pharmaceutics

Article
Application of Machine-Learning Algorithms for Better
Understanding of Tableting Properties of Lactose Co-Processed
with Lipid Excipients
Jelena Djuris 1, *, Slobodanka Cirin-Varadjan 2 , Ivana Aleksic 1 , Mihal Djuris 3 , Sandra Cvijic 1
and Svetlana Ibric 1

1 Department of Pharmaceutical Technology and Cosmetology, University of Belgrade-Faculty of Pharmacy,

Vojvode Stepe 450, 11221 Belgrade, Serbia; [email protected] (I.A.);
[email protected] (S.C.); [email protected] (S.I.)
2 Hemofarm STADA A.D., Beogradski put bb, 26300 Vršac, Serbia; [email protected]
3 Department of Catalysis and Chemical Engineering, Institute of Chemistry,
Technology and Metallurgy—National Institute of the Republic of Serbia, University of Belgrade,
Njegoševa 12, 11000 Belgrade, Serbia; [email protected]
* Correspondence: [email protected]

Abstract: Co-processing (CP) provides superior properties to excipients and has become a reliable
option to facilitated formulation and manufacturing of variety of solid dosage forms. Development of
directly compressible formulations with high doses of poorly flowing/compressible active pharma-
ceutical ingredients, such as paracetamol, remains a great challenge for the pharmaceutical industry





 due to the lack of understanding of the interplay between the formulation properties, process of
Citation: Djuris, J.; Cirin-Varadjan,
compaction, and stages of tablets’ detachment and ejection. The aim of this study was to analyze
S.; Aleksic, I.; Djuris, M.; Cvijic, S.; the influence of the compression load, excipients’ co-processing and the addition of paracetamol on
Ibric, S. Application of Machine- the obtained tablets’ tensile strength and the specific parameters of the tableting process, such as
Learning Algorithms for Better (net) compression work, elastic recovery, detachment, and ejection work, as well as the ejection force.
Understanding of Tableting Two types of neural networks were used to analyze the data: classification (Kohonen network) and
Properties of Lactose Co-Processed regression networks (multilayer perceptron and radial basis function), to build prediction models and
with Lipid Excipients. Pharmaceutics identify the variables that are predominantly affecting the tableting process and the obtained tablets’
2021, 13, 663. https://doi.org/
tensile strength. It has been demonstrated that sophisticated data-mining methods are necessary to
10.3390/pharmaceutics13050663
interpret complex phenomena regarding the effect of co-processing on tableting properties of directly
compressible excipients.
Academic Editor: Peter Timmins

Keywords: co-processed excipients; compaction analysis; machine learning; neural networks; multi-
Received: 19 April 2021
Accepted: 3 May 2021
layer perceptron; sensitivity analysis; tensile strength; lipid excipients; lactose; monohydrate
Published: 5 May 2021

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in 1. Introduction
published maps and institutional affil- Increase in the new forms of active pharmaceutical ingredients (APIs), in terms of their
iations. physicochemical and stability profiles, has put a great pressure to the selection of excipients
with the appropriate functionalities. In terms of large-scale manufacturing, co-processing
(CP) of excipients has become a reliable option to facilitated formulation and manufacturing
of variety of solid dosage forms for oral administration. CP provides superior properties
Copyright: © 2021 by the authors. to excipients, compared to the simple physical mixture of the components, and yet the
Licensee MDPI, Basel, Switzerland. absence of chemical changes ensures the safety of the novel excipients. The worldwide
This article is an open access article market of co-processed excipients (CPEs) is steadily growing and is expected to exceed
distributed under the terms and USD 2.6 billion in 2027 [1].
conditions of the Creative Commons Development of directly compressible formulations with high doses of poorly flow-
Attribution (CC BY) license (https:// ing/compressible API remains a great challenge for the pharmaceutical industry [2]. Franc
creativecommons.org/licenses/by/ et al. have reviewed benefits of CPEs for direct compression of tablets, especially in terms
4.0/).

Pharmaceutics 2021, 13, 663. https://doi.org/10.3390/pharmaceutics13050663 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2021, 13, 663 2 of 18

of their positive influence on API content uniformity and tablets’ mass variation, disin-
tegration, dissolution, mechanical resistance and stability [3]. Other studies report that
CPEs had improved formulations’ tableting properties [4–6]. Although spray-drying is
still the predominant method for development of CPEs, wet-granulation, melt-granulation
and melt-extrusion have also gained attention [1,7–9]. Selection of the binder used for the
co-processing can be a predominant factor that affects tableting properties of CPEs [10].
Dynamic compaction analysis has been recognized as a valuable tool for evalua-
tion of directly compressible CPEs and development of high-load tablets of poorly flow-
able/compressible API [2,11]. Osamura et al. [12] have demonstrated how small-scale
measurements of tableting properties can aid formulation development and assessment
of excipients’ functionality. Direct compression is, in essence, a relatively simple process
whereby the powder mixture is compressed by applying a sufficient compaction pres-
sure. Once the compaction phase is over, tablet needs to be detached from the tableting
punch and ejected from the die. Most problems, in the industrial manufacturing of tablets,
come from the lack of understanding of the interplay between the formulation properties,
process of compaction, and stages of tablets’ detachment and ejection. E.g., it has been
demonstrated recently that detachment process affects tablets’ tensile strength [13]. Ex-
cessive lubrication is often needed to overcome tablets’ sticking, lamination, and capping.
Furthermore, wearing of tableting tools, as a result of inappropriate compaction pressures,
frequently occurs [14]. Due to the complex nature of the interaction between the formula-
tion, compaction process, and the obtained tablets’ mechanical properties, it seems that
sophisticated data-mining methods, such as machine-learning (ML) tools, are required
for the appropriate interpretation of such phenomena. In opposition to the traditional
statistical methods, ML tools offer a distinct opportunity to model complex relationships
between several input and output data, thus gaining valuable insights on the process of
interest and allowing accurate predictions. Historically, ML tools, such as artificial neural
networks (ANN), have been predominantly used to optimize formulation composition
and/or processing parameters, based on product properties that are routinely assessed
(e.g., drug release profile, tablet disintegration time, hardness and friability) as indicators
of a formulation performance [15–21]. In addition, some review papers also highlight
various applications of ML methods in the development of solid dosage forms [22–26].
One of the first mentions of ML tools applied to material tableting properties, and the
related compression/compaction phenomena, is the study of Bourquin et al. [27] who
used ANN to quantitatively assess the influence of excipients concentration on the ejection
and residual forces during tablet ejection. Due to the non-linear relationship between the
investigated input variables and the resulting ejection properties, they found that ANN
performs much better than classical response surface methodology (RSM) modeling tech-
nique. The study of Belic et al. [28] highlighted that ANN and fuzzy models can be used
for interpretation of the material particle size and tableting machine settings effect on the
resulting tablet capping tendency. Khalid et al. [29] used different machine-learning tools
(decision trees, random forests, fuzzy systems, ANN, symbolic regression) to model the
dependence of tablet tensile strength on the formulation (varying excipients quantities) and
process parameters (varying compaction machines, pressures and speeds), highlighting the
importance of predicting tensile strength as an important indicator of tablets mechanical
properties. Lou et al. [30] used six different machine-learning algorithms to model the
relationships between the raw material type (core/shell powders vs. physical mixtures)
and ingredients concentration, as well as the materials compactibility (measured as ten-
sile strength and brittleness index). According to their results, all the applied algorithms
provided acceptable predictability and indicated improved compactibility of core/shell
powders. Similarly, Millen et al. [31] assessed the effect of the selected formulation and
process variables (categorical and numerical) on the compressibility, compactibility, and
manufacturability of a granulate blend. A recent study of Khalid and Usman [32] confirmed
the utility of ML models for characterization of pharmaceutical excipients.
Pharmaceutics 2021, 13, 663 3 of 18

Lactose is one of the most commonly used diluents for tablets and there are already
numerous examples of novel CPEs that have been developed to provide multifunctionality
and/or enable direct compression [3,33]. However, none of these CPEs contains conven-
tional lubricating aids, such as magnesium-stearate, due to its insolubility in water and
difficult processing via the common CP methods, such as spray-drying. Therefore, CPE
usually require additional lubricating aids. Compritol® (glyceryl behenate) and Precirol®
(glyceryl palmitostearate) are well-known lipophilic glycerides with low HLB (hydrophilic-
lipophilic balance) values that can be used as lubricants or matrix-forming agents in the
conventional solid oral dosage forms [34] and are also suitable for several melting-based
processing methods [35]. Melt-granulation has already been recognized as a suitable CP
method for directly compressible CPEs [9].
The aim of this study was to analyze the influence of the compression force (load),
co-processing of excipients, and the addition of the model API (paracetamol) on the
obtained tablets’ tensile strength and the specific parameters of the tableting process, such
as (net) compression work, elastic recovery, detachment, and ejection work, as well as the
ejection force. Lactose monohydrate was co-processed with Compritol® or Precirol® by
the melt-granulation method. Due to the multivariate nature of the studied parameters,
and the inclusion of a categorical variable (physical mixtures vs. co-processed excipients),
neural networks were used to build prediction models and identify the variables that are
predominantly affecting the tableting process and the obtained tablets’ tensile strength. To
the best of our knowledge this is the first study that uses ML algorithms for interpretation
of the effect of co-processing on the tableting properties.

2. Materials and Methods

2.1. Materials
Paracetamol (Acros Organics, Geel, Belgium) was used as the model active pharma-
ceutical ingredient (API). Lactose monohydrate (Carlo Erba Reagents, Milan, Italy) was
used as a diluent. Precirol® ATO 5 (glyceryl palmitostearate) and Compritol® 888 ATO
(glyceryl behenate) kindly supplied by Gattefossé S.A.S. (Saint-Priest, France) were used as
the lipid meltable binders.

2.2. Co-Processing of Excipients

In situ fluid bed melt-granulation process with Precirol® was performed in Mycrolab
bed processor (OYSTAR Hüttlin, Schopfheim, Germany) while granules with Compritol®
were obtained in a custom—made fluid bed. The batch size was 200 g. To obtain the novel
co-processed lactose-based excipients, different amount of the Precirol® or Compritol®
(10 or 15% (w/w)) were used. All starting materials, lactose monohydrate (90 or 85%
(w/w)) and lyophilic, meltable binders Precirol® or Compritol® were filled in the fluid
bed processor, fluidized and preheated to the product temperature of 65 ◦ C (Precirol® )
or 85 ◦ C (Compritol® ). The starting point of granulation was defined as the time when
product temperature reached the required temperature. The inlet air heating was switched
off 10 min after the products reached predefined temperature. During the whole process,
the inlet air flow rate was kept at the approximately 30 m3 /h. The final point and the end
of the fluidization process was when the products temperature decreased below 30 ◦ C. The
fluid bed processor was stopped, and the obtained granules were collected.

2.3. Dynamic Compaction Analysis

The comprehensive dynamic compaction analysis of the investigated excipients was
conducted using an instrumented laboratory Gamlen tablet press (GTP D series, Gamlen
Tableting Ltd., Nottingham, UK). The compaction studies were performed using the single
punch tablet press with cylindrical flat-faced punches (6 mm diameter). In this study,
compacts (100 mg) were compressed under the compression loads of 100 kg, 250 kg and
500 kg and at the compaction speed of 60 mm/min. Immediately after compression, the
resistance to crushing of tablets was measured. The measuring of the resistance to crushing
Pharmaceutics 2021, 13, 663 4 of 18

(Erweka tablet hardness tester TBH125D, Langen, Germany) was performed on at least
three samples. Based on the obtained values of the resistance to crushing, the tensile
strength (σ) of the investigated samples was calculated using the following equation:

σ = 2F/πDt (1)

where F is the applied force for tablet breaking, D is the compact diameter and t is the
out-of-die compact thickness.
Total work of compression (sum of net compression and elastic work), detachment
work and ejection work were calculated from force-displacement curves that have been
generated using the supporting software of the tablet press. Based on the constructed
displacement profile, the compression, detachment, and ejection profiles were determined.
The area under the compression force-displacement curve is the total work of compression
and using the trapezoidal method both the total and the net compression work can be
calculated. Detachment and ejection force-displacement curves were generated by the
instrument software as well and represent the work used during detachment and ejection
phase, respectively. Ejection force has been evaluated based on the recorded maximum
value of the force during the ejection phase.
Percentage of in-die elastic recovery was determined, based on the difference between
the upper punch base position and punch positions corresponding to maximum and
minimum values of compression load, using the following equation:

Elastic recovery (%) = (Hmax − Hmin)/Hmin × 100%, (2)

where Hmax and Hmin represent the in-die compact thickness corresponding to maximum
and minimum values of the compression load, respectively.
As represented in Figure 1, during the dynamic compaction analysis several process
parameters can be obtained. In the present study, process parameters highly correlated pro-
cess parameters have been excluded from further analysis: elastic work (since it is calculated
as the difference between TWC (total work of compression) and NWC (net work of com-
pression)) as well as detachment force due to high correlation with DW (detachment work).

2.4. Artificial Neural Networks

Statistica version 13.5.0.17 (TIBCO Software Inc., Frankfurt am Main, Germany) was
used to build and analyze different neural networks to investigate the influence of the
input parameters (co-processing with the lipid excipients (binders), content of the lipid
excipients, addition of API, compression load) on the seven outputs. The outputs will be
hereinafter referred to as TS (tensile strength), TWC (total work of compression), NWC
(net work of compression), ER (elastic recovery), DW (detachment work), EJW (ejection
work) and EF (ejection force). Two types of neural networks were used to analyze the data:
classification (Kohonen network, KN) and regression networks (multilayer perceptron,
MLP, and radial basis function, RBF). Kohonen network was used to identify clusters in the
data. Regression neural networks were developed to model the aforementioned outputs
both separately and in combination.
Dataset for neural networks development and analysis consisted of the 90 entries
that covered variation in the compression load (100 and 500 kg), content of Compritol®
or Precirol® in the physical mixtures or co-processed excipients (0, 10 and 15%) and the
content of API (0, 25 and 50%), according to Table 1. Each formulation was tested in
triplicate. Apart from the numerical variables, the state of excipients was introduced as
a categorical variable with the two entries: physical mixture (PM) and co-processed (CS)
excipient. This dataset was split into training (70% of the data), test (15% of the data) and
validation (15% of the data). Additional dataset was used for external validation of the
developed neural network models, and it contained information on the 8 formulations that
were made by varying the content of API (25 and 50%) and using Compritol® or Precirol®
in the form of PM or CS excipients for the formulation. Compression load of 250 kg was
Pharmaceutics 2021, 13, 663 5 of 18

used for tableting during the preparation of the external validation dataset formulations.
Summary of the data, i.e., formulations’ properties and compression load that were used in
the study, is represented in Table 1.

Figure 1. Schematic representation of the dynamic compaction analysis and studied parameters.

In Statistica software, Kohonen neural network was first built. Kohonen training
algorithm was used in automated neural networks cluster analysis, with the training,
testing, and validation data (Table 1) used to construct the network. All variables were
selected (formulation composition, compression load, co-processing of excipients, as well as
the obtained tablets’ TS, TWC, NWC, ER, DW, EJW, and EF). Dimensions of the topological
map were set to 2 × 2 (topological height × width) of the self-organizing feature map
(SOFM) and the training cycles were set to 1000. Upon training of the network, the obtained
clusters and network’s weights were assessed, and the external validation data was also
analyzed in terms of identification of the cluster that the data is mostly similar to.
Afterwards, automated search for regression neural networks (MLP or RBF) was
performed. A total of 20 networks, either MLP or RBF, were trained and 5 of them were
to be retained, according to the training, test, and validation performance. The following
activation functions were tested for both hidden and output neurons: identity, logistic,
Tanh, and exponential. Broyden–Fletcher–Goldfarb–Shanno (BFGS) was used as a powerful
second order training algorithm. Although conjugate gradient algorithms are more often
used due to the quicker calculations, BFGS generally converges in fewer iterations even
though it requires more computations [36]. Radial basis function was used as the training
algorithm. Gaussian and identity functions were used as activation functions for hidden
and output neurons, respectively. For both MLP and RBF networks, sum of squares (SOS)
was used as the error function.
Pharmaceutics 2021, 13, 663 6 of 18

Table 1. Summary of composition, compression load and excipient state used to prepare tablets (abbreviations: API—active
pharmaceutical ingredient, CS—co-processed, PM—physical mixture).

Lactose Compression State of

Datasets API (%) Compritol® (%) Precirol® (%)
Monohydrate (%) Load (kg) Excipients
0 0 100
10 0 90
0 0 10 90
15 0 85
0 15 85 PM
25 11.25 0 63.75
50 7.50 0 42.50
25 0 11.25 63.75 500
50 0 7.50 42.50
Training, testing, and validation data

15 0 85
0
0 15 85
25 11.25 0 63.75
CS
50 7.5 0 42.50
25 0 11.25 63.75
50 0 7.5 42.50
0 0 100
10 0 90
0 0 10 90
15 0 85
0 15 85 PM
25 11.25 0 63.75
50 7.5 0 42.50
25 0 11.25 63.75 100
50 0 7.5 42.50
15 0 85
0
0 15 85
25 11.25 0 63.75
CS
50 7.5 0 42.50
25 0 11.25 63.75
50 0 7.5 42.50
11.25 0 63.75
External validation

PM
0 11.25 63.75
25
11.25 0 63.75
CS
dataset

0 11.25 63.75
250
7.5 0 42.50
PM
0 7.5 42.50
50
7.5 0 42.50
CS
0 7.5 42.50

To assess the performance of the developed neural network models, Pearson correla-
tion coefficient was calculated between the experimentally obtained and values predicted
by neural networks. Global sensitivity analysis was performed to evaluate the relative
importance of the input variables for the developed neural network models. According
to the supporting documentation [37] Statistica calculates the ratio of the network error
with a given input omitted to the network error with the input available, to determine
how sensitive the model is to that input. If the ratio is 1 or less, that input variable can be
pruned from the network.
Figure 2 represents the workflow of machine-learning algorithms and data analysis
that was performed in this study.
Pharmaceutics 2021, 13, 663 7 of 18

Figure 2. Schematic representation of the workflow of machine-learning algorithms that were applied for data analysis
in the presented study (abbreviations: DW—detachment work, EF—ejection force, EJW—ejection work, ER—elastic
recovery, MLP—multilayer perceptron, NWC—net work of compression, RBF—radial basis function, TS—tensile strength,
TWC—total work of compression).

3. Results and Discussion

3.1. Clustering with Kohonen Neural Networks
Kohonen neural networks were applied as a clustering algorithm to search for the
similarities in the data. Kosugi et al. [13] have recently demonstrated that self-organizing
maps can be successfully used for classification of powders with different properties in
distinct clusters. Our aim was to assess whether a classification algorithm could identify
patterns in the available data, including both inputs and outputs. Once the Kohonen
algorithm was applied with the pre-set 2 × 2 architecture, 2 × 2 SOFM (represented in
Figure 3) was obtained.
As represented in Figure 3, and according to the obtained activations, developed
SOFM 13-4 network has clustered all data in the following manner: position (1,1) is
occupied by physical mixtures compressed at 500 kg, position (1,2) refers to co-processed
excipients compressed also at 500 kg, followed by positions (2,1) and (2,2) that are occupied
by physical mixtures and co-processed excipients, respectively, compressed at 100 kg.
Therefore, Kohonen neural network has recognized co-processing and the compression
load as the predominant factors that affect variability in the data. The obtained networks’
weights for all variables are represented in Figure 4. SOFM has separated all samples
appropriately into the four listed clusters, and the obtained weights provide means to
identify variables that separate the clusters. Differences in networks’ weights may be
indicative of the variables that are affecting properties of specific formulations. As such,
model can be used to classify additional samples.
Pharmaceutics 2021, 13, 663 8 of 18

Figure 3. Self-organizing feature map for clustering of the training data. Positions are occupied by physical mixtures (1,1)
and co-processed excipients (1,2) compressed at 500 kg, followed by physical mixtures (2,1) and co-processed excipients
(2,2) that compressed at 100 kg.

Figure 4. SOFM weights for all variables (abbreviations: API—active pharmaceutical ingredient, CS—co-processed,
DW—detachment work, EF—ejection force, EJW—ejection work, ER—elastic recovery, NWC—net work of compression,
PM—physical mixture, TS—tensile strength, TWC—total work of compression).
Pharmaceutics 2021, 13, 663 9 of 18

As described in the Methods section, external validation data (Table 1) was used for
classification and the obtained results are represented in Table 2.

Table 2. Predictions of neuron position for the external validation data (abbreviations: DW—detachment work, EF—ejection
force, EJW—ejection work, ER—elastic recovery, NWC—net work of compression, TS—tensile strength, TWC—total work
of compression).

API Compritol® Precirol® TS TWC NWC DW EJW Neuron

State ER (%) EF (N)
(%) (%) (%) (MPa) (Nm) (Nm) (Nm) (Nm) Position
25 11.25 0 PM 0.64 1.10 0.93 19.3 0.14 0.58 123 (2,1)
25 0 11.25 PM 0.57 0.81 0.63 21.5 0.09 0.01 30 (2,1)
25 11.25 0 CS 1.05 0.86 0.69 22.5 0.10 0.01 35 (2,2)
25 0 11.25 CS 0.53 0.68 0.51 21.6 0.18 0.03 54 (2,2)
50 7.5 0 PM 0.51 4.05 3.89 17.5 0.12 8.00 692 (2,1)
50 0 7.5 PM 0.30 0.83 0.64 20.9 0.10 0.01 36 (2,1)
50 7.5 0 CS 0.70 0.85 0.68 21.6 0.25 0.01 50 (2,2)
50 0 7.5 CS 0.00 0.76 0.58 21.0 0.30 0.19 190 (2,2)

Formulations presented in Table 2 were all made at compression load of 250 kg. SOFM
has clustered all PM formulations (regardless of the API and lipid binder content) in the
position (2,1) that corresponds to the training data of PM formulations compressed at
100 kg load. Similarly, all CS formulations were grouped within the (2,2) position that
corresponds to the training data of CS formulations compressed at 100 kg. Therefore, the
obtained model has successfully separated PM from CS formulations, and has classified
samples compressed at 250 kg compression load as being similar to clusters of 100 kg
compression load samples.

3.2. Modeling of the Individual Outputs

As described in the Methods section, the next step was development of regression
models, based on MLP and RBF networks, to model the influence of the input variables on
each of the studied outputs. Once the data were input, according to the software specific
settings MLP networks were selected with the minimum of 3 and a maximum of 11 hidden
units, whereas RBF networks were selected with the minimum of 13 and maximum of
18 hidden units. Networks were built and the obtained results are represented in Table 3.
Table 3 reports the optimal MLP and RBF networks that were selected based on their
performance during the network development (training, test and validation data) and
additional external validation.
Names of neural networks represent the number of neurons in the input, hidden,
and the output layer. Therefore, in Table 3 each MLP network had one output that was
predicted based on five inputs (a bias term, the amount of API, Compritol® and Precirol® ;
compression load and state of the excipients) and varying number of neurons in the
hidden layer. The number next to the BFGS training algorithm refers the number of
cycles that were necessary for networks to reach the optimal outcomes. Automated search
was used to facilitate the selection of the activation functions that are also represented
in Table 3. Correlation coefficient for the external validation data was used as a main
criterion to evaluate the overall networks’ performance. The obtained data illustrate that
MLP and RBF networks were, in general, able to identify and model the influence of the
input variables on the target outputs. Predictions for TS of the external validation tablets
were the least accurate. Since this was in fact the most important of the target outputs,
additional efforts were put to build new models for TS prediction and are represented in
the subsequent sections.
Sensitivity analysis was used to identify the input variables that are especially impor-
tant for the developed models, i.e., for successful prediction of the target output variables.
Sensitivity analysis was performed for RBF model for TS, and for the MLP models for all
other target outputs excluding TS. Selection of neural network models for the sensitivity
Pharmaceutics 2021, 13, 663 10 of 18

analysis was based on the highest performance, i.e., overall correlation coefficient. The
obtained results are represented in Figure 5. Two graphs were used due to the differences
in the size ranges of the obtained values.

Table 3. The optimal multilayer perceptron (MLP) and radial basis function (RBF) networks developed for single variable
outputs (abbreviations: BFGS—Broyden–Fletcher–Goldfarb–Shanno, DW—detachment work, EF—ejection force, EJW—
ejection work, ER—elastic recovery, Exp—exponential, NWC—net work of compression, TS—tensile strength, TWC—total
work of compression.

Correlation Coefficients Activation Functions

Target Optimal Training
Neural External
Output Training Validation Algorithm Hidden Output
Network Test Data Validation
Data Data Layer Layer
Data
MLP 6-10-1 0.9958 0.9943 0.9994 0.6978 BFGS 98 Exp Exp
TS
RBF 6-16-1 0.9685 0.9830 0.9852 0.9218 RBF Gaussian Identity
MLP 6-3-1 0.8920 0.9932 0.9934 0.9996 BFGS 146 Logistic Exp
TWC
RBF 6-18-1 0.8628 0.9089 0.8553 0.9890 RBF Gaussian Identity
MLP 6-7-1 0.8772 0.9973 0.9944 0.9998 BFGS 177 Logistic Identity
NWC
RBF 6-16-1 0.8570 0.7915 0.8095 0.9736 RBF Gaussian Identity
MLP 6-11-1 0.9786 0.9699 0.9557 0.9554 BFGS 49 Logistic Tanh
ER
RBF 6-13-1 0.9114 0.9462 0.9354 0.9448 RBF Gaussian Identity
MLP 6-4-1 0.9839 0.9951 0.9736 0.9720 BFGS 107 Exp Exp
DW
RBF 6-15-1 0.9534 0.9585 0.8769 0.9379 RBF Gaussian Identity
MLP 6-5-1 0.9151 −0.1924 0.8487 0.9997 BFGS 6 Exp Logistic
EJW
RBF 6-17-1 0.9531 0.2711 0.8236 0.9715 RBF Gaussian Identity
MLP 6-5-1 0.9994 0.9805 0.9772 0.9945 BFGS 147 Tanh Logistic
EF
RBF 6-17-1 0.9566 0.6982 0.6248 0.9726 RBF Gaussian Identity

Based on the represented sensitivity analysis, it can be concluded that apart from
the compression load, which was expected to affect the tested materials’ tableting prop-
erties [38], formulations’ composition (API, Precirol® and Compritol® content) and the
excipients co-processing were also identified as significant. The margin for the significant
model terms is marked by red vertical line in Figure 5. In the case of EF and DW all terms
substantially exceed the sensitivity margin.
TS model was affected to the same extent, approximately, by the co-processing and
the compression load. The influence of the amount of API and co-processing on TS of
tablets prepared at 100 and 500 kg compression loads is represented in Figure 6. As for the
compression at 100 kg, the highest TS was obtained for the co-processed excipient with
Compritol® (1.28 MPa), followed by the co-processed excipient with Precirol® (0.93 MPa).
The inability to form compact/tablet of tensile strength sufficient for measurement is
represented by missing bars in Figure 6. It is also important to mention that pure lactose
monohydrate was not compactible at 100 kg compression load, whereas the lactose compact
prepared at 500 kg had TS of 1.28 MPa.
Neural network model for TWC was predominantly affected by the compression load,
whereas in the case of NWC and ER co-processing had the major effect. With the increase
in compression load TWC increased as well, as expected. In the case of excipients co-
processed with both Compritol® and Precirol® , NWC was lower compared to the physical
mixtures, especially for formulations that contained 50% of API (Figure 7). It is important
to emphasize that co-processing has led to the increase in TS and decrease in NWC at the
same time. This means that the energy generated during the process of compression was
more efficiently exploited. Changes in NWC are indicative of changes in the deformation
mechanism, and as such may be useful for process development and control [39].
Pharmaceutics 2021, 13, 663 11 of 18

Figure 5. Sensitivity analysis for neural networks models that successfully predict tableting process properties based on
the formulation composition, state of the excipients, and the compression load (abbreviations: DW—detachment work,
EF—ejection force, EJW—ejection work, ER—elastic recovery, NWC—net work of compression, TS—tensile strength,
TWC—total work of compression). Red line in the upper subfigure denotes the sensitivity margin (value of 1).

Sensitivity analysis has further revealed that the model for DW is mostly affected by
the compression load, followed by the amount of the lipid binders, whereas co-processing
of excipients, amount of API (%) and Precirol® impact models for EJW and EF (Figure 5).
Co-processing leads to the lower EJW values, whereas EJW increases with the increase in
API (%). It is important to emphasize that co-processing also reduced EF, with the smallest
forces being required to eject tablets containing high amounts of Precirol® (Figure 7). EF
and/or EJW are much more often reported and discussed compared to their detachment
counterparts. The obtained findings illustrate that it may lead to neglecting of the com-
pression load effect on DW. DW often needs to be decreased, to avoid capping and/or
Pharmaceutics 2021, 13, 663 12 of 18

lamination tableting issues, and it can be achieved by lowering the compression load
and/or addition of lubricants [40].

Figure 6. Influence of the compression load (kg), co-processing and the amount of API (%) on the TS of tablets formulated
with (a) Compritol® or (b) Precirol® . Abbreviations: API—active pharmaceutical ingredient, CS—co-processed, PM—
physical mixture.

3.3. Modeling of Tablets Tensile Strength

As accentuated previously, tablets’ TS is an essential parameter for characterization
since it is representative of tablets’ mechanical properties. During the previously presented
modeling approaches in Section 3.2, it was evident that the models’ ability to predict tablets’
TS based on the available inputs can be improved. Therefore, MLP networks were further
evaluated, in terms of changing the status of TWC, NWC, ER, DW, EJW, and EF to inputs,
Pharmaceutics 2021, 13, 663 13 of 18

and analyzing TS as the sole output of the network. The automated search was performed,
as previously described, and MLP 12-11-1 network was the obtained network selected for
evaluation due to its high predictive abilities, as represented in the Table 4 and Figure 8.

Figure 7. The influence of co-processing on NWC, EF, and EJW for formulations containing varying amounts of API.
Abbreviations: API—active pharmaceutical ingredient, CS—co-processed, EF—ejection force, EJW—ejection work, NWC—
net work of compression, PM—physical mixture.

Table 4. Properties of MLP 12-11-1 network developed for prediction of tablets’ TS. Abbreviations: BFGS—Broyden–
Fletcher–Goldfarb–Shanno, TS—tensile strength.

Correlation Coefficients Errors Activation Functions

External Training
Training Validation Training Validation Algorithm Hidden Output
Test Data Validation Test Data
Data Data Data Data Layer Layer
Data
0.9999 0.9999 0.9999 0.9263 0.00002 0.00005 0.00006 BFGS 140 Logistic Identity
Pharmaceutics 2021, 13, 663 14 of 18

Figure 8. Correlation between the experimentally obtained and values for the tensile strength predicted by MLP (multilayer
perceptron) 12-11-1 neural network.

For the MLP 12-11-1 network, correlation coefficient between the experimentally
obtained and values predicted for the external validation dataset was 0.9263. To compare
the prediction ability of the model with the previously reported ML-based models [29],
normalized RMSE (root mean squared error) of 11.72% was calculated. Performance of
MLP 12-11-1 is comparable to the published results [29], in terms of error metric, whereas
the correlation coefficient is higher in the present study.
This has proved that apart from the co-processing, formulation composition, and the
compression load, parameters monitored during different stages of tableting can also be
correlated with tablets’ TS. Global sensitivity analysis has revealed that EF and EJW are,
among the additional inputs, those with the highest impact to the model for prediction
of TS.
The same search was also performed with RBF networks and the optimal RBF network
provided correlation coefficient of 0.8738 and higher errors in prediction, for the external
dataset, making MLP 12-11-1 favorable network for TS prediction.

3.4. Development of Models for Simultaneous Predictions of Seven Outputs

In the next step MLP and RBF networks were trained to model seven outputs (TS,
TWC, NWC, ER, DW, EJW, and EF) simultaneously, i.e., models were developed to predict
seven outputs at the same time. As described previously, automated network search
was performed and details on the developed networks are represented in Table 5. Five
best performing artificial neural networks (three of them were MLP and two were RBF
networks) were selected for further evaluation.
Based on the obtained results MLP 6-11-7 network, with BFGS 215 training algorithm,
was selected for further analysis, due to its highest overall performance. This network
consists of six neurons in the input layer, 11 neurons in the hidden layer and seven
outputs. Activation functions for its hidden and output layer were exponential and Tanh,
respectively. Sensitivity analysis performed for MLP 6-11-7 network revealed that the
model is, overall, mostly affected by the co-processing of excipients, amount of API (%)
Pharmaceutics 2021, 13, 663 15 of 18

and Precirol® (%), as represented in Figure 9. All studied input parameters exceed the
models’ sensitivity margin.

Table 5. The optimal MLP and RBF networks developed for multiple variable outputs. Abbreviations: BFGS—Broyden–
Fletcher–Goldfarb–Shanno, MLP—multilayer perceptron, RBF—radial basis function).

Correlation Coefficients Activation Functions

Artificial Training
Neural External
Training Validation Algorithm Hidden Output
Networks Test Data Validation
Data Data Layer Layer
Data
MLP 6-11-7 0.9538 0.8857 0.9328 0.9048 BFGS 151 Logistic Tanh
MLP 6-11-7 0.9553 0.8716 0.9416 0.9416 BFGS 215 Exponential Tanh
MLP 6-6-7 0.9451 0.8510 0.9163 0.8572 BFGS 158 Logistic Exponential
RBF 6-14-7 0.9199 0.6477 0.8200 0.8915 RBF Gaussian Identity
RBF 6-16-7 0.9162 0.7197 0.8746 0.9111 RBF Gaussian Identity

Figure 9. Sensitivity analysis for MLP model developed to successfully predict seven outputs
simultaneously (TS, TWC, NWC, ER, DW, EJW, EF), based on the formulation composition, state of the
excipients, and the compression load. Abbreviations: API—active pharmaceutical ingredient, DW—
detachment work, EF—ejection force, EJW—ejection work, ER—elastic recovery, MLP—multilayer
perceptron, NWC—net work of compression, TS—tensile strength, TWC—total work of compression.

4. Conclusions
The presented results support further development and usage of CPEs obtained by
the melt-granulation procedure with the lipophilic glycerides. It has been demonstrated
that CPE have superior properties compared to their physical mixture counterparts. Devel-
oped CPE enable direct compression without the necessity for additional lubricating aids.
Furthermore, glycerides have already been recognized for their potential to be used as
matrix-forming excipients [41], therefore these CPEs could be used for direct compression
of matrix tablets with modified drug release.
This study has confirmed the great potential of ML algorithms for the assessment
of direct compression process. For the first time, different neural networks were applied
to study the influence of co-processing, compression load, and formulation composition
on the obtained tablets’ TS, TWC, NWC, ER, DW, EJW, and EF. It has been demonstrated
that co-processing has affected positively tablets’ TS and facilitated the process of direct
compression. Classification neural network, based on Kohonen algorithm, was designed
and tested. It has efficiently clustered samples, based on the co-processing and the compres-
sion load. Both types of regression neural networks that were tested, MLP and RBF, have
Pharmaceutics 2021, 13, 663 16 of 18

been demonstrated as suitable for the sensitivity analysis. MLP networks have slightly
outperformed, especially in terms of an MLP model that was developed for the successful
prediction of tablet’ TS with high correlation coefficient and acceptable prediction error.
Validation of both classification and regression models was demonstrated with the addi-
tional data that was not presented to networks during the training and internal testing and
validation procedures. The obtained classification model is in accordance with results of
regression models, and can be used as additional tool for the assessment of differences
between the formulations.
Based on the overall results that were obtained and presented, it can be concluded
that ML algorithms can provide significant aid in understanding tableting properties of
co-processed excipients. By developing neural network models, it was possible to success-
fully identify and compare the influence of several input parameters (five or eleven) on the
studied outputs. Compared to the conventional direct analysis of the data or more sophisti-
cated multivariate analysis, where each studied output needs to be analyzed separately,
neural networks can simultaneously model multiple outputs. Conventional modeling
techniques are usually restrictive in terms of regression analysis of solely numerical data,
whereby neural network models of regression type can be developed using categorical
variables as well. These are the main benefits of ANNs since significant saving in resources
and facilitated development of new products, including multicriteria optimization, can
be provided.

Author Contributions: Conceptualization, J.D. and I.A.; methodology, S.C.-V.; software, J.D. and
S.I.; validation, I.A., S.C. and M.D.; formal analysis, S.C.-V and I.A; investigation, S.C.-V. and
M.D.; resources, J.D. and S.I.; data curation, S.C.-V. and J.D.; writing—original draft preparation,
J.D.; writing—review and editing, S.C.-V., I.A., S.C. and M.D.; visualization, J.D. and S.I.; funding
acquisition, S.I. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Ministry of Education, Science and Technological Devel-
opment, Republic of Serbia under the contracts number 451-03-9/2021-14/200161 and 451-03-9/2021-
14/200026.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.
Conflicts of Interest: The authors declare no conflict of interest. S.C.-V. is the employee of Hemofarm
STADA A.D. The company had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Abbreviations
Active pharmaceutical ingredient (API), artificial neural networks (ANN), Broyden–Fletcher–Goldfarb–
Shanno (BFGS), co-processing (CP), co-processed excipient (CPE), DW (detachment work), EF (ejec-
tion force), EJW (ejection work), ER (elastic recovery), Kohonen network (KN), machine learning
(ML), multilayer perceptron (MLP) NWC (net work of compression), physical mixture (PM), ra-
dial basis function (RBF), response surface methodology (RSM), root mean squared error (RMSE),
self-organizing feature map (SOFM), sum of squares (SOS), tensile strength (TS), total work of com-
pression (TWC).

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