the total feed rate reasonable.
Another aspect that needs to be assessed is the refilling of feeders.
Since the tableting processes can be long and the hopper volumes are
limited, the feeders need to be refilled and the consequences of this
refilling process on the consistency of feeding should be considered
(Engisch and Muzzio, 2015b). Often the goal from a manufacturing
standpoint is increased tablet press speed to reduce the cycle time of
the process and increase manufacturing efficiency, but this may not be
the best oper- ating range for the system (feeders, mixers, and tablet
press). The force feeder speed is an adjustable tableting parameter that
is commonly set empirically, and the value affects tablet weight, inter-
tablet weight variation and tablet strength (Narang et al., 2010). It is
evident that tablet weight variation should be minimized to ensure
uniformity of content i.e. that the dose in a tablet is precise. (Mendez
et al., 2010; Mills and Sinka, 2013; Schomberg et al., 2020; Yaginuma
et al., 2007; Zaid et al., 2013). Inconsistent filling of the dies can also
affect tensile strength and other quality attributes like friability and
disintegration.
This study aims to demonstrate the possibility to exploit a technology
transfer from a batch-based direct compression of selected commercial
tablets to continuous direct compression without changes to the
composition of the formulation. If changes are made to the
manufacturing of a product that is already licensed, a registration
renewal evaluation is required before it can be released to the market
(Fonteyne et al., 2015). Both new compounds and previously batch
manufactured products have been produced in a continuous manner
and received marketing approval (Allenspach et al., 2021; Badman et
al., 2019). Studies regarding the comparison of batch and continuous
pro- cesses where a granulation step is included have been published
earlier (Matsunami et al., 2019; Miyazaki et al., 2020; Taipale-
Kovalainen et al., 2020). As far as we are aware, this is the first
publication where certain process parameter values of a CDC process
are explored when converting the production technique from batch to
continuous manufacturing while keeping the original product
ingredients and their proportions unchanged. The handled materials are
thus encountering new requirements for their properties since the early
process steps of CDC differ from batch production. The technology transfer
with original product compositions is assumed to be more
straightforward when multiple batch manufactured products are
commercially brought to continuous manufacturing lines because the
quality requirements can be compared or based on the already existing
specifications. An additional point in this work is the utilization
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J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355
continuous manufacturing of tablets which has not been published
previously.

2. Materials and methods

In this study, the manufacturing technology transfer trials were

conducted with a bisoprolol 10 mg tablet formulation. The
formulation composition is based on commercially batch-
manufactured immediate- release tablets of Zentiva. Their production
was tested with a continuous direct compression setup, and the
materials which are listed in Table 1 were used in the tableting.

2.1. Powder characterization

The raw materials were characterized with a scanning electron mi-

croscope (SEM) and with measurements describing flowability. The SEM
images of bisoprolol were taken with a Carl Zeiss Sigma HD VP
(Carl Zeiss NTS, UK). The powder samples were attached to
aluminum stubs with graphite conductive adhesive and then coated
for 120 s with gold using Agar Auto Sputter Coater (Agar Scientific ltd.,
UK). Magnifications of 200 and 1000 were used in capturing the
images. The angle of repose was measured with a PT-X Powder tester
(Hosokawa Micron Corpora- tion, Japan) to assess powder flow
properties. All excipients (except colorants), bisoprolol and the pre-
blend were tested in triplicate (the preparation of pre-blend is
described in section 2.3). The bulk and tapped density measurements
were conducted in triplicate according to European Pharmacopoeia
(2.9.34) in 250 ml measuring glasses. The tapping device was Erweka
SVM (Germany). Flowability was also assessed with another method
i.e. the Carr (compressibility) index was calculated according to Ph.
Eur. 2.9.36.

2.2. Feeding performance tests

Based on preliminary material-specific studies with different

feeder- screw combinations, the feeding performance was assessed by
comparing the relative standard deviations (RSD%) of the mass flow
rates. The values were recorded with a LabView-based software
(Lab- View 12.0, National Instruments, USA) and the results were
analyzed in Excel. The feeding data were also inspected visually and
the configu- rations with the least variation in the mass flow were
selected for the tableting runs. The feeding performance test results
are not shown. The screw types that were used in these studies can be
seen in Fig. 1. How- ever, there are also other screw types available
on the market (Engisch and Muzzio, 2015a). The K-CL-SFS-MT12 is
a microfeeder and the screws that fit this model were notably smaller
than the other feeders, but otherwise, their appearance was similar to
the larger fine concave screws.

2.3. Continuous direct compression setup

Up to four feeders can be placed around the mixer inlet in this

particular CDC setup. As the studied formulation consists of eight
different components, four feeders were used in this study and a pre-
blend was prepared to be fed with one of the feeders. The pre-blend
consisted of starch, crospovidone, silica and coloring agents. These
materials were selected for the pre-blending because silica would be
practically impossible to feed separately based on preliminary experi-
ments, and the amounts of coloring agents were small and thus their
separate feeding was not an option. Starch and povidone were
included to modify the physical properties of the blend so silica could
remain as an ingredient of the product. Overall, by selecting the
described com- ponents to be pre-blended the feed rate of the blend
became suitable. A V-blender (SNH509, SKF, Sweden) was used in
the pre-blend prepara- tion and around 3 kg of material was mixed at
one time. Optimization of the mixing process led to the addition of
silica in four parts every-three minutes to the rest of the components
in order to decrease the formation

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Table 1
Tableting materials.
Material Abbreviation Trade name Manufacturer Function % (m/m) in formulation

Bisoprolol fumarate Bisoprolol Moehs Active substance 9.09

Microcrystalline cellulose MCC Avicel PH-102 Mingtai Chemical Co. ltd. Filler 69.64
Pregelatinized maize starch Starch Starch 1500 Colorcon Inc. Binder 13.64
Crospovidone Polyplasdone XL ISP Chemicals LLC Disintegrant 3.00
Colloidal anhydrous silicon dioxide Silica Aerosil 200 Evonik Glidant 2.45
Magnesium stearate MgSt Peter Greven Lubricant 1.91
Iron oxide yellow Venator Pigments Coloring agent 0.18
Iron oxide brown Venator Pigments Coloring agent 0.09

Fig. 1. (A) Fine concave screws and (B) coarse auger screws. Fig. 2. The impeller of the Modulomix mixer.

of lumps. The total mixing time of one batch was 12 min and the
8 or 16 round and concave three-tip punches that had embossed marks
mixing speed was 20 rpm. After this first phase of mixing, the blend
and a score line. The tablet diameter was 6 mm, the target tablet
was transferred to a standard feeder fitted with fine concave screws.
weight was 110 mg, and the acceptable breaking force range was 40–130
The second mixing was done by feeding the material at a rate of 20
kg/h into a continuous mixer (Modulomix, Hosokawa Micron B.V., N. The
process was controlled and recorded with LabView-based software
Netherlands) which was operated at a rate of 700 rpm. The reasons for
(LabView 12.0, National Instruments, USA). Theoretical API% was
double mixing were guaranteeing the adequate uniformity of
calculated to evaluate feeding accuracy by adding the feed rate values
components as well as reducing the presence of lumps in the mixture.
(averaged 30 s) from separate feeders and then calculating the percent
The types of feeders that were used in this study can be found in
of the API feed rate. Tablet weight and breaking force values were followed
Table 2. The predetermined amounts of materials were fed to the
with process control samples using an analytical scale (202A, Precisa,
process by setting the individual feeder mass flows according to the
Switzerland) and a breaking force tester (CT5, Engineering systems,
formulation in such a way that the total feed rate of materials was 9.5
Nottingham ltd., England). The filling depth of the tablet press was
kg/h. The powders were guided to the continuous mixer (Modulomix,
adjusted manually according to the process control results.
Hosokawa Micron B.V., The Netherlands) via two ports: API, pre-
blend and MCC entered the mixer from the first port and MgSt from
2.3.1. Preliminary tableting studies
the second. The three first-mentioned materials entered the mixer
In the very first tableting experiments, every second of the 16 tablet
earlier to ensure a longer mixing time than for the lubricant which
press stations was in use. The press was operated with a turret speed of
entered the process slightly later to minimize the risk of overmixing.
60 rpm with a force feeder speed of 90 rpm (1.5 × turret speed), while
The impeller of the continuous mixer can be seen in Fig. 2. The rotary
the mixer impeller speed was 700 rpm. However, the process control
tablet press was a PR1000 (PTK, South Korea). Details of the CDC setup
tests revealed considerable variation in the tablet weight and breaking
which was used in these studies have been described in earlier
force values. As these kinds of phenomena are closely related to insuf-
publications (Ervasti et al., 2020; Simonaho et al., 2016). The tablet
ficient die filling, all 16 stations were taken into use decreasing the
press force feeder consisted of three paddle wheels, two of which were
turret speed to half (and the force feeder speed correspondingly)
interchangeable. The wheel options were either round or flat paddles.
providing additional time for a more uniform die filling. These settings
Tableting was conducted with
were tested with two one-hour tableting runs, the first run with flat and
the second run with round force feeder paddles. Round force feeder
paddles led to less tablet weight variation than the flat paddles, and
Table 2
thus
The feeder types and the materials that were fed with them.
they were used in all the following tableting runs. Since decreasing the
Feeder type (Coperion K-Tron, Switzerland) Twin screw type Material turret speed and changing the force feeder wheels did not eliminate the
K-ML-D5-KT20 Fine concave Pre-blend high variation in the described quality attributes, the possibility for
K-ML-D5-KT20 Fine concave MCC excessive material build-up in the mixer was studied. However, since
K-CL-SFS-KT20 Coarse auger Bisoprolol
no solution was found from these inspections, the challenge was
K-CL-SFS-MT12 Fine concave MgSt
approached with a design of experiments (DoE).
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2.3.2. Design of experiments DoE, half black and red dots are the same design points as in the first DoE.
After the preliminary studies, a DoE approach was used to examine
extensively the effect of force feeder and continuous mixer impeller
speeds on tablet weights. MODDE Pro 12.1. (Sartorius AG) was
utilized in the design of experiments. The first DoE was full factorial two
factors - two levels with a center point design. The factors and their
levels are presented in Fig. 3. In addition, the second DoE that was
also a full factorial two factors - two levels with center point design,
was built based on the results from the first DoE (Fig. 3). The response
was the standard deviation of tablet weight at 10 and 20 min in both
cases. In each design point, data were divided into three sets of tablets
(15 tab- lets/set) and included in the model (MLR, main effects and
interaction term included) to estimate the uncertainty in each design
point (these are not real replicates, since data was obtained from the
same run). In the first DoE, Cox-plot indicated considerable skewness
of responses, and therefore a log-transformation was used to remove
skewness. The goodness of models was evaluated based on R2 and Q2
values. In total, eight 20-minute tableting runs were completed to
acquire data for two DoE models. Before collecting the first samples,
the tablet weights and breaking forces had been adjusted based on in-
process control tests such that they should meet the earlier described
limits, so the powder feeding had settled before the process was
considered as having started. Tablets were collected for two seconds at
the time points of 10 and 20 min after which the tablet weights were
measured with an analytical scale (AG245, Mettler Toledo, Germany)
to assess the weight variation of tablets that were compressed in
approximately one turret round. In this way, the effects of the punches
and die filling could be assessed.

2.3.3. Process transfer verification run with optimized settings

The most suitable settings were chosen based on the knowledge
gained from DoE runs and were piloted by running the process for 3 h.
The turret speed was 30 rpm as in the DoE runs. The force feeder speed
was 60 rpm and the mixer was set to operate at 1000 rpm. The feeders
were refilled manually at 1 h 50 min — 2 h of processing time. The refill
of the API occurred first followed by the pre-blend, MCC and MgSt.
MgSt was refilled also at 1 h due to the volume of the hopper which was
small compared to the other feeder types in the setup whereas the other
ma- terials were filled only to study the effect of refilling on the feeding
performance. The collecting of samples at five-minute intervals was
started after finding the suitable compression settings. In this run, the
first samples were taken 17 min after the feeding had been started. The
filling depth was 9.85 mm at the beginning, and it was adjusted
throughout the process to maintain the tablet weights within acceptable
limits. At the end of the process, the filling depth was 7.78 mm. The
pre- compression and main compression settings were not changed. In
this run, the composition of the pre-blend was slightly modified from
the DoE runs as no coloring agents were used. However, this should
not

Fig. 3. Parameter settings in the DoE. The first DoE design points are illustrated
as black dots and the second DoE design points are in red dots. In the second

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J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355
affect the process since the amount of these materials would be very low.

2.4. Tablet tests

The quality of the tablets which were produced in the 3-hour run
with the optimized settings was assessed with some of the regular off-
line quality control tests of this product. Average tablet weight (n =
20 in triplicate), breaking force (n = 10), friability and disintegration
were assessed by analyzing samples that were collected every 15 min.
The tablets were weighed with an analytical scale AG245 (Mettler
Toledo, Germany). A CT5 breaking force tester (Engineering
systems, Nottingham ltd., England) was used in the measuring of
tablet breaking forces. Friability tests were done according to Ph. Eur.
2.9.7. with a TA3 (Erweka, Germany). A disintegration test was done
for six tablets from each of the selected time points with a DT3
(Sotax, Switzerland) appa- ratus following test A of Ph. Eur. 2.9.1.
Purified water was used as a solvent and discs were used in the test.
The acceptability limit for disintegration time was 15 min. Content
uniformity tests were per- formed according to Ph. Eur. 2.9.40.
and the internal procedure of
Zentiva. The samples for content uniformity analysis were taken
every 1 h meaning that there were four analyzed time points in the
process (0 h, 1 h, 2 h, 3 h).

3. Results and discussion

3.1. Powder characterization

The SEM images (Fig. 4) of bisoprolol revealed that the particles

were plate-like and had sharp corners and rough surfaces. Particle
size seemed to vary, with small particles showing a tendency to be
found in the vicinity of larger ones. Fig. 5 shows the angle of repose
results of the raw materials. Ph. Eur. chapter 2.9.36. describes the
flow properties of the materials based on the angle of repose results as
follows: starch, crospovidone and silica possessed fair flow properties
which means that aid regarding their flowability is not necessary.
MCC PH-102 was assessed as passable and these kinds of materials may
hang up. The MgSt was categorized as a poor flowing material along
with the pre-blend. Bisoprolol had very poor flowability. When the
Carr index results (Fig. 5) were assessed according to the same
chapter of Ph. Eur., it was noticed that MgSt and bisoprolol would be
categorized as materials with poor flow properties. In summary,
bisoprolol and MgSt displayed the poorest flowability based on both
measurements conducted in this study. This should be kept in mind
since cohesive and poorly flowing materials can introduce challenges
in LIW feeding (Allenspach et al., 2021; Byrn et al., 2015). However,
CDC has been successfully used in earlier studies to process cohesive
raw materials (Lakio et al., 2017; Roth et al., 2017).
It can be noticed from Fig. 6 that by mixing starch, crospovidone
and
silica to form the pre-blend, the bulk densities of the materials that
were placed in the feeders (MCC, pre-blend, MgSt and bisoprolol)
were more uniform than when all the densities of pure materials are
compared separately. Thus, the materials which were placed in the
feeders did not have significantly different bulk densities. This is
worth noticing since different densities between components are
factors that would affect the tendency of mixtures to segregate; for
example, this has been reported to increase the risk of high variations
in tablet weights leading to tablets failing to meet the set quality
requirements (Axe, 1995; Tang and Puri, 2007). Some additional
studies regarding mixture homogeneity after separate feeding of all
the components could be beneficial when seeking knowledge about
the possibility of material segregation with this product. However,
based on our experience, the feeding of silica alone has proved to be
challenging and thus some pre-blending of the in- gredients might be
necessary when one wishes to conserve the compo- sition of the
original materials present in this product.

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J. Lyytika¨inen et al.
Fig. 4. SEM images of bisoprolol at magnifications of (A) 200 X and (B) 1000 X.
Fig. 5. The angle of repose and Carr index results of raw materials and the
pre-blend.
Fig. 6. Bulk density results of raw materials and the pre-blend.
3.2. Process data analysis from the transfer verification run with
optimized settings
3.2.1. Feeder data-based estimation of the API content
It has been demonstrated in earlier studies that the feeders need to
run for a certain time at the start of the process before they will reach a
controlled state of feeding accuracy (Almaya et al., 2017; Ervasti et al.,
2015). This finding has been taken into account here i.e. the sample
collection was started after the tablet weight and breaking force results
had reached acceptable values. To obtain desired weights and breaking
forces adjustments were made to the filling depth, the pre-compression
and main compression forces. Fig. 7 illustrates the estimation of biso-
prolol concentration based on the feeding data from all four feeders.
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International Journal of Pharmaceutics 628 (2022) 122355
Fig. 7. Theoretical API%. The red line represents the average calculated %
during the whole run. The target setpoint is shown with the black dotted line.
There are some peaks caused by the deviations from the massflow set-
points in the graph, but this is common with feeding data (Bostijn et
al., 2019; Taipale-Kovalainen et al., 2019). The effect of these peaks
can be assessed with the tablet test results which will be discussed later
in the text. It should be considered, however, that the deviations in the
pro- portion of the API massflow cannot be seen exactly at the same
moment in the tablets. The powder is transported to the tablet press via
the mixer and other sections of the setup, which demands some time
before the material is compressed. In addition, these deviations in the
feeding can be smoothened to some extent by the axial mixing in the
continuous mixer (Portillo et al., 2010).
3.2.2. Compression force
The compression force is the most influential process parameter in
the determination of mechanical tablet strength (Pawar et al., 2016;
Sinka et al., 2009). The level of compression force (Fig. 8) was
relatively constant during the 3-hour tableting run, varying from 8.18
to 10.92 kN, and thus the fluctuation appeared to be acceptable based
on the breaking force results which can be found later in the text. The
undu- lation of the average main compression force occurred also in
the DoE tableting runs (Supplementary data, Fig. S1).
Powder bulk density, punch displacement and filling depth are ex-
amples of factors that affect the compression force (Singh et al., 2015).
The filling depth was adjusted multiple times during the process to
adjust the tablet weights. The need for adjustment is common during
the
J. Lyytika¨inen et al.
Fig. 8. The main compression force during the 3 h continuous direct
compression run.
tableting process. In this tableting run, however, the filling depth was
adjusted throughout the tableting and the depth was only decreased to
lower the tablet weights. This unexpected phenomenon might be
explained by some changes occurring in the powder densities. The die
filling depth changes (Supplementary data, Table S2) can thus be used
to explain the wave-like characteristics of the main-compression force
curve. The compression force tended to decrease after the adjustments to
the filling depth. One possible reason for some of the changes in
material properties is the heat that is generated in the tablet press
during the compaction process (Cespi et al., 2013). The temperature of
the mixer was also increasing during the process (Supplementary data,
Fig. S2). Punch displacement (or minimum tablet thickness) was kept
constant in this run, so that does not explain the wavy shape of the
curve. It is common, however, that the settling of the compression
force requires some time at the beginning of the process (Pawar et al.,
2016).
3.3. Tablet analysis
3.3.1. Design of experiments
In the first DoE, R2 and Q2 were 0.94 and 0.90, respectively, at the
Fig. 9. The effect of mixer and force feeder paddle speeds on the standard deviation of the tablet weights according to the DoE model. Results that are formed from
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International Journal of Pharmaceutics 628 (2022) 122355
10 min time point, and 0.96 and 0.92 at the 20 min time point. The
main factors and interaction terms were statistically significant (p less
than 0.05). Coefficients of all terms indicated that the increase of mixer
and force feeder rpm and the interaction term decreased the standard
de- viation of tablets weights (Fig. 9). The second DoE was conducted
with even higher mixer and force feeder rpm values (Fig. 3) to explore
if the standard deviation of tablet weights could be decreased further.
How- ever, higher mixer and force feeder rpm values produced
extensive variability in the replicates and no statistically valid MLR-
model could
be created (results not shown). Additional information on the model is
available in the supplementary material (Fig. S3 – Fig. S5, Table S1).
The tablet weight results with standard deviations are presented in
Fig. 10. Since the results are formed from the individual weights of
tablets that were compressed within one turret round, the standard
deviations describe the variability within narrow time points in the
process. The results are highly similar at both time points which
implies that the phenomenon was a property resulting from die filling
and not a temporary effect that would be present at a specific time
point. This hypothesis was confirmed also by the process control
results where the variance in the adjustability of the tablet weights was
examined. In some instances, it might be suspected that punches with
multiple tips might have been responsible for the weight variation of
tablets (Kurashima et al., 2020). However, the weight variation found
in this study cannot be explained due to the multi-tip design of the
punches since the same punches were used in all the runs. When the
settings of a force feeder speed of 60 rpm and a mixer impeller speed
of 400 rpm were scrutinized, the high variability of the average weight
was evident. Despite the ef- forts to keep the weights as constant as
possible, the result did not meet the objective with the described
parameter values. When the other ex- tremity regarding the standard
deviation and remaining close to the target weight was reviewed, the
parameter values of force feeder speed 60 rpm and mixer impeller
speed 1000 rpm were determined as the optimal combination of the
studied settings. According to the standard deviation results, the
greatest variation occurred when the mixer speed was low. It appears
that the round paddles in the force feeder were acting as an additional
mixer since a higher paddle speed could offset a lower feeding speed.
On the other hand, increasing the mixer impeller speed to 1300 rpm
increased the variability, especially when also the force feeder speed
was elevated. The same principle of finding an optimal parameter
value concerned the force feeder speed since choosing too low or too
high values expanded the level of variation.
The results illustrate the importance of selecting suitable parameter
values from the perspectives of product quality and model formation.
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355
samples taken at 10 min are shown on the left side (A) and at 20 min on the right (B).

9
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355

Fig. 10. Average weights of tablets that were produced with different combinations of force feeder and mixer speeds. The analyzed tablets were taken from the
processing time points of (A) 10 and (B) 20 min.

Though, it has been reported that the influence of force feeder speed
compression force curve (Fig. 8). Fig. S7 and Fig. S8 in the
might depend on the materials being tested (Peeters et al., 2015). The
supplemen- tary data assist the comparisons of these two figures. The
effect of some parameter values has been investigated in an earlier
greatest weight variation occurred at the beginning of the process
publication (Roth et al., 2017). It was concluded that the effect of
which can be attrib- uted to variations in the compression force, die
continuous mixer speed values exerted a low impact on the critical
filling and possible al- terations in material characteristics caused by
quality attributes in a CDC process where a cohesive API was used. In
the increasing heat during the compression (Cespi et al., 2013; Patel et
our experiments, a wider range of speed values was used, which might
al., 2015; Rou`eche et al., 2006). In summary, some variability in
have helped to reveal the different levels of mass variations. The mixer
tablet weights must be accepted since tablet presses are currently not
speed value of 400 rpm caused the greatest standard deviations in these
capable of producing identical tablets but nonetheless, the variability in
experiments. The best controllability and the lowest standard
the measured samples is considered acceptable.
deviations were achieved with a force feeder speed of 60 rpm and a
The average breaking forces are presented in Fig. 12. The
mixer speed of 1000 rpm. The suitability of these settings was tested in
acceptable range of breaking forces was 40–130 N according to the
a longer tab- leting run. The angle of repose measurements were
specification and all the measured time points complied with the
conducted with powder blends that were collected from the force
limits. The breaking
feeder after each DoE run. The results can be found in the
force values changed during the process probably due to the alterations
supplementary data (Fig. S6). No significant differences were found in
in the filling depth. Nevertheless, no results were close to either the
the results to explain the differ- ences in tablet weight variabilities.
upper or lower limit at any measured point.
All the studied tablets passed the friability and disintegration tests.
3.3.2. Process transfer verification run with optimized settings
Tablet friability results were below 0.1 % whereas the acceptability
The average tablet weights can be found in Fig. 11. All samples
limit was 1 % weight loss. Based on the breaking force and friability
complied with the requirements since the lower limit was 106.7 and
results, it can be assumed that the tablets possessed sufficient
the upper limit was 113.3 mg. The weights followed the shape of
mechanical integrity to stay intact during bulk handling until
the
administration (Sinka et al.,

Fig. 11. Average tablet weights from the 3 h tableting run.

Fig. 12. Average tablet breaking forces from the process transfer verifica-
10
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355
tion run.

11
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355

2009). The disintegration of tablets occurred in less than 7.5 min in all 3h 4.78
the analyzed time points and thus the results met the specification limit.
The formulation contains crospovidone as a disintegrant to degrade the
tablets into fragments when they encounter fluids. This ensures a rapid
increase in the contact area between the drug and the gastric fluids
(Basaleh et al., 2020; Desai et al., 2016). Details of the friability and
disintegration results can be found in the supplementary data (Table
S3). Table 3 shows the calculated content uniformity acceptance values
(AV%) of the selected time points. The upper limit for the AV is 15 ac-
cording to Ph. Eur. 2.9.40. which in this case means that the samples
passed the requirements applying for the batch-manufactured product.
As can be seen from Fig. 8 which illustrates the calculated bisoprolol-%
based on the feeder data, the process was still settling at the time when
the first samples were collected. The content uniformity results were
acceptable even at the beginning of the process at the 0 h time point
where the measured weight variation was the highest. The relatively
high value at 2 h might be related to the refilling of the feeders.
It is sometimes reasonable to prepare a pre-blend in continuous
tablet manufacturing (Roth et al., 2017; Stauffer et al., 2019). The
reason why pre-blending of materials is beneficial can be traced to the
poor flowability of the API. When the API is pre-blended, the risk of
segregation should be considered, for example when the mass flow
data from the feeders is scrutinized. Nowadays, PAT tools like near
infrared (NIR) spectroscopy can be used to monitor the blend potency
in the tablet press feed frame providing information from the late
phase of the process (de Leersnyder et al., 2018; Mateo-Ortiz et al.,
2014; Wahl et al., 2014). Nonetheless, reports have been published
regarding the lower tendency for segregation in the continuous process
in comparison to batch manufacturing (Lakio et al., 2017; Oka et al.,
2017). Even if a pre- blending of materials is sometimes justified, the
aim in many processes at the industrial scale of continuous tablet
manufacturing is to supply each of the materials from a separate feeder
(Destro et al., 2021). There should be adequate space for enough
feeders in the process to avoid the unnecessary pre-blending of raw
materials, which can save both time and resources. Aspects that should
be considered to gain a deeper un- derstanding of the process would be
to determine the residence time distribution (RTD), which can be used
in tracking the materials in the process (Furukawa et al., 2020) and the
implementation of PAT tools, such as NIR (Cogoni et al., 2021;
Goodwin et al., 2018).
According to the angle of repose and Carr index results, the API that
was used in this study was poorly or very poorly flowing, but nonethe-
less, it was fed separately into the process. Perhaps it could be even
claimed that traditional flowability tests do not always predict a mate-
rial’s behavior reliably in CDC processes, and further studies should
be
conducted to verify this possibility. Naturally, the same poorly flowing
materials, like APIs are used in batch processing, but they are incorpo-
rated in a mixture where the properties of the excipients affect the
flowability of the material to be tableted. As the tablet properties are
dependent on the ingredients as well as the equipment and their
settings (Sinka et al., 2009), another approach that could be adopted
when switching from batch production to continuous manufacturing
would be changing the composition of the formulation. One additional
option is to test different excipient or API grades before changing the
materials of the formulation. By changing material grades, particle
properties like density can be altered while pursuing the best properties
for the studied process. However, it is advisable at first to try a
conversion of the pro- duction technique with the original materials to
process materials and

Table 3
Content uniformity acceptance values.
Time point AV%

0h 10.00
1h 4.20
2h 7.70

12
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355
their mixtures with known properties and behavior. On the other
hand, if the tableting process is not successful despite a full
evaluation of the process parameters, some attempts at formulation
optimization could be worthwhile.
Based on the DoE results of this study, it can be observed that the
selection of the parameter values to form the model affect the
success- fulness of its utilization. The process knowledge could
perhaps be increased by shifting the parameter values of the second
DoE towards the optimal values of mixer and force feeder speeds that
were found based on the first DoE. Even though multiple tablet
quality tests were undertaken, not all the tests that are required to
release a batch of the studied product were performed since it would
not be reasonable to perform those on tablets that are manufactured
with a setup and facil- ities that are intended only for research
purposes. Whether or not batch- to-batch variations of raw materials
cause changes in the process could be studied in the future. Studies
with multiple refills during the process could reveal if variability in
feeding performance emerges when the process is stressed further.
Especially repeated refilling tests of highly cohesive materials might
be beneficial to gain a better understanding of material behavior in a
continuous process. Additionally, suitable parameter values for
different CDC setups would presumably require studies with the
utilized equipment.
The results of this feasibility study support the concept of trans-
ferring batch-based direct compression into a CDC process without
inevitably altering the product composition. The production of the
described tablets was conducted in the floor space of a few square
meters which would not often be the case in a full-scale batch-based
tableting process.

4. Conclusions

The production of bisoprolol tablets with the demanded quality

was conducted with the described continuous direct compression
setup. Despite the challenging material properties according to the
flowability tests, the original composition of the formulation was
utilized. A design of experiments approach for studying the effect of
process parameters proved to be beneficial for the given formulation.
With the optimized process settings, acceptable levels of weight and
breaking force values were reached based on the specification limits.
The importance of pro- cess parameter optimization in the production
of tablets became clear. It was demonstrated that the possibility of
evaluating the force feeder and mixer speeds should be kept in mind
if quality challenges emerge in the continuous direct compression of
tablets. The results presented in this study support the conception of
possibilities and benefits of continuous direct compression as a
rational and modern tablet manufacturing technique.

CRediT authorship contribution statement

Jenna Lyytika¨inen: Methodology, Investigation, Visualization,

Writing – original draft, Writing – review & editing. Pawel Stasiak:
Project administration, Conceptualization, Resources, Writing –
review
& editing. Toma´ˇs Kubelka: Project administration, Conceptualization,
Resources, Writing – review & editing. Tino Olenius: Investigation,
Visualization, Writing – original draft. Ossi Korhonen: Project
admin- istration, Methodology, Conceptualization, Supervision,
Writing – original draft, Writing – review & editing. Jarkko
Ketolainen: Super- vision, Writing – review & editing. Tuomas
Ervasti: Methodology, Conceptualization, Supervision, Investigation,
Visualization, Writing – original draft, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial

interests or personal relationships that could have appeared to
influence the work reported in this paper.

13
J. Lyytika¨inen et al.
Data availability
The data that has been used is confidential.
Acknowledgements
This work was supported by the Pharmaceutical Applied Research
Center (The Parc). Zentiva is acknowledged for supporting this study
financially and for providing the raw materials, tablet press punches
and dies that were used in these studies. The analytical department of
Zen- tiva is thanked for conducting the content uniformity
measurements.
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijpharm.2022.122355.
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TUGAS

16
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355

1. Abstrak sudah Abstract dalam jurnal penelitian ini sudah memenuhi kaidah IMRAD,
memenuhi kaidah
dengan rincian sbb:
IMRAD
Introduction:
Penelitian ini bertujuan untuk mengevaluasi transfer teknologi dari
kompresi langsung berbasis batch ke kompresi langsung kontinu tanpa
mengubah komposisi formulasi tablet bisoprolol komersial.
Method:
Penelitian menggunakan pendekatan desain eksperimen untuk
mengoptimalkan parameter proses seperti kecepatan pengumpan,
kecepatan impeler mixer, dan kecepatan paddle pengumpan gaya.
Result and Analysis:

Penelitian ini menunjukkan bahwa produksi tablet bisoprolol dengan

kualitas yang diinginkan dapat dicapai dengan menggunakan

komposisi asli dengan kompresi langsung kontinu. Penelitian ini

mendukung konsep kompresi langsung kontinu sebagai teknik
pembuatan tablet yang rasional dan modern.
Discussion:

Dalam diskusi penelitian ini, penulis menyimpulkan bahwa produksi

tablet bisoprolol dengan menggunakan metode kompresi langsung
secara kontinu tanpa melakukan perubahan pada komposisi
formulasi tablet memungkinkan untuk dilakukan dengan kualitas
tablet yang memenuhi kriteria spesifikasi yang ditetapkan.
Pengoptimalan parameter-proses dengan menggunakan pendekatan
desain eksperimen terbukti efektif dalam mengontrol berat tablet
dan memastikan kualitas tablet yang dihasilkan. Selain itu, penelitian
ini juga menunjukkan bahwa penggunaan multi-tip punches dalam
produksi tablet secara kontinu dapat menjadi suatu aspek yang
menarik untuk dieksplorasi lebih lanjut.

17
J. Lyytika¨inen et al. International Journal of Pharmaceutics 628 (2022) 122355

Penjelasan:

Pada penelitian ini ditekankan pentingnya pengoptimalan

parameter-proses dalam produksi tablet secara kontinu, terutama
dalam mengatasi tantangan yang muncul akibat sifat bahan baku
yang sulit untuk diolah. Penulis juga menyarankan untuk melakukan
studi lebih lanjut mengenai efek variasi bahan baku antar batch
terhadap proses produksi tablet secara kontinu. Selain itu,
disarankan untuk melakukan studi lebih lanjut mengenai pengaruh
parameter-proses lainnya, seperti kecepatan pengumpanan dan
kecepatan impeller mixer kontinu, terhadap kualitas tablet yang
dihasilkan. keseluruhan, penelitian ini memberikan kontribusi dalam
memperoleh pemahaman yang lebih baik mengenai produksi tablet
secara kontinu tanpa perubahan pada komposisi formulasi, serta
memberikan pandangan yang positif mengenai potensi penggunaan
teknologi produksi tablet secara kontinu dalam industri farmasi.

18
 2. Masalah Yang Rumusan masalah dalam penelitian ini mencakup beberapa poin
Diangkat
utama:
Penulis
1. Bagaimana cara mengevaluasi transfer teknologi dari kompresi
langsung berbasis batch ke kompresi langsung kontinu tanpa
mengubah komposisi formulasi tablet bisoprolol komersial?
2. Apa saja parameter proses yang perlu dioptimalkan dalam transfer
teknologi dari kompresi langsung berbasis batch ke kompresi
langsung kontinu?
3. Apakah produksi tablet bisoprolol dengan kualitas yang diinginkan
dapat dicapai dengan menggunakan komposisi asli dengan
kompresi langsung kontinu?
4. Apakah konsep kompresi langsung kontinu dapat mendukung
teknik pembuatan tablet yang rasional dan modern?
3. Pendekatan Peneliti menggunakan MODDE Pro 12.1 (Sartorius AG) untuk
Penulis untuk
melakukan eksplorasi efek kecepatan pengumpanan dan kecepatan
menentukan
desain impeller mixer kontinu pada berat tablet. Mereka menerapkan
eksperimen
pendekatan full factorial two factors - two levels dengan desain titik
tengah untuk kedua desain eksperimen. Respons yang diamati
adalah standar deviasi berat tablet pada 10 dan 20 menit. Data pada
setiap titik desain dibagi menjadi tiga set tablet (15 tablet/set) dan
dimasukkan ke dalam model (MLR, termasuk efek utama dan
interaksi) untuk memperkirakan ketidakpastian pada setiap titik
desain. Pada desain eksperimen pertama, terdapat skewness yang
signifikan pada respons, sehingga dilakukan transformasi log untuk
menghilangkan skewness.

4. Cara Pengambilan Dalam penelitian ini, pengambilan sampel dilakukan dengan

Sampel
membagi data pada setiap titik desain menjadi tiga set tablet (15
tablet/set) dan dimasukkan ke dalam model untuk memperkirakan
ketidakpastian pada setiap titik desain. Selain itu, penulis juga
menjelaskan bahwa dalam eksperimen awal, sampel diambil setelah
hasil berat tablet dan kekuatan pecah mencapai nilai yang dapat
 diterima. Hal ini dilakukan karena penulis menemukan bahwa
pengumpanan perlu berjalan selama beberapa waktu pada awal
proses sebelum mencapai tingkat akurasi yang terkontrol.
5. Cara Analisis/ Analisis data yang digunakan dalam penelitian ini dilakukan dengan
Penjelasan
menggunakan model regresi linier berganda (MLR) dengan
analisnya
memasukkan efek utama dan interaksi dari variabel-variabel yang
diteliti. Hasil analisis menunjukkan bahwa kecepatan pengumpanan
dan kecepatan impeller mixer kontinu memiliki efek signifikan
terhadap standar deviasi berat tablet pada 10 dan 20 menit. Selain
itu, peneliti juga melakukan analisis Cox-plot untuk mengevaluasi
skewness pada respons dan melakukan transformasi log untuk
menghilangkan skewness tersebut. Hasil analisis menunjukkan
bahwa kecepatan pengumpanan dan kecepatan impeller mixer
kontinu memiliki efek yang signifikan pada standar deviasi berat
tablet. Peneliti menemukan bahwa meningkatkan kecepatan
pengumpanan dan kecepatan impeller mixer kontinu dapat
mengurangi standar deviasi berat tablet. Selain itu, peneliti juga
menemukan bahwa terdapat interaksi antara kecepatan
pengumpanan dan kecepatan impeller mixer kontinu yang
mempengaruhi standar deviasi berat tablet. Dalam keseluruhan
penelitian, analisis data dilakukan dengan menggunakan metode
statistik yang sesuai untuk memperoleh pemahaman yang
mendalam mengenai proses produksi tablet. Hasil analisis
memberikan informasi yang berguna bagi pengembangan proses
produksi tablet yang lebih efektif dan efisien.

REVIEW JURNAL
1. Judul Parameter optimization in a continuous direct compression process of
commercially batch-produced bisoprolol tablets
2. Nama Jurnal International Journal of Pharmaceutics

3. Tahun dan 2022 Dec ; 628 (2022)122325

Volume
Tahun Terbit 2022
Penulis Jenna Lyytikainen , Pawel Stasiak , Tomas Kubelka, Tino Olenius , Ossi
Korhonen , Jarkko Ketolainen , Tuomas Ervasti

4. Abstrak Abstrak dalam jurnal penelitian ini membahas tentang Pembuatan

tablet berkelanjutan adalah pilihan kompetitif untuk menggantikan
pembuatan batch tradisional pendekatan. Tujuan dari penelitian ini
adalah untuk mengevaluasi transfer teknologi dari kompresi
langsung berbasis batch formulasi tablet komersial untuk kompresi
langsung terus menerus tanpa perubahan pada komposisi
formulasi. Beberapa studi serbuk dilakukan dengan bahan baku dan
pukulan multi-tip digunakan dalam studi pembuatan tablet. Untuk
menurunkan tingkat variabilitas berat tablet yang tinggi yang
terbukti selama pendahuluan tes, optimasi parameter proses
dilakukan dengan menggunakan desain eksperimental dengan nilai
rpm yang berbeda pengumpan gaya dan impeler pencampur.
Dengan memilih pengaturan yang paling tepat dari parameter ini
untuk produk, bobot tablet dapat dikontrol secara memadai untuk
memenuhi kriteria spesifikasi. Fungsionalitas pengaturan parameter
dengan kinerja terbaik diselidiki dengan proses pembuatan tablet
selama tiga jam. Tablet tablet dievaluasi dengan kriteria kualitas
yang sama dengan tablet yang diproduksi secara komersial, dan
mereka lulus semua tes yang dilakukan dalam penelitian ini.
Meskipun sifat material yang menantang menurut uji sifat alir tes,
produksi tablet dengan kualitas yang diinginkan dicapai dengan
menggunakan komposisi asli dengan
kompresi langsung .
5. Tujuan Penelitian Tujuan dari penelitian ini adalah untuk mengevaluasi teknologi
transfer dari produksi tablet berbasis batch menggunakan metode
 kompresi langsung ke produksi kontinu tanpa melakukan perubahan
pada komposisi formulasi tablet. Penelitian ini juga bertujuan untuk
mengoptimalkan parameter-proses untuk mengontrol berat tablet
dengan baik agar memenuhi kriteria spesifikasi yang ditetapkan.
Selain itu, penelitian ini juga bertujuan untuk memahami efek dari
kecepatan pengumpanan dan kecepatan impeller mixer kontinu
terhadap kualitas tablet yang dihasilkan. Dengan demikian,
penelitian ini memberikan kontribusi dalam memperoleh
pemahaman yang lebih baik mengenai proses produksi tablet secara
kontinu tanpa perubahan pada komposisi formulasi
6. Subjek Penelitian Subjek penelitian ini adalah produksi tablet bisoprolol dengan
menggunakan metode kompresi langsung secara kontinu tanpa
melakukan perubahan pada komposisi formulasi tablet. Penelitian ini
fokus pada evaluasi teknologi transfer dari produksi tablet berbasis
batch ke produksi kontinu, serta pengoptimalan parameter-proses
untuk mengontrol berat tablet dan memastikan kualitas tablet yang
dihasilkan memenuhi kriteria spesifikasi yang ditetapkan.

Kriteria inklusi :
Penggunaan formulasi tablet bisoprolol 10 mg yang didasarkan pada
formulasi tablet yang diproduksi secara batch oleh Zentiva. Selain itu,
kriteria inklusi juga mencakup penggunaan metode kompresi
langsung secara kontinu tanpa melakukan perubahan pada
komposisi formulasi tablet. Penelitian ini juga melibatkan
penggunaan multi-tip punches dalam produksi tablet, yang
merupakan suatu aspek yang belum pernah dipublikasikan
sebelumnya.

Kriteria Eksklusi :
Penggunaan formulasi tablet selain bisoprolol 10 mg, penggunaan
metode produksi tablet selain metode kompresi langsung secara
kontinu, dan melakukan perubahan pada komposisi formulasi tablet.
 Selain itu, penelitian ini juga tidak melibatkan penggunaan teknologi
atau peralatan yang tidak tersedia atau tidak dapat diakses oleh
peneliti.

7. Assement Data Data dikumpulkan dari penelitian ini bersifat rahasia/ Confidental.
Data yang ditampilkan diantaranya : Hasil karakteristik powder;
Proses verifikasi transfer yang dijalankan dengan parameter optimal;
Data analisa tablet;

8. Metode Sebuah studi menggunakan pendekatan eksperimental untuk

Penelitian
mengoptimalkan parameter-proses dalam produksi tablet bisoprolol
secara kontinu tanpa melakukan perubahan pada komposisi
formulasi. Mereka menggunakan desain eksperimen (DoE) untuk
mempelajari efek dari kecepatan pengumpanan dan kecepatan
impeller mixer kontinu terhadap berat dan kualitas tablet yang
dihasilkan. Selain itu, peneliti juga melakukan analisis data proses
dari percobaan verifikasi transfer dengan pengaturan yang
dioptimalkan untuk memperoleh estimasi kandungan API
berdasarkan data pengumpanan dari semua pengumpan.
Pendekatan eksperimental ini memungkinkan peneliti untuk
memahami pengaruh parameter-proses terhadap kualitas tablet
yang dihasilkan secara sistematis, sehingga memungkinkan untuk
mengoptimalkan proses produksi secara lebih efisien.

9. Hasil Penelitian Produksi tablet Hasil penelitian ini menunjukkan bahwa produksi
tablet bisoprolol dengan menggunakan metode kompresi langsung
secara kontinu tanpa melakukan perubahan pada komposisi
formulasi tablet memungkinkan untuk dilakukan dengan kualitas
tablet yang memenuhi kriteria spesifikasi yang ditetapkan.
Pengoptimalan parameter-proses dengan menggunakan pendekatan
desain eksperimen terbukti efektif dalam mengontrol berat tablet
dan memastikan kualitas tablet yang dihasilkan. Selain itu, penelitian
 ini juga menunjukkan bahwa penggunaan multi-tip punches dalam
produksi tablet secara kontinu dapat menjadi suatu aspek yang
menarik untuk dieksplorasi lebih lanjut. Penulis menekankan
pentingnya pengoptimalan parameter-proses dalam produksi tablet
secara kontinu, terutama dalam mengatasi tantangan yang muncul
akibat sifat bahan baku yang sulit untuk diolah. Secara keseluruhan,
penelitian ini memberikan kontribusi dalam memperoleh
pemahaman yang lebih baik mengenai produksi tablet secara
kontinu tanpa perubahan pada komposisi formulasi, serta
memberikan pandangan yang positif mengenai potensi penggunaan
teknologi produksi tablet secara kontinu dalam industri farmasi.
10. Kelebihan 1. Penerapan Teknologi Modern: Penelitian ini menerapkan
Penelitian
teknologi modern dalam produksi tablet farmasi dengan
menggunakan pendekatan kontinu, yang merupakan inovasi dalam
proses manufaktur farmasi.
2. Penggunaan Desain Eksperimen: Penggunaan desain eksperimen
memungkinkan peneliti untuk secara sistematis mempelajari
pengaruh parameter-proses terhadap kualitas tablet yang
dihasilkan, sehingga memungkinkan untuk mengoptimalkan proses
produksi dengan pendekatan yang terstruktur.
3. Pemeliharaan Komposisi Formulasi: Penelitian ini menunjukkan
bahwa produksi tablet secara kontinu dapat dilakukan tanpa
melakukan perubahan pada komposisi formulasi, yang
menunjukkan potensi untuk mentransfer teknologi produksi dari
batch-based ke continuous manufacturing tanpa mengubah bahan
baku.
4. Kontribusi terhadap Industri Farmasi: Hasil penelitian ini
memberikan kontribusi dalam memperoleh pemahaman yang lebih
baik mengenai produksi tablet secara kontinu tanpa perubahan
pada komposisi formulasi, serta memberikan pandangan yang
positif mengenai potensi penggunaan teknologi produksi tablet
secara kontinu dalam industri farmasi.
 5. Potensi Penggunaan Multi-Tip Punches: Penelitian ini juga
menyoroti potensi penggunaan multi-tip punches dalam produksi
tablet secara kontinyu, yang dapat menjadi suatu aspek yang
menarik untuk dieksplorasi lebih lanjut.

1. Penelitian ini tidak memeriksa parameter pengujian tablet

Kekurangan
Penelitian seperti disolusi, disentigrasi tablet dan parameter kualitas tablet
lain.
2. Tidak ada pemeriksaan kadar dari tablet Bisoprolol tsb.

11. Kesimpulan Dengan Produksi tablet bisoprolol dengan kualitas yang diminta
adalah dilakukan dengan pengaturan kompresi langsung kontinu
yang dijelaskan. Meskipun sifat material seperti laju alir, komposisi
asli dari formulasi digunakan. Sebuah desain pendekatan eksperimen
untuk mempelajari pengaruh parameter proses terbukti bermanfaat
untuk formulasi yang diberikan. Dengan optimasi proses, tingkat
berat yang dapat diterima dan nilai kekuatan dapat dicapai
berdasarkan batas spesifikasi. Pentingnya optimasi parameter proses
dalam produksi tablet menjadi jelas. Ini ditunjukkan bahwa
kemungkinan mengevaluasi pengumpan gaya dan kecepatan mixer
harus diingat jika tantangan kualitas muncul di kompresi langsung
tablet secara terus menerus. Hasil yang disajikan dalam penelitian ini
mendukung konsepsi kemungkinan dan manfaat dari kontinu
kompresi langsung sebagai pembuatan tablet yang rasional dan
modern teknik.