Control Strategy For Process Development of High Shear Wet Granulation and Roller Compaction To Prepare A Combination Drug Using Integrated Quality by Design

pharmaceutics
Article
Control Strategy for Process Development of High-Shear Wet
Granulation and Roller Compaction to Prepare a Combination
Drug Using Integrated Quality by Design
Ji Yeon Kim 1 , Myung Hee Chun 2 and Du Hyung Choi 1, *
1 Department of Pharmaceutical Engineering, Inje University, Gyeongnam 621-749, Korea;

delayeon18@naver.com
2 School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea; hiyachun@naver.com
* Correspondence: choidh@inje.ac.kr; Tel.: +82-55-320-3395
Abstract: In this study, we developed a control strategy for a drug product prepared by high-shear
wet granulation and roller compaction using integrated quality by design (QbD). During the first
and second stages, we optimized the process parameters through the design of experiments and
identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship,
respectively. In the first stage, we conducted an initial risk assessment by selecting critical process
parameters with high impact on IQAs and CQAs and confirmed the correlation between control and
response factors. Additionally, we performed Monte Carlo simulations by optimizing the process
parameters to deriving and building a robust design space. In the second stage, we identified the
IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on
MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution
rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and
granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated
Citation: Kim, J.Y.; Chun, M.H.; with granule size. Our results suggest that the desired drug quality may result through IQAs
Choi, D.H. Control Strategy for monitoring during the process and that the integrated QbD approach utilizing MVA can be used to
Process Development of High-Shear develop a control strategy for producing high-quality drug products.
Wet Granulation and Roller
Compaction to Prepare a Keywords: quality by design; multivariate analysis; control strategy; intermediate quality attributes;
Combination Drug Using Integrated high-shear wet granulation; roller compaction
Quality by Design. Pharmaceutics
2021, 13, 80. https://doi.org/
10.3390/pharmaceutics13010080
1. Introduction
Received: 5 December 2020
Accepted: 5 January 2021 The drug manufacturing process is initially developed at the laboratory scale; it is
Published: 8 January 2021 then scaled up to the pilot scale and the commercial scale. In the same manner, a design
space for process parameters is prepared by the quality by design (QbD) approach at the
Publisher’s Note: MDPI stays neu- laboratory scale. However, it is difficult to apply a design space built at the laboratory
tral with regard to jurisdictional clai- scale to the pilot or commercial scale because of process variability parameters such as
ms in published maps and institutio- batch size variability, changes in the process parameter values, and changes in the manu-
nal affiliations. facturing equipment during scale-up [1–3]. Therefore, a scale-up strategy is essential for
the QbD approach. In general, model-based scale-up strategies such as empirical models,
physics-based models, and engineering principle-based models have been used in the
pharmaceutical industry [4]. The empirical models are used to identify the relationship be-
Copyright: © 2021 by the authors. Li-
tween input (control factors) and output variables (response factors) [5]. Empirical models
censee MDPI, Basel, Switzerland.
include multivariate analysis (MVA), design of experiment (DoE), and process analytical
This article is an open access article
technology (PAT) based on empirical, semi-empirical, or statistical methods [6]. Physics-
distributed under the terms and con-
ditions of the Creative Commons At-
based models include the discrete element model, computational fluid dynamics, the finite
tribution (CC BY) license (https://
element method, and hybrid models [5]. Engineering principles-based models include the
creativecommons.org/licenses/by/ dimensionless number, thermodynamic model, and heat and mass transfer model [7].
4.0/).
Pharmaceutics 2021, 13, 80. https://doi.org/10.3390/pharmaceutics13010080 https://www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2021, 13, 80 2 of 27
QbD in pharmaceutical development focuses on process design, understanding the

relationship between control factors [critical material attributes (CMAs) and critical pro-
cess parameters (CPPs)] and response factors [intermediate quality attributes (IQAs) and
critical quality attributes (CQAs)], and control CPPs [3,8]. Pharmaceutical manufacturing
processes must be robustly designed and fully understood. Rigidly designed manufactur-
ing processes and a full understanding of the process provide regulatory and economic
advantages [9]. In general, understanding a process means that all variables are identified
and described, variability is controlled by the process, and product quality attributes can
be accurately and reliably predicted. Sufficient information needs to be gathered to clearly
understand these relationships. DoE can be a powerful tool for collecting sufficient infor-
mation and a powerful statistical technique used to study the effects of various variables
affecting the drug product. The use of DoE increases the understanding of the process and
provides insight, leading to process improvement and cost reduction [4].
Active pharmaceutical ingredient (API) variability, excipient variability, and process
variability affect the drug product quality [8,10]. In the manufacturing process development
stage, API variability and excipient variability might have a low effect on the quality of drug
products because fixed values such as drug product formulation and API specifications
are used at the pilot scale or the commercial scale. However, process variability (e.g.,
values of process variables and types of equipment used in the process) can have a high
impact on the quality of the drug product. The manufacturing process consists of unit
operations to produce the desired quality product. Pharmaceutical unit operations include
mixing, granulation, milling, drying, compression, and coating. After a unit operation
is completed, the intermediate product, which is a substance, undergoes physical and
chemical changes. In particular, the physical properties of granules produced through
granulation are greatly influenced by process variables, which can seriously affect the
quality of the drug product. The pharmaceutical granulation process entails wet and dry
granulation. Wet granulation involves low-shear, high-shear, and fluid bed. There are two
dry granulation methods; slugging and roller compaction. In high-shear wet granulation
process variability affects drug product quality. For example, inadequate impeller speed
leads to inadequate granule growth [11–13]. Inadequate granule growth leads to unwanted
granular porosity and strength, which in turn affects the drug product. In roller compaction
the pressure of the roller is an important parameter determining powder cohesion [14].
Powder cohesion is directly related to ribbon density [14]. As the pressure of the roller
increases, the force exerted on the powder increases, thereby increasing the strength of the
ribbon [15]. The roller gap also affects the physical properties of the ribbon. Even if the
same force is applied to the ribbon, the degree of transmission of the force varies depending
on the thickness of the ribbon. If the ribbon is thick, its strength decreases, which, in turn,
results in smaller and weaker granules [16]. In the granulation process, the variability in
the design space occurs due to the variability of process variables, so a scale-up strategy is
required accordingly.
In order to use the model-based strategy mentioned above, it is necessary to secure
correlations between process parameters, intermediate products, and drug products as well
as to select and manage CPPs, IQAs, and CQAs. The relationship between CPPs and IQAs
and the relationship between CPPs and CQAs can be identified through the DoE process,
but the relationship between IQAs and CQAs is difficult to identify. Therefore, the DoE
process should be supplemented. MVA can be used to analyze multiple variables simulta-
neously, and can act complementary to the DoE process because it is useful for the intensive
management of process parameters or material properties. In fact, many studies have
analyzed the correlation between intermediate products and drug products using MVA.
Huang et al. used MVA methods such as PCA and PLS to identify the correlation between
control factors and response factors and the correlation among response factors [17]. As a
result, CPPs, such as compression force, wet massing time, and water amount, and IQAs,
such as particle size and loss on drying (LOD), were significantly correlated with disso-
lution. In addition, Haware, et al. used PCA and PLS to identify the correlation between
control factors and response factors and the correlation among response factors [18]. As a
result, PCA identified that the Hausner ratio, work of compression, and tensile strength
are negatively correlated with the yield pressure of plastic and elastic deformation. Using
empirical models such as DoE and MVA, correlations between control factors and response
factors and correlations between response factors can be identified. A scale-up strategy can
be secured by managing and controlling CPPs and IQAs based on these relationships and
by monitoring the correlations through techniques such as PAT.
The objective of this study was to develop a control strategy for a combination drug
prepared by the high-shear wet granulation and roller compaction processes using the
integrated QbD approach. The metformin and dapagliflozin might show a poor compaction
property, it is difficult to produce tablets which have acceptable mechanical strength [19].
This disadvantage can overcome using high-shear wet granulation and roller compaction.
The response surface design was used to obtain optimal the process parameters for each
process. Based on the initial risk assessment CPPs, IQAs, and CQAs were selected as
control factors and response factors for DoE. The effect of CPPs on IQAs and CQAs was
analyzed using coded equations. A design space was established to satisfy the target values
using coded equations. Monte Carlo simulations were conducted to evaluate the risk of
uncertainty in design space predictions. In addition, by utilizing MVA methods, such as
the Pearson correlation coefficient and PCA, we confirmed the relationships between IQAs
and CQAs.
2. Materials and Methods

2.1. Materials
Metformin and dapagliflozin were supplied from Kyung-dong pharm (Seoul, Korea).
Hydroxypropyl methylcellulose (100,000 cps, SR type) and Low-substituted hydroxypropyl
cellulose (L-HPC) were purchased from Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Lac-
tose monohydrate, magnesium stearate, silicon dioxide, and microcrystalline cellulose were
purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Calcium silicate was purchased
from Fluka (Buchs, Switzerland). All other reagents were analytical or HPLC grade.
2.2. Experimental Design to Optimize the Manufacturing Process

2.2.1. Experimental Design of High-Shear Wet Granulation
The experimental design used to optimize the manufacturing process of high-shear
wet granulation was produced using Design-Expert® software (version 12; Stat-Ease Inc.,
Minneapolis, MN, USA). Response surface design was used to identify the optimal process
parameters of high-shear wet granulation with three control factors: p1 (impeller speed),
p2 (massing time), and p3 (binder solvent). The control factors were in the 50–100 rpm,
10–50 s, and 1–4 mL ranges, respectively. IQAs, such as intrinsic dissolution rate (q1 ),
granule size (q2 –q6 ), true density (q7 ), bulk density (q8 ), Carr’s index (q9 ), angle of repose
(q10 ), and granule strength (q11 ), and CQAs, such as swelling property at 1 h (q12 ), 3 h (q13 ),
and 5 h (q14 ); weight gain at 1 h (q15 ), 3 h (q16 ), and 5 h (q17 ); mass loss at 1 h (q18 ), 3 h (q19 ),
and 5 h (q20 ); gel strength at 1 h (q21 ), 3 h (q22 ), and 5 h (q23 ); dissolution at 1 h (q24 ), 3 h (q25 ),
and 10 h (q26 ); and contact angle (q27 ), were evaluated as response factors.
The test drug components used were metformin (API) 1000 mg, calcium silicate
(excipient) 30 mg, HPMC (binder) 10 mg, HPMC (release control agent) 255 mg, and St-
Mg (lubricant) 10 mg. To prepare the test drug, metformin granules were using a high-
shear granulator (MIXER TORQUE RHEOMETER 3; Caleva, Sturminster Newton, UK).
Purified water was selected as the binding solvent. The process parameters (impeller speed,
massing time, and binder solvent) were set following the experimental design, and the
binding solvent spray speed was fixed at 100 mL/h. After granulation, the mass granules
were dried in an oven at 50 ◦ C for 1 h. Dry granules that reached the appropriate water
content were sieved through a #25-mesh sieve to remove any aggregates. IQAs were
evaluated using intermediate products after granulation (dried granules). HPMC and
St-Mg were added to the dried granules and mixed using an LM 40 Lab Blender (L.B. Bohle,
Ennigerloh, Germany).
2.2.2. Experimental Design of Roller Compaction

To optimize the manufacturing process of roller compaction, the experimental design
was produced using Design-Expert® software (version 12; Stat-Ease Inc., Minneapolis,
MN, USA). Response surface design was used to identify the optimal process parame-
ters of roller compaction with three control factors: c1 (roller pressure), c2 (roller gap),
and c3 (mill screen size). The control factors were in the 25–85 bar, 1.2–2.4 mm, and
0.5–1.5 mm ranges, respectively. IQAs, such as the intrinsic dissolution rate (d1 ), gran-
ule size (d2 –d6 ), ribbon density (d7 ), bulk density (d8 ), tapped density (d9 ), granule strength
(d10 ), and granule uniformity (d11 ), and CQAs, such as tablet C.U. (d12 ); dissolution at
5 min (d13 ), 10 min (d14 ), and 15 min (d15 ); and contact angle (d16 ), were evaluated as
response factors.
The test drug components used were dapagliflozin (API) 15.63 mg, MCC (excipient)
191.37 mg, lactose (excipient) 10.00 mg, L-HPC (disintegrants) 20.00 mg, silicon dioxide
8.00 mg, and St-Mg (lubricant) 2.00 mg and 3.00 mg (post-mix). To prepare the test drug,
dapagliflozin granules were produced using a POLYGRAN® (Gerteis, Rapperswil-Jana,
Switzerland). The process parameters (roller pressure, roller gap, and mill screen size) were
set following the experimental design, and roll speed, feed screw, and roller pressure were
fixed at 4 rpm, 10 rpm, and 55 bar, respectively. The ribbon was formed by the force of the
compression roller from the powder mixture transferred by the screw feeder. The formed
ribbon was crushed into small particles to form dry granules. After granulation, St-Mg was
added to the intermediate product, which was then mixed using an LM 40 Lab Blender
(Bohle, Germany).
2.3. Measurement of IQAs and CQAs

2.3.1. Measurement of Intrinsic Dissolution Rate
The intrinsic dissolution test used two methods. The first method is USP <1087>
stationary disk apparatus for metformin granules [20]. Metformin granules content HPMC
which has swelling property. Due to the property of HPMC, it is difficult to test the
drug release behavior at a constant surface area in the Franz diffusion cell, so metformin
granules were tested using a different method. After weighing 300 mg of metformin
granules, they were put into a die and then compressed with a pressure of 200 kg/cm2
using a single punch press (RIKEN KIKI Co., Ltd., Tokyo, Japan) to produce a drug disk.
One surface of the drug disk was exposed, and the surface was covered with a membrane
filter (cellulose acetate, 0.2 µm) [21]. Then, the die was placed on the bottom of the vessel
with a flat bottom (Distek Inc., North Brunswick, Nj, USA). In the intrinsic dissolution test,
1000 mL of pH 6.8 phosphate buffer maintained at 37 ± 0.5 ◦ C was used as the dissolution
medium, and the paddle speed was 100 rpm. At the sampling time, 5 mL of sample
was withdrawn and filtered through a 0.45 µm membrane filter to remove impurities.
The intrinsic dissolution rate was calculated from Equation (1) [22].
The second method is Franz diffusion cell for dapagliflozin granules. The test was
conducted by Franz diffusion cell tester (Logan instruments Corp., Somerset, NJ, USA).
Before testing, the membrane filter (cellulose acetate, 0.2 µm) was wetted with the test
medium. After wetting membrane filter was put on the tester, 200 mg of dapagliflozin
granules were put into the test and spread flat to contact the membrane. As the test
medium, a pH 6.8 phosphate buffer maintained at 37 ± 0.5 ◦ C was used. The test was
conducted for 3 h, and 5 mL of sample was withdrawn every 30 min, and then filtered
through a 0.45 µm membrane filter.
Vdc 1
J = × (1)
dt A
where J is dissolution flow (µg mm−2 min−1 ), V is the volume of the dissolution medium
(mL), c is the concentration of dissolved drug in the medium (µg/mL), A is surface area of
the sample (mm2 ), and t is time (min).
2.3.2. Measurement of Granule Properties (Granule Size, Granule Density, Flowability,

and Granule Strength)
The laser diffraction method was used to evaluate the granule size. Approximately,
a 5 g granule was introduced into a Malvern Mastersizer 3000E (Malvern Instruments
Ltd., Worcestershire, UK). The granule size distribution diameters (D10 , D50 , D90 , D(3,2),
and D(4,3)) were determined. The measurements were repeated three times and the mean
value was used in this study.
The granule density was evaluated as true density, bulk density, and tapped density.
To evaluated granule true density, a helium pycnometer (AccuPyc 1330; Micromeritics
Instrument Co., Norcross, GA, USA) was used. After accurately weighing the granules,
the granules were poured into a sample cell, and then helium gas was filled into the
sample cell to measure the pressure in the cell, thereby calculating the volume of the
granules. Bulk density and tapped density were measured using a 10 mL mass cylinder.
First, the bulk density was measured by pouring excess granules into a 10 mL mass cylinder
and then scraping the top of the cylinder to remove excess granules. The tapped density
was calculated by measuring the reduced volume by pouring the excess granules into
a 10 mL mass cylinder, scraping the top of the cylinder to remove the excess granules,
and then tapping the cylinder 100 times at a constant speed and height.
To evaluated granule flowability, Carr’s index and angle of repose was measured.
The Carr’s index calculated using Equation (2). Granules fed through a funnel with
a diameter of 12 mm until the powder formed a cone. Then, the angle of repose was
measured by measuring the angle of the formed cone [23].
ρT − ρB
Carr’ s index = × 100% (2)
ρB
where ρB is the bulk density of the granules and ρT is the tapped density of granules.
The granule strength test was conducted by a texture analyzer (TA.XT plus, Stable Mi-
cro Systems Ltd., Surrey, UK). 710–850 µm granules were selected to test. 30 mg granules
were accurately weighed and placed under the probe. Individual granule was compressed
with a 10 mm cylinder probe. The test mode was operated in compression mode. The trig-
ger force was set as 0.0049 N. Using area under the curve in the force versus distance graph
measured granule strength.
For the test of granule strength, 30 mg of 710–850 µm granules were weighed and
placed under the probe of the texture analyzer. The test used a texture analyzer (TA.XT
plus, Stable Micro Systems Ltd., UK). The probe used a 10 mm cylinder probe and the
test mode was operated in compression mode. The trigger force was set to 0.0049 N.
Granule strength was measured by calculating the area under the curve in the force versus
distance graph [24].
2.3.3. Measurement of Swelling Property

To evaluated swelling of the metformin tablet swelling property test was conducted.
The test tablet was prepared by weighing 1305 mg of metformin granules and insert granules
in a 15 mm cylindrical-shaped die and compressed at 200 kg/cm2 using a single punch press
(RIKEN SEIKI Co., Ltd., Japan). The front and back of the tablet were closed with clear acrylic
plates (6 × 4 cm), and both sides were firmly held with a rubber band. Since both sides of the
acrylic plates are exposed, when the acrylic plates are placed in the test medium, the medium
enters the acrylic plates, and the tablet starts to swell as the tablet and the medium contact.
The tablets fixed on the acrylic plate were immersed in 250 mL of pH 6.8 phosphate buffer,
and a magnetic bar was placed on the acrylic plate, followed by stirring at 250 rpm using a
magnetic stirrer (Scilab Korea Co., Ltd., Seoul, Korea). At a predetermined time, the acrylic
plate was taken out and the diameters of the gelled and non-gelled portions of the tablet were
measured using a digital caliper (Mitutoyo, Kawasaki-shi, Kanagawa, Japan). The swelling
property was calculated using Equation (3) [25].
( )
( L2 )3
Swelling property (%) = 1 − × 100 (3)
( L1 )3
where L2 is diameter of the portion not gelled after the test and L1 is diameter of the tablet
before the test.
2.3.4. Measurement of Weight Gain and Mass Loss

To prepared the test tablets for weight gain and mass loss, 1305 mg of granules
weighted and insert in a 15 mm cylindrical-shaped die and compressed at 200 kg/cm2
using a single punch press (RIKEN SEIKI Co., Ltd., Japan). To evaluated weight gain,
12 tablets were added to the 500 mL of pH 6.8 phosphate buffer, and then a magnetic
bar was added and stirred at 450 rpm using a magnetic stirrer (Scilab Korea Co., Ltd.,
Korea). At a predetermined time, 4 tablets withdrawn from the medium, and the excess
medium on the surface was removed using an absorbent tissue, and the weight of tablets
was measured. After that, the swollen tablets were completely dried in an oven at 50 ◦ C
for mass loss testing and the dried tablets were weighted. The weight gain and mass loss
were calculated using Equations (4)–(5), respectively [25].
W2 − W1
Weight gain (%) = × 100 (4)
W1
W1 − W3
Mass loss (%) = × 100 (5)
W1
where W 1 is initial weight of tablet, W 2 , and W 3 is weight of the tablet with water at time t
and weight of the dried tablet, respectively.
2.3.5. Measurement of Gel Strength

To prepare the test tablets for gel strength, 1305 mg of granules weighted and insert
granules into a 15 mm semi-circular die and compressed at 200 kg/cm2 using a single
punch press (RIKEN SEIKI Co., Ltd., Japan). Four tablets were put between two clear acrylic
plates, and both ends were firmly fixed with a rubber band. Since both sides of the acrylic
plates are exposed, when the acrylic plates are placed in the test medium, the medium
enters the acrylic plates, and the tablet starts to swell as the tablet and the medium contact.
The tablets fixed on the clear acrylic plate were immersed in 250 mL of pH 6.8 phosphate
buffer, and a magnetic bar was placed on the acrylic plate, and then stirred at 250 rpm using
a magnetic stirrer (Scilab Korea Co., Ltd., Korea). At a predetermined time, each tablet
was withdrawn. The gel strength test was conducted by texture analyzer (TA.XT plus,
Stable Micro Systems Ltd., UK). The probe used a 5 mm cylinder probe. The swollen tablet
placed under the probe. The test mode was operated in compression mode, where the
probe penetrated the gel layer at a speed of 1 mm/s. The gel strength was calculated using
the area under the curve in force versus time.
2.3.6. In Vitro Dissolution Test

To prepare the test tablets for metformin, 1305 mg of granules weighted and insert
in a 15 mm cylindrical-shaped die and compressed at 200 kg/cm2 using a single punch
press (RIKEN SEIKI Co., Ltd., Japan). To prepare the test tablets for dapagliflozin, 250 mg
of granules weighted and insert in an 8 mm cylindrical-shaped die and compressed at
160 kg/cm2 using a single punch press (RIKEN SEIKI Co., Ltd., Japan). To prevent the
tablet adhesion to the bottom of the vessel, dissolution was conducted according to the
USP Apparatus 1 guidelines (Basket Apparatus) (ERWEKA GmbH, Langen, Germany) [26].
The dissolution medium used 1000 mL of pH 6.8 phosphate buffer maintained at 37 ± 0.5 ◦ C.
A basket rotation speed was set at 100 rpm. At a predetermined time, a 5 mL sample was
withdrawn and filtered through a 0.45 µm membrane filter. After withdrawn the sample,
the metformin sample diluted 20 times with the dissolution medium.
2.3.7. Measurement of Contact Angle

The test medium was used dissolution medium (pH 6.8 phosphate buffer). Dropped
8 µL medium on a tablet and then measured contact angle imaging it with a video camera
(Contact angle analyzer, Phoenix 300 TOUCH, SEO, Suwon-si, Korea). The angles were
calculated directly from the video monitor. The contact angle was calculated Young’s
equation using Equation (6) [27]. In order to obtain the rate at which water permeates into
the tablet, used the slope of the time versus contact angle graph.
γSV − γSL − γLY cos θ = 0 (6)
where γSV , γSL , and γLV are solid-vapor interfacial energy, solid-liquid interfacial energy,
and liquid-vapor interfacial energy, respectively.
2.4. HPLC Analysis Method

To evaluated drug content HPLC analysis was conducted by HPLC (Agilent, Santa Clara,
CA, USA). The method of HPLC analysis following: UV wavelength 255 nm for metformin
and 224 nm for dapagliflozin, column used were an XTerra® RP 18 (4.6 × 150 mm, 5 µm)
(Waters, Santa Milford, MA, USA) maintained 40 ◦ C, mobile phase was used 60:40 volume
mixture of buffer (made by dissolving monoammonium phosphate and sodium dodecyl
sulfate) and acetonitrile, flow rate was 1.5 mL/min, and the injection volume was 10 µL for
metformin and 20 µL for dapagliflozin. To prepare a stock standard solution, accurately
12.00 mg of metformin and 18.756 mg of dapagliflozin were inserted into a 10 mL of clean
dry volumetric flasks add about 7 mL of methanol and sonicate to dissolve and removal
of air completely and make volume up to the mark with the same methanol. To prepared
calibration standards the metformin stock solution was diluted 20 times and dapagliflozin
stock solution was diluted 100 times. From this solution calibration standards, ranging
from 60.00 to 5.00 µg/mL of metformin and from 18.756 to 1.563 µg/mL of dapagliflozin,
were prepared before quantitative analysis.
2.5. Multivariate Analysis

MVA methods, such as the Pearson correlation coefficient and PCA, were used to
identify the correlation between IQAs and CQAs. PCA is a technology that reduces
the dimension of highly correlated multidimensional data and transforms them into a
new variable system, principal components [28,29]. PCA was conducted using SIMCA©
software (Sartorius Stedim Biotech., version 15, Umeå, Sweden). The Pearson correlation
coefficient is a type of correlation analysis, a technique that identifies whether there is
a correlation between two variables [30]. This can quantitatively evaluate the effect of
one variable on another. Pearson correlation coefficients were obtained using Origin 2020
software (OriginLab, Northampton, MA, USA). IQAs and CQAs were used as variables.
The Pearson correlation coefficient is the product of the covariance of two variables divided
by the product of the standard deviation [31]. The Pearson correlation coefficient was
calculated using Equation (7). The value of the Pearson correlation coefficient ranged
from −1 to 1. An approximate value of −1 suggested a strong negative correlation,
and an approximate value of 1 indicated a strong positive correlation. In addition, a value
approximating 0 indicated that there was no correlation.
∑in Xi − X Yi − Y

r = q 2 q n 2 (7)
n
∑i X i − X ∑i Yi − Y
where r is the strength of the linear correlation between the X and Y variables, n is the
number of samples, X is the average of X samples, and Y is the average of Y samples.
2.6. Initial Risk Assessment for the Manufacturing Process Development

The quality target product profile (QTPP) of the bilayer tablet was defined based
on the XIGDUO™ XR (AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA). As is
shown in Table 1, QTPP includes the dosage form, dosage design, route of administration,
dosage strength, pharmacokinetics, stability, drug product quality attributes, intermediate
product quality attributes, and container closure system. A risk assessment was conducted
to identify the high-risk process parameter that might have a significant effect on IQAs and
CQAs. The initial risk assessment was evaluated by failure mode event analysis (FMEA),
and the severity, probability, and detection were evaluated on a scale of 1–5 in terms of
risk. The risk priority number (RPN) was calculated by multiplying the three severity,
probability, and detectability, and RPN values of 1–19, 20–39, and 40–125 were classified as
low, medium, and high risk, respectively.
Table 1. Quality target product profile (QTPP) for a bilayer tablet containing 10 mg dapagliflozin and 1000 mg metformin.
Quality Attributes Target Justification Critical

Bilayer tablet with Pharmaceutical equivalence
Dosage form Not critical
coating film requirement: same dosage form.
Bilayer tablet composed
with immediate release
and sustained release Sustained release design needed to
Dosage design Not critical
containing 10 mg of meet label claims.
dapagliflozin and 1000 mg
of metformin, respectively
Pharmaceutical equivalence
Route of administration Oral requirement: same route Not critical
of administration.
dapagliflozin Pharmaceutical equivalence
Dosage strength Not critical
10 mg/metformin 1000 mg requirement: same strength.
Cmax within 2 h of
dapagliflozin consumption
under the fasting state and
Pharmacokinetics Cmax withn 4.0 to 8.0 h of Bioequivalence requirement. Not critical
metformin consumption;
bioequivalent to
XIGDUO™ XR
At accelerated conditions:
40 ◦ C/75% RH Equivalent to or better than the shelf-life
Stability Not critical
At long term storage of XIGDUO™ XR.
condition: 25 ◦ C/60% RH
Assay variability will affect safety and
efficacy. Both material attributes and
90% to 110% w/w of process parameters may affect the assay
Assay Critical
label claim of the drug product. Thus, the assay
should be evaluated throughout the
Drug product product and process development.
quality attributes Variability in content uniformity will
affect safety and efficacy. Both
Content Conforms to USP<905> formulation and process variables
Critical
uniformity (C.U.) uniformity of dosage units impact content uniformity, so this CQA
should be evaluated throughout
product and process development.
Table 1. Cont.

Swelling property The swelling property, gel strength,
weight gain, and mass loss of tablets
Weight gain Critical
Similar to XIGDUO™ XR may affect safety and efficacy as these
Mass loss are directly correlated with dissolution
that will affect bioavailability.
Gel strength
Metformin: 10% to 40% after
Failure to meet the dissolution
1 h; 40% to 70% after 3 h;
specifications can affect bioavailability.
Dissolution more than 75% after 10 h. Critical
Process variables affect the
Dapagliflozin: more than
dissolution profile.
70% after 30 min
An extremely hard tablet could indicate
Ranging from 17.0 kp to
excessive bonding potential between
18.0 kp for metformin and
Hardness API and the excipients, which can Critical
from 27.0 kp to 28.0 kp
prevent the proper dissolution of the
for dapagliflozin
tablet needed for accurate dosing.
Friability is a routine test as per the
compendial requirements of tablets.
A target of less than 1.0% w/w of mean
Friability Not more than 1.0% w/w Critical
weight loss assures a low impact on
patient safety and efficacy and
minimizes customer complaints.
The contact angle of tablets may affect
safety and efficacy as it is directly
correlated with dissolution that will
Contact angle Similar to XIGDUO™ XR affect bioavailability. Thus, it affects Critical
bioavailability. Thus, the contact angle
should be evaluated throughout
product and process development.
Identification Not critical
Degradation
Not critical
products
Pharmaceutical equivalence requirement: Must meet the same
Residual solvents applicable (quality) standards (i.e., identity, assay, purity, and quality). Not critical
Microbial limits Not critical
Physical
Not critical
attributes
Intrinsic dissolution rate and solubility
are the main physicochemical aspects
pertaining to drug absorption. The
intrinsic dissolution test may offer
Intrinsic
greater correlation to the in vivo Critical
dissolution rate
dissolution dynamic than the solubility
test. Thus, the intrinsic dissolution test
should be investigated throughout
Intermediate product and process development.
product quality Similar to XIGDUO™ XR The particle size affects flowability and
attributes
content uniformity. Thus, size should be
Granule size Critical
evaluated throughout
product development.
Table 1. Cont.

Granule flowability is relative to
granule size, assay, CU, and dissolution.
Granule
Thus, granule flowability should be Critical
flowability
evaluated throughout the product and
process development.
Container closure system Needed to achieve the target shelf-life
Container closure system qualified as suitable for this and to ensure tablet integrity Not critical
drug product during shipping.
3. Results and Discussion

3.1. Initial Risk Assessment for the Manufacturing Process Development
3.1.1. Initial Risk Assessment for High-Shear Wet Granulation
The quality of the intermediate product after the unit process has an effect on the down-
stream process, which, in turn, affects the quality characteristics of the drug product [3,24].
The intrinsic dissolution rate may be significantly related to the drug product dissolution
profile, which affects bioavailability. In addition, the intrinsic dissolution rate may have a
greater correlation with the in vivo dissolution kinetics than the solubility test [22]. The
size of the granules and the strength of the granules can affect fluidity, content uniformity,
and solubility [32–34]. Granule fluidity parameters such as Carr’s index and the angle
of repose are related to the assay, content uniformity, and dissolution. The density of the
granules can affect compressibility [35]. Therefore, the quality characteristics of intermedi-
ate products such as the intrinsic dissolution rate, granule size, true density, bulk density,
Carr’s index, the angle of repose, and granular strength should be evaluated throughout
process development. The assay and content uniformity can affect the safety and efficacy of
the drug product [36]. Undesired dissolution may result in unexpected bioavailability [36].
Inappropriate tablet hardness can affect safety and efficacy [37]. Friability of less than
1.0% w/w can reduce the impact on patient safety and efficacy [36]. Swelling property,
weight gain, mass loss, and gel strength are related to dissolution, which affects bioavail-
ability [38]. The wettability of tablets can be assessed by measuring the contact angle,
and as the contact angle is directly related to dissolution, which affects bioavailability,
it affects safety and efficacy [39]. Therefore, the quality characteristics of drug products
such as assay, content uniformity, swelling property, weight gain, mass loss, gel strength,
dissolution, hardness, friability, and contact angle should be evaluated throughout process
development; herein, these characteristics were evaluated as response factors of DoE in the
manufacturing process development.
The process parameters to be considered in the high-shear wet granulation process
include the binding solvent spray rate, binding solvent amount, impeller speed, massing
time, drying temperature, and drying time. Initial risk assessment was conducted to
select process variables that have a significant influence on the quality characteristics of
intermediate and drug products among process variables. Although the spray rate of the
binder solvent may affect the quality characteristics of intermediate and drug products,
it was classified as having medium and low risk, as it was used as a fixed value in the
process. A high ratio of liquid binders increases residence time and torque, and forms more
spherically shaped granules, owing to the formation of more liquid bridges [40]. In addition,
the binder solvent affects the porosity and size of the granules [41,42]. Therefore, the binder
solvent poses a high risk for intrinsic dissolution rate, granule size, granule strength,
dissolution, true density, bulk density, Carr’s index, angle of repose, content uniformity,
swelling property, weight gain, mass loss, gel strength, and contact angle. Inadequate
impeller speed can lead to inadequate granule growth [11–13]. Inadequate granule growth
leads to undesired granule porosity and strength [24]. In addition, the impeller speed
creates a high shear between the particles, and the growth and densification of the granules
proceeds [43,44]. For this reason, the impeller speed was classified as high risk because
it can have a significant effect on the intrinsic dissolution rate, granule size, true density,
bulk density, Carr’s index, angle of repose, granule strength, gel strength, dissolution,
and contact angle. In addition, it was classified as medium risk because it can affect assay,
content uniformity, swelling property, weight gain, mass loss, hardness, and friability.
Failure to control the massing time can produce weak granules or granules of inadequate
density [11,45,46]. In addition, as the massing time increases, high shear occurs between
particles, thereby leadings to granule growth and densification. Therefore, the massing
time was classified as a high risk because it can have a significant effect on the intrinsic
dissolution rate, granule size, true density, bulk density, granule strength, and dissolution.
Moreover, massing time was classified as medium risk because it can affect Carr’s index,
angle of repose, assay, content uniformity, swelling property, weight gain, mass loss,
gel strength, hardness, friability, and contact angle. Drying temperature and drying time
can affect the quality characteristics of intermediate and drug products, but they are
fixed based on previous experience and are therefore low risk. Based on the initial risk
assessment, the impeller speed, massing time, and binder solvent were selected as CPPs.
3.1.2. Initial Risk Assessment for Roller Compaction

As mentioned above, the intrinsic dissolution rate, granule size, ribbon density, bulk
density, tap density, angle of repose, granule strength, and granule uniformity in roller
compaction process were selected as the quality characteristics of the intermediate products.
The assay, content uniformity, hardness, friability, dissolution, tablet C.U., and contact
angle were selected as the quality characteristics of the drug product. IQAs and CQAs
were evaluated as DoE response factors in the manufacturing process development.
The process parameters to be considered in roller compaction include feed screw
speed, roller pressure, roller speed, roller gap, mill screen type, mill speed, mill screen
size, and environment (temperature and RH). Roller pressure is important for processing
parameters that determine powder cohesion [14]. Powder cohesion is directly related
to ribbon density [14]. As the roller pressure increases, the force applied to the powder
increases [16]. As the force increases, the air introduced into the powder is discharged,
resulting in an increase in ribbon density and strength [16]. Strong ribbons produce stronger
and larger granules after milling. This can affect granule flowability, content uniformity,
and compressibility. Thus, roller pressure was classified as high risk because it can have a
significant effect on the intrinsic dissolution rate, granule size, ribbon density, bulk density,
tapped density, granule uniformity, tablet C.U., and dissolution. When the gap between
the rolls increases, a thick ribbon is created. Even if the same force is applied to the ribbon,
the degree of force transmission varies depending on the thickness of the ribbon; thus,
the strength of the ribbon is lowered in the case of a thick ribbon, and smaller and weaker
granules are produced [16]. Ultimately, the roller gap determines the ribbon density and
affects the granule properties [47]. Therefore, the roller gap was classified as high risk
for the intrinsic dissolution rate, granule size, ribbon density, bulk density, tap density,
granule uniformity, tablet content uniformity, and dissolution. In addition, the contact
angle was judged as medium risk. Roller speed is a variable that determines the throughput
of the process. It can affect IQAs and CQAs but is low risk because it is fixed, based on
previous experience. The mill screen type can affect the properties of the granules; however,
generally, the mill screen type does not change significantly, so the effect on the CQAs
and IQAs is low. The mill speed can affect the granule properties, but its risk is low.
Mill screen size can affect the physical properties of granules, which can affect granule size
and flowability [48]. Therefore, mill screen size was classified as high risk because it can
have a significant effect on the intrinsic dissolution rate, granule size, granule strength,
granule uniformity, assay, content uniformity, hardness, friability, dissolution, tablet C.U.,
and contact angle. The effect of the working environment on the CQAs and IQAs is
low because the manufacturing facility maintains a constant temperature and humidity.
Based on the initial risk assessment, roller pressure, roller gap, and mill screen size were
selected as CPPs.
3.2. Effect of CPPs on the IQAs and CQAs of High-Shear Wet Granulation
3.2.1. Effect of CPPs on the Intrinsic Dissolution Rate (q1 )
The intrinsic dissolution rate was in the 5.63–7.32 mg·mm−2 ·min−1 range. The stan-
dard deviation was 0.44. An ANOVA was conducted to identify the individual influence
of control factors (CPPs) on response factors (IQAs and CQAs). The individual influence of
control factors is described by the reduced linear mathematical model, which is presented
in Equation (8).
q1 = 0.1978p1 − 0.1576p2 + 0.0014p3 + 0.5776p1 p2 − 0.1703p1 2 − 0.1648p2 2 + 0.3614p3 2 (8)
A p-value less than 0.05 indicates that control factors had a significant effect on the
response factors. The intrinsic dissolution rate ANOVA results showed that the p-values of
all control factors were less than 0.05. The R2 value of the response factors (q1 ) was 0.9689,
which indicates that the control factors had a significant effect on the response factors.
According to Equation (8), massing time had a negative effect on the intrinsic dissolution
rate. Larger-sized granules have a smaller water contact area than smaller-sized granules,
so the disintegration rate is slow [24]. Therefore, larger granules have slow dissolution.
In general, increasing the massing time could increase the granule size because it presents
the mechanical energy required for mixing the powder [24]. Thus, the intrinsic dissolution
rate could be negatively influenced by the massing time.
3.2.2. Effect of CPPs on Granule Size (q2 –q6 )

The granule sizes (D10 , D50 , D90 , D(3,2), and D(4,3)) were in the 17.00–37.77 µm,
29.30–286.07 µm, 181.07–1420.28 µm, 32.97–96.40 µm, and 121.67–690.33 µm ranges, respec-
tively. The standard deviations were 7.79, 102.18, 412.17, 24.57, and 219.59, respectively.
Based on the granule size results, we used an ANOVA to identify the individual influence
control factors is described by the reduced linear mathematical model, which is presented
in Equations (9)–(13).
q2 = 0.7325p1 + 9.47p3 + 1.94p1 2 + 5.01p3 2 (9)
q3 = 10.48p1 + 12.05p2 + 224.23p3 + 51.76p1 p2 + 44.25p2 2 + 161.10p3 2 (10)

q4 = 100.59p2 + 578.71p3 (11)
2 2
q5 = 2.31p1 + 2.53p2 + 30.05p3 + 3.40p1 p2 + 4.16p1 + 16.31p3 (12)
q6 = 17.53p1 + 18.24p2 + 265.46p3 + 75.08p1 p2 + 63.86p2 2 + 124.95p3 2 (13)
According to the ANOVA results regarding granule size, the p-values of all control
factors were less than 0.05. The R2 values of the response factors (q2 –q6 ) were 0.9706,
0.9895, 0.9338, 0.992, and 0.9787, respectively, which indicates that the control factors had
a significant effect on the response factors. According to Equations (9)–(13), the binder
solvent had a positive effect on granule size. This is because when a large amount of
binding solvent is added to the powder bed, strong liquid bridges are formed between the
particles, which increases the particle size [41,42].
3.2.3. Effect of CPPs on True Density, Bulk Density, Carr’s Index, and Angle of Repose (q7 –q10 )
The true density, bulk density, Carr’s index, and angle of repose were in the 0.69–0.70g/mL,
0.052–0.059 g/mL, 19.75–26.59, and 27.4–43.3◦ ranges, respectively. The standard deviations
of the true density and bulk density approximated 0.00. The standard deviations of Carr’s
index and the angle of repose were 2.36 and 4.42, respectively. Based on the results of true
density, bulk density, Carr’s index, and angle of repose results, an ANOVA was conducted
to identify the individual influence of the control factors (CPPs) on the response factors
(IQAs and CQAs). The individual influence of control factors is described by the reduced
quadratic mathematical model and the reduced 2FI (factor of interaction) mathematical
model, which is presented in Equations (14)–(17).
q7 = 0.0007p1 − 0.0005p2 + 0.0005p3 − 0.0027p1 p2 + 0.0023p2 p3 (14)
q8 = −0.0008p1 + 0.0001p2 − 0.0014p3 + 0.0025p1 p2 − 0.0023p3 2 (15)

2 2
q9 = 0.2000p2 + 4.03p3 + 0.6250p2 p3 − 0.3923p2 + 0.6577p3 (16)
q10 = −0.6000p1 + 1.76p2 + 4.99p3 − 1.70p1 p2 + 2.80p1 p3 (17)
According to the ANOVA results regarding true density, bulk density, Carr’s index,
and angle of repose, the p-values of all control factors were less than 0.05. The R2 values of
the response factors (q7 –q10 ) were 0.8815, 0.9171, 0.9937, and 0.9870, respectively, which in-
dicates that the control factors had a significant effect on the response factors. According to
Equation (14), the true density was positively affected by the impeller speed, binder solvent,
and interaction between impeller speed and massing time. Bulk density was negatively
affected by the impeller speed and binder solvent. If the impeller speed increases, the gran-
ule size may increase because granule coalescence and growth may occur [24,41,42,49]. In
addition, when many binding solvents are added to the powder bed, strong liquid bridges
are formed between the particles, which increases the particle size [41,42]. Larger granules
have a lower bulk density than smaller granules because less can fit in the same volume.
Therefore, impeller speed and binder solvent can negatively affect bulk density. According
to Equation (16), an increase in the binder solvent increases Carr’s index, which results in a
decrease in the granule flowability. According to Equation (17), an increase in the binder
solvent increases the angle of repose and decreases granule flowability.
3.2.4. Effect of CPPs on Granule Strength (q11 )

The granule strength was in the 0.05–0.69 N·sec range. The standard deviation was
0.17. Based on the results of the granule strength analysis, an ANOVA was conducted to
identify the individual influence of control factors (CPPs) on response factors (IQAs and
CQAs). The individual influence of control factors is described by the reduced 2FI (factor
of interaction) mathematical model, which is presented in Equation (18).
q11 = 0.0900p1 − 0.0400p2 − 0.0725p3 − 0.1400p1 p2 − 0.2200p1 p3 (18)
According to the ANOVA results regarding granule strength, the p-values of all
control factors were less than 0.05. The R2 value of the response factors (q11 ) was 0.9752,
According to Equation (18), the impeller speed increases granule strength. This might
increase the impeller speed, which increases granule hardness because increasing the
impeller speed applies high shearing to granules, thereby leading to increased granule
density and strength [43,44].
3.2.5. Effect of CPPs on the Swelling Property (q12 , q13 , and q14 )
The swelling properties (1 h, 3 h, and 5 h) were in the 29.01–32.34%, 46.49–51.08%,
and 62.11–64.42% ranges, respectively. The standard deviations were 0.99, 1.38, and 0.70,
respectively. Based on the swelling property results, an ANOVA was conducted to identify
the individual influence of control factors (CPPs) on response factors (IQAs and CQAs).
The individual influence of control factors is described by the reduced 2FI (factor of
interaction) mathematical model, which is presented in Equations (19)–(21).
q12 = −0.3152p1 + 1.07p2 + 0.6223p3 (19)
q13 = −0.4956p1 − 0.7939p2 − 0.8415p3 + 0.4619p1 p2 − 1.22p1 p3 − 1.20p2 p3 (20)
q14 = 0.7322p1 + 0.1269p2 − 0.1833p3 − 0.1572p1 p2 − 0.1929p1 p3 + 0.6752p2 p3 − 0.0763p1 2 − 0.0763p2 2 + 0.1197p3 2 (21)
According to the ANOVA results regarding the swelling property, the p-values of all
control factors were less than 0.05. The R2 values of the response factors (q12 , q13 , and q14 )
were 0.9804, 0.9532, and 0.9998, respectively, which indicates that the control factors had
a significant effect on the response factors. According to Equation (19), an increase in
massing time increases the swelling property. In addition, as the impeller speed increased,
the swelling property increased at 5 h. According to Equation (3), increased erosion increases
the swelling property. The erosion rate increases as the particle size increases [50,51]. If the
massing time and impeller speed are increased, the granule size may increase because
granule coalescence and growth may occur [24,41,42,49]. Therefore, the impeller speed
and massing time increased the swelling property because the erosion rate increased as the
impeller speed and massing time increased.
3.2.6. Effect of CPPs on Weight Gain (q15 , q16 , and q17 ) and Mass Loss (q18 , q19 , and q20 )
The weight gains (1 h, 3 h, and 5 h) were in the 54.90–69.57%, 55.13–75.59%, and
44.55–75.68% ranges, respectively. The standard deviations of weight gain were 3.88, 5.78,
and 7.85, respectively. Mass losses (1 h, 3 h, and 5 h) were in the 24.10–33.76%, 45.08–50.71%,
and 68.29–77.50% ranges, respectively. The standard deviations of mass loss were 2.51, 1.64,
and 2.48, respectively. Based on the weight gain and mass loss results, an ANOVA was
conducted to identify the individual influence of control factors (CPPs) on response factors
2FI (factor of interaction) mathematical model, which is presented in Equations (22)–(27).
q15 = 1.35p1 − 4.43p2 + 0.5916p3 + 2.92p1 p2 (22)
q16 = 2.06p1 − 5.23p2 + 0.1889p3 + 5.12p1 p2 − 4.58p1 p3 + 2.41p2 p3 (23)

q17 = −0.9555p1 − 8.39p2 − 0.7901p3 + 3.97p1 p2 + 7.25p2 p3 (24)
q18 = 0.5310p1 + 2.88p2 − 0.3433p3 + 1.15p1 p2 − 1.71p2 p3 (25)
q19 = −0.3141p1 + 1.80p2 − 0.7558p3 − 0.7325p1 p2 − 1.01p2 p3 (26)
q20 = −0.1045p1 + 2.66p2 − 1.58p3 − 0.9154p1 p2 − 1.07p2 p3 (27)
According to the ANOVA results for weight gain and mass loss, the p-values of all
control factors were less than 0.05. The R2 values of the response factors (q15 , q16 , and q17 )
were 0.9892, 0.9938, and 0.9838, respectively, which indicates that the control factors had
a significant effect on the response factors. The R2 values of the response factors (q18 , q19 ,
and q20 ) were 0.9841, 0.9911, and 0.9842, respectively, which indicates that the control factors
had a significant effect on the response factors. According to Equations (22)–(24), massing
time decreases weight gain. Generally, an increase in massing time leads to a decrease
in granule porosity [52–54]. When the granule porosity decreases, water penetration into
the tablet decreases, which negatively affects weight gain. In addition, when hydrophilic
polymers are used, the weight gain increases rapidly due to the rapid absorption of water
at the beginning; however, as time passes, the gel layer acts as a barrier, so the weight gain
is slightly changed by absorbing the aqueous medium slowly.
According to Equations (25)–(27), massing time increases mass loss. According to the
Equation (5), increased tablet erosion increases mass loss. The erosion rate increases as the
particle size increases [50,51]. If the massing time is increased, the granule size may increase
because granule coalescence and growth may occur [24,41,42,49]. Therefore, massing time
increases mass loss because the erosion rate increases as the massing time increases.
3.2.7. Effect of CPPs on Gel Strength (q21 , q22 , and q23 )

The gel strengths (1 h, 3 h, and 5 h) were in the 1.41–13.29 N·sec, 1.97–10.15 N·sec,
and 1.58–7.22 N·sec, ranges respectively. The standard deviations were 3.53, 2.48, and 1.85,
respectively. Based on the results of gel strength analysis, an ANOVA was conducted to
identify the individual influence of control factors (CPPs) on response factors (IQAs and
CQAs). The individual influence of control factors is described by the reduced 2FI (factor
of interaction) mathematical model, which is presented in Equations (28)–(30).
q21 = +1.17p1 − 1.56p2 + 4.05p3 (28)
q22 = −0.1167p1 − 1.49p2 + 0.5977p3 − 0.6932p1 p2 − 2.78p1 p3 − 2.74p2 p3 (29)

q23 = −0.1729p1 − 0.7796p2 + 0.2926p3 + 2.08p1 p2 − 2.05p1 p3 + 1.18p2 p3 (30)
According to the ANOVA results regarding gel strength, the p-values of all control
factors were less than 0.05. The R2 values of the response factors (q21 , q22 , and q23 ) were
0.9287, 0.9696, and 0.9501, respectively, which indicates that the control factors had a
significant effect on the response factors. According to Equations (28)–(30), the gel strength
at 1 h was positively affected by the impeller speed and binder solvent, while at 3 h it was
negatively affected by the interaction between the impeller speed and binder solvent and
the interaction between the massing time and the binder solvent. According to Equation
(30), the gel strength at 5 h was positively affected by the interaction between the impeller
speed and massing time.
3.2.8. Effect of CPPs on Dissolution (q24 , q25 , and q26 )

The dissolution profiles (1 h, 3 h, and 10 h) were in the 41.66–46.42%, 74.55–82.57%,
and 104.06–108.97% ranges, respectively. The standard deviations were 1.50, 2.15, and
1.50, respectively. Based on the dissolution results, an ANOVA was conducted to identify
interaction) mathematical model, which is presented in Equations (31)–(33).
q24 = −0.2500p1 + 0.4275p2 + 0.6700p3 − 1.03p1 p2 − 1.87p1 p3 − 1.20p2 p3 (31)
q25 = −0.9363p1 + 0.1425p2 + 0.7788p3 − 1.40p1 p3 − 3.18p2 p3 (32)

q26 = 0.1137p1 + 0.4375p2 + 0.09386p3 + 1.85p1 p2 + 0.6100p1 p3 − 1.87p2 p3 (33)
According to the ANOVA results regarding dissolution, the p-values of all control fac-
tors were less than 0.05. The R2 values of the response factors (q24 , q25 , and q26 ) were 0.9400,
0.9338, and 0.9833, respectively, which indicates that the control factors had a significant
effect on the response factors. At the initial 1 h, the dissolution was negatively influenced
by the interaction between the impeller speed and the binder solvent. If the impeller speed
increases, the granule size may increase because granule coalescence and growth may
occur [24,41,42,49]. Furthermore, when a large amount of binding solvent is added to the
powder bed, strong liquid bridges are formed between the particles, which increases the
particle size [41,42]. The increased granule size has a smaller surface area compared to
the smaller granule size. Larger-sized granules have a smaller water contact area than the
smaller-sized granules, so the disintegration rate is slow [24]. Therefore, larger granules
have slow dissolution. Thus, the dissolution could be negatively influenced by the massing
time and binder solvent. At 3 h and 10 h, the interaction between massing time and
binder solvent decreased the dissolution. Increasing the massing time could increase the
granule size because it presents the mechanical energy required for mixing the powder [24].
Furthermore, when a large amount of binding solvent is added to the powder bed, strong
liquid bridges are formed between the particles, which increases the particle size [41,42].
Large granules have a smaller surface area than small granules, so drug release is slow [24].
Thus, the dissolution could be negatively influenced by the massing time and amount of
binder solvent.
3.2.9. Effect of CPPs on the Contact Angle (q27 )

The contact angle was in the 3.88–10.76 θ/sec range. The standard deviation was
1.80. Based on the results of the contact angle, an ANOVA was conducted to identify
interaction) mathematical model, which is presented in equation (34).
q27 = −0.7754p1 − 0.6704p2 + 0.3488p3 + 2.13p1 p2 + 2.00p2 p3 (34)
According to the ANOVA results regarding the contact angle, the p-values of all
control factors were less than 0.05. The R2 value of the response factors (q27 ) was 0.9580
According to Equation (34), the impeller speed and massing time decrease the contact
angle. If the massing time and impeller speed increase, the granule size may increase
because granule coalescence and growth may occur [24,41,42,49]. The increased granule
size results in a smaller surface area than smaller granule size. Therefore, larger granules
have a smaller water contact area than smaller sized granules, so the wetting rate is slow,
which negatively affects the contact angle.
3.3. Effect of CPPs on the IQAs and CQAs of Roller Compaction

3.3.1. Effect of CPPs on the Intrinsic Dissolution Rate (d1 )
The intrinsic dissolution rate was in the 0.0138–0.0198 µg·mm−2 ·min−1 range. The standard
deviation was approximately 0.00. Based on the results of the intrinsic dissolution rate,
an ANOVA was conducted to identify the individual influence of control factors (CPPs) on
response factors (IQAs and CQAs). The individual influence of control factors is described
by the reduced linear mathematical model, which is presented in Equation (35).
d1 = −0.009c1 − 0.0023c3 (35)
According to the ANOVA results regarding the intrinsic dissolution rate, the p-values
of all control factors were less than 0.05. The R2 values of the response factors (d1 ) were
0.9225, which indicates that the control factors had a significant effect on the response
factors. According to Equation (35), the roller pressure and mill screen size decrease the
intrinsic dissolution rate. It is possible that increasing the roller pressure and increasing
the mill screen size generated large granules [48,55]. Large granules have a smaller surface
area than small granules, so drug release is slow [24]. Therefore, the roller pressure and
mill screen size can decrease the intrinsic dissolution rate.
3.3.2. Effect of CPPs on Granule Size (d2 –d6 )

The granule sizes (D10 , D50 , D90 , D(3,2), and D(4,3)) were in the 8.62–10.10 µm,
59.80–68.09 µm, 245.78–317.14 µm, 14.71–15.70 µm, and 106.10–128.54 µm ranges, respec-
tively. The standard deviations were 0.51, 2.19, 19.96, 5.77, and 19.96, respectively. Based
on the granule size results, an ANOVA was conducted to identify the individual influence
control factors is described by the reduced 2FI (factor of interaction) mathematical model,
which is presented in Equations (36)–(40).
d2 = 0.4225c1 − 0.0075c2 + 0.0900c3 + 0.7075c2 c3 (36)
d3 = 2.12c1 − 1.23c2 + 1.33c3 (37)

d4 = 23.14c1 + 8.92c3 (38)
d5 = 0.3125c1 + 0.0687c2 + 0.1462c3 (39)
d6 = 5.46c1 + 4.88c3 (40)
According to the ANOVA results regarding granule size, the p-values of all control
factors were less than 0.05. The R2 values of the response factors (d2 –d6 ) were 0.9553, 0.9178,
0.8821, 0.9519, and 0.9190 indicating that the control factors had a significant effect on the
response factors. According to equation (36), the interaction between the roller gap and
mill screen size increases the granule size. According to equations (37)–(40), the roller
pressure increases the granule size. Generally, increasing the roller pressure and increasing
the mill screen size generate large granules [48,55]. Therefore, the roller pressure and mill
screen size increase the granule size.
3.3.3. Effect of CPPs on Ribbon Density, Bulk Density, and Tapped Density (d7 , d8 , and d9 )
The ribbon density, bulk density, and tapped density were in the 1.01–1.26 g/cm3 ,
0.046–0.055 g/mL, and 0.064–0.067 g/mL ranges, respectively. The standard deviation
of the ribbon density was 0.08. The standard deviations of the bulk density and tapped
density were approximate 0.00. Based on the ribbon density, bulk density, and tapped
density results, an ANOVA was conducted to identify the individual influence of control
factors (CPPs) on response factors (IQAs and CQAs). The individual influence of control
factors is described by the reduced linear mathematical model and generates the reduced
quadratic mathematical model, which is presented in Equations (41)–(43).
d7 = 0.1037c1 − 0.0163c2 + 0.0100c3 (41)
d8 = −0.0016c1 − 0.0008c2 − 0.0021c3 + 0.0027c3 2 (42)
d9 = 0.0001c1 − 0.0003c2 − 0.0001c3 − 0.0002c1 c2 − 0.0008c2 c3 + 0.0008c1 2 + 0.0005c2 2 + 0.0012c3 2 (43)

According to the ANOVA results regarding ribbon density, bulk density, and tapped
density, the p-values of all control factors were less than 0.05. The R2 values of the response
factors (d7 , d8 , and d9 ) were 0.9816, 0.9575, and 0.9779, respectively, indicating that the
control factors had a significant effect on the response factors. According to Equation (41),
roller pressure increases ribbon density. Generally, an increase in roller pressure increases
ribbon density [15]. Therefore, ribbon density is positively influenced by roller pressure.
According to Equation (42), the mill screen size decreases the bulk density. Generally, large
pore size sieves generate large-sized granules [55]. Larger granules have a lower blk
density than smaller granules because less can fit in the same volume. Thus, the mill screen
size decreases the bulk density. According to Equation (43), an increase in the roller gap
decreases the tapped density.
3.3.4. Effect of CPPs on Granule Strength and Granule Uniformity (d10 and d11 )
The granule strength and granule uniformity were in the 0.04–0.34 N·sec and
1.22–3.90% RSD ranges, respectively. The standard deviations were 0.09 and 0.7, respec-
tively. Based on the granule strength and granule uniformity results, an ANOVA was
conducted to identify the individual influence of control factors (CPPs) on response factors
2FI (factor of interaction) mathematical model, which is presented in Equations (44)–(45).
d10 = 0.1094c1 + 0.0406c2 (44)
d11 = 0.1575c1 − 0.0350c2 + 0.3025c3 + 1.17c2 c3 (45)

According to the ANOVA results regarding granule strength and granule uniformity,
the p-values of all control factors were less than 0.05. The R2 values of the response factors
(d10 and d11 ) were 0.9687 and 0.9435, respectively, which indicates that the control factors
had a significant effect on the response factors. According to Equation (44), roller pressure
increases granule strength. Generally, increasing roller pressure results in increased ribbon
density and thus granules harder [15]. Therefore, the granule strength was positively
influenced by the roller pressure. According to Equation (45), granule uniformity was
positively affected by the mill screen size and the interaction between the roller gap and
mill screen size.
3.3.5. Effect of CPPs on Tablet C.U. (d12 )

The tablet C.U. was in the 2.08–4.10% RSD range. The standard deviation was 0.53.
Based on the tablet C.U. result, an ANOVA was conducted to identify the individual
influence of control factors (CPPs) on response factors (IQAs and CQAs). The individual in-
fluence of control factors is described by the linear mathematical model, which is presented
in Equation (46).
d12 = −0.5375c1 + 0.2537c2 − 0.3562c3 (46)
According to the ANOVA results regarding tablet C.U., the p-values of all control
factors were less than 0.05. The R2 value of the response factors (d12 ) was 0.9641, which in-
dicates that the control factors had a significant effect on the response factors. According to
Equation (46), the tablet C.U. was negatively affected by roller pressure and mill screen
size. Increasing the roller pressure and the mill screen size generated large granules [48,55].
In general, the smaller the particle size, the better the content uniformity [56]. Thus, roller
pressure and mill screen size had a negative effect on tablet C.U.
3.3.6. Effect of CPPs on Dissolution (d13 –d15 )

The dissolution profiles (5 min, 10 min, and 15 min) were in the 37.19–65.78%,
53.56–83.15%, and 77.92–93.87% ranges, respectively. The standard deviations were 10.77,
10.19, and 5.66, respectively. Based on the dissolution results, an ANOVA was conducted
to identify the individual influence of control factors (CPPs) on response factors (IQAs
and CQAs). The individual influence of control factors is described by the reduced linear
mathematical model, which is presented in Equations (47)–(49).
d13 = −3.93c1 − 12.98c3 (47)
d14 = −4.17c1 − 12.43c3 (48)

d15 = −2.15c1 − 6.83c3 (49)
According to the ANOVA results regarding dissolution, the p-values of all control
factors were less than 0.05. The R2 values of the response factors (d13 –d15 ) were 0.9057,
0.9459, and 0.9144, respectively, which indicates that the control factors had a significant
effect on the response factors. According to Equations (47)–(49), dissolution was negatively
affected by mill screen size. Generally, large pore size sieves generate large-sized granules.
Large granules have a smaller surface area than small granules, so drug release is slow [24].
Therefore, dissolution was negatively affected by the mill screen size.
3.3.7. Effect of CPPs on the Contact Angle (d16 )

The contact angle was in 6.07–7.89 θ/s range. The standard deviation was 0.41. Based
on the contact angle result, an ANOVA was conducted to identify the individual influence
of control factors (CPPs) on response factors (IQAs and CQAs). The individual influence
of control factors is described by the linear mathematical model, which is presented
in Equation (50).
d16 = −0.2525c1 − 0.4337c3 (50)
According to the ANOVA results regarding the contact angle, the p-values of all
control factors were less than 0.05. The R2 value of the response factors (d16 ) was 0.8746,
According to Equation (50), the mill screen size decreases the contact angle. The increased
granule size results in a smaller surface area compared to the smaller granule size. There-
fore, the larger granules have a smaller water contact area than the smaller sized granules,
so the wetting rate is slow, which negatively affects the contact angle. Generally, large pore
size sieves generate large-sized granules [55]. Therefore, mill screen size had a negative
effect on the contact angle.
Pharmaceutics 2021, 13, x 19 of 28

3.4. Design Spaces of Process Parameters
3.4.1. Design Space of High-Shear Wet Granulation
The optimization conditions of response factors for high-shear wet granulation pro-
3.4. Design Spaces of Process Parameters
cess 3.4.1.
wereDesign
as follows: optimal range of angle of repose (30.5–40.5°); optimal range of a
Space of High-Shear Wet Granulation
granule size D10 (18–36.8 μm); optimal range of D50 (30–280 μm); optimal range of a gran-
The optimization conditions of response factors for high-shear wet granulation process
ule size
were D (400–1200
as90follows: μm);range
optimal optimal range
of angle of D(3,2)
of repose (33.2–95.4
(30.5–40.5 μm);range
◦ ); optimal optimal range of a
of a granule
granule
size Dsize D(4,3) (170–680 μm); optimal range of granule strength (0.15–0.65 N∙sec); op-
10 (18–36.8 µm); optimal range of D50 (30–280 µm); optimal range of a granule size
timalD90
ranges
(400–1200of gel strength
µm); optimalatrange
1 h (3.78–11.25 N∙sec),µm);
of D(3,2) (33.2–95.4 3 h (2.61–8.61
optimal range N∙sec), and 5 hsize
of a granule (1.59–
7.21 D(4,3)
N∙sec); optimalµm);
(170–680 range of weight
optimal range gain at 5 hstrength
of granule (45.07–75.07%);
(0.15–0.65optimal range of
N·sec); optimal the con-
ranges
tact of gel strength
angle (4.95–9.95 at 1θ/s).
h (3.78–11.25
The intrinsicN·sec), 3 h (2.61–8.61
dissolution ·sec),density,
rate,Ntrue and 5 h (1.59–7.21
bulk density,N·sec);
Carr’s
optimal range of weight gain at 5 h (45.07–75.07%); optimal range of
index, dissolution at 1 h, 3 h, and 10 h, the swelling property at 1 h, 3 h, and 5 h, the weightthe contact angle
gain(4.95–9.95
at 1 h andθ/s). 3 h, The
andintrinsic
mass loss dissolution rate,
at 1 h, 3 h, andtrue
5 hdensity,
results bulk density,
satisfied bothCarr’s index,and
the upper
dissolution at 1 h, 3 h, and 10 h, the swelling property at 1 h, 3 h, and 5 h, the weight
lower limits of the target value and were excluded from the design space. The response
gain at 1 h and 3 h, and mass loss at 1 h, 3 h, and 5 h results satisfied both the upper
factors were combined to produce a design space with a 95% confidence interval. Figure
and lower limits of the target value and were excluded from the design space. The re-
1a shows
sponsethe design
factors werespace for high-shear
combined to producewet granulation.
a design space withThea yellow area represents
95% confidence interval. the
95%Figure
confidence interval. To evaluate the robustness of the design
1a shows the design space for high-shear wet granulation. The yellow area space and therep-
risk of
uncertainty
resents the in 95%
model predictions,
confidence a Monte
interval. Carlo
To evaluate thesimulation
robustness was of theconducted
design space using
and the
MODDEthe risk of uncertainty
® software in model
(Sartorius Stedimpredictions,
Biotech.,a version
Monte Carlo
12.0.1, simulation was conducted
Umeå, Sweden). Figure 1b
using ®
shows thethe MODDE
result of the software
Monte Carlo (Sartorius Stedim with
simulation Biotech.,
the version
probability12.0.1,ofUmeå, Sweden).
failure. The green
area represents a quality certainty of 99.9%, which indicates a 0.1% probabilityfailure.
Figure 1b shows the result of the Monte Carlo simulation with the probability of of failure.
The green area represents a quality certainty of 99.9%, which indicates a 0.1% probability
In contrast, the red area represents a higher probability of failure. As a result, the roller
of failure. In contrast, the red area represents a higher probability of failure. As a result,
pressure had 99.9% quality certainty in an impeller speed range of approximately 50–150
the roller pressure had 99.9% quality certainty in an impeller speed range of approximately
rpm50–150
and a binder
rpm andsolvent
a binder range
solventof approximately 2.3–3.4 mL
range of approximately 2.3–3.4when
mLthewhen massing time was
the massing
fixedtime
at 30 s.
was fixed at 30 s.
%
4 4 50
10
2
Binder solvent (mL)
3.4 3.4 10
Binder solvent (mL)
1
2.8 2.8 5
0.5
2.2 2.2 5 2
50
1.6 1.6 1
0.5
1 1
50 70 90 110 130 150 50 70 90 110 130 150
Impeller speed (rpm) Impeller speed (rpm)
(a) (b)
Figure Figure
1. (a) Design spacespace
1. (a) Design for high-shear wetwet
for high-shear granulation
granulationbybycombining
combiningresponse
response factors basedononoptimization
factors based optimization conditions:
conditions:
the massing time was
the massing timefixed at 30ats.30
was fixed The yellow
s. The area
yellow represents
area representsthe
the95%
95% confidence interval.(b)
confidence interval. (b) Results
Results of the
of the Monte
Monte CarloCarlo
simulation for high-shear
simulation wet wet
for high-shear granulation: thethe
granulation: massing
massingtime
time was fixedatat3030s. s.The
was fixed The intensity
intensity bar bar stands
stands forprobability
for the the probability
of
of failure. TheThe
failure. green area
green represents
area representsaaquality
quality certainty of99.9%.
certainty of 99.9%.
3.4.2.3.4.2.
Design Space of Roller Compaction
Design Space of Roller Compaction
TheTheoptimization
optimization conditions
conditionsofofthe
theresponse factorsfor
response factors forthe
the roller
roller compaction
compaction process
process
werewere
as follows: optimal
as follows: optimalrange
rangeofofintrinsic dissolutionrate
intrinsic dissolution rate (0.0014–0.01847
(0.0014–0.01847 μg/min/mm
µg/min/mm 2 ); 2);
optimal range
optimal of D
range of50D(61.04–68.08
50 (61.04–68.08μm);
µm);optimal rangeofofaagranule
optimal range granule size
size D90D(400–1200
90 (400–1200
µm);μm);
optimal
optimal range
range of of D(3,2)
D(3,2) (33.2.95.4μm);
(33.2.95.4 optimal range
µm); optimal rangeofofgranule
granule strength
strength(0.0096–0.296
(0.0096–0.296
N·sec);
N∙sec); optimal
optimal range
range ofofdissolution
dissolution at
at 55min
min(37.5–64.28%);
(37.5–64.28%); optimal range
optimal of dissolution
range at
of dissolution
at 10 min (57.43–82.10%). The ribbon density, bulk density, tapped density, granule size
D10, granule size(3,2), granule size(4,3), granule uniformity, tablet C.U., dissolution at 15,
Pharmaceutics
Pharmaceutics x 13, 80
2021, 13,2021, 20 of20
27of 28
10 and
30, 45, min (57.43–82.10%). The ribbon
60 min, and contact angledensity,
resultsbulk density,
satisfied tapped
both the density,
upper andgranule sizelimits
lower D10 , of
granule size(3,2), granule size(4,3), granule uniformity, tablet C.U., dissolution at 15, 30, 45,
the target value and were excluded from the design space. The response factors were com-
and 60 min, and contact angle results satisfied both the upper and lower limits of the target
bined to produce
value and werea excluded
design spacefrom with a 95%space.
the design confidence interval.
The response Figure
factors were2acombined
shows the to de-
sign produce
space for roller compaction.
a design space with a 95% Theconfidence
yellow area represents
interval. Figurethe 95% confidence
2a shows interval.
the design space
To evaluate
for roller compaction. The yellow area represents the 95% confidence interval. To evaluatepre-
the robustness of the design space and the risk of uncertainty in model
dictions, a Monte Carlo
the robustness of thesimulation
design space wasandconducted using
the risk of the MODDE
uncertainty ® software
in model (Sartorius
predictions, a
Monte Carlo version
simulation was conducted using the MODDE ® software (Sartorius Stedim
Stedim Biotech., 12.0.1, Umeå, Sweden). Figure 2b shows the results of the Monte
CarloBiotech., version
simulation with12.0.1,
the Umeå, Sweden).
probability Figure 2b
of failure. The shows
greenthe results
area of the Monte
represents Carlocer-
a quality
tainty of 99.9%, which suggests a 0.1% probability of failure. In contrast, the red areaofrep-
simulation with the probability of failure. The green area represents a quality certainty
99.9%, which suggests a 0.1% probability of failure. In contrast, the red area represents a
resents a higher probability of failure. As a result, roller pressure had 99.9% quality cer-
higher probability of failure. As a result, roller pressure had 99.9% quality certainty in an
tainty in an approximate
approximate 45–85 bar 45–85
range andbar the
range
milland thesize
screen millin screen size in an
an approximate approximate
0.7–1.3 mm range0.7–
1.3 mm
when range whengap
the roller thewas
roller gap
fixed was
at 1.8 fixed at 1.8 mm.
mm.
%
1.5 1.5 50
5
Mill screen size (mm)
Mill screen size (mm)
1.3 1.3 2 10
1.1 1.1 5
50 0.5
10
0.9 0.9 2
0.7 0.7 1
0.5 0.5 0.5

25 35 45 55 65 75 85 25 35 45 55 65 75 85
Roller pressure (bar) Roller pressure (bar)
(a) (b)
Figure 2. (a) Design
Figure space space
2. (a) Design for roller compaction
for roller compactionby combining
by combiningresponse
responsefactors
factorsbased on optimization
based on optimization conditions:
conditions: thethe roller
roller
gap wasgapfixed
wasatfixed
1.8 mm.
at 1.8The
mm.yellow area area
The yellow represents thethe
represents 95% confidence
95% confidenceinterval.
interval. (b) Results
Resultsofofthe
theMonte
Monte Carlo
Carlo simulation
simulation
for roller
forcompaction: the roller
roller compaction: gap was
the roller fixed
gap was at 1.8
fixed mm.
at 1.8 The
mm. intensity
The intensitybar
barstands
stands for the
theprobability
probabilityofof failure.
failure. TheThe green
green
area represents a quality
area represents certainty
a quality of 99.9%.
certainty of 99.9%.
3.5. Multivariate Analysis between IQAs and CQAs

3.5. Multivariate Analysis between IQAs and CQAs
As theAs pharmaceutical
the pharmaceutical process
processconsists
consistsof
of unit operations,the
unit operations, theintermediate
intermediate product
product
afterafter
the unit process affects the downstream process. Therefore, if we confirm the
the unit process affects the downstream process. Therefore, if we confirm the relation- rela-
tionship
ship between IQAsand
between IQAs andCQAs,
CQAs, thethe latter
latter cancan be predicted
be predicted through
through the former.
the former. As DoEAs canDoE
can process onlyaalimited
process only limited number
number of variables,
of variables, the correlation
the correlation between
between IQAs
IQAs and andwas
CQAs CQAs
confirmed using MVA that can analyze multiple variables simultaneously.
was confirmed using MVA that can analyze multiple variables simultaneously. In this In this study,
wewe
study, used the the
used Pearson correlation
Pearson coefficient
correlation and PCA.
coefficient and PCA.
3.5.1. Correlation between IQAs and CQAs of High Shear Wet Granulation Process
3.5.1. Correlation between IQAs and CQAs of High Shear Wet Granulation Process
Pearson correlation coefficient analysis was performed to evaluate the correlation
Pearson
among thecorrelation coefficient
response factors. analysis
The correlation was performed
coefficient to from
value ranged evaluate
−1 to the correlation
1. Each value
among the response
indicated factors.
the following The correlation
correlations: coefficient
−1, negative value0, ranged
correlation; from −1
uncorrelation; to 1. Each
1, positive
valuecorrelation.
indicatedFigure
the following correlations:
3 visualizes −1,among
the correlation negative correlation;
the response 0, uncorrelation;
factors as a heat map. 1,
The red
positive color indicates
correlation. a value
Figure of 1, and the
3 visualizes the blue color indicates
correlation among a value of −1. factors as a
the response
Figure 3 shows the correlation between IQAs and CQAs in the high-shear
heat map. The red color indicates a value of 1, and the blue color indicates a value wet gran-
of −1.
ulation process. According to Figure 3, we confirmed that dissolution had a positive
correlation with the intrinsic dissolution rate, Carr’s index, bulk density, and angle of
repose. On the other hand, dissolution had a negative correlation with granule strength,
granule size, and true density. In particular, the relationship between D10 and dissolution
at 1 h and the relationship between bulk density and dissolution at 1 h were strongly
correlated. This means that as the granule size decreases, dissolution and bulk density
increase. In addition, as is shown in Figure 3, the bulk density and granule size have a
negative correlation.
To evaluate the relationship between IQAs and CQAs, PCA was conducted using the
SIMCA© software (Sartorius Stedim Biotech., version 15, Umeå, Sweden). The first, second,
third, and fourth PCs explained 32.3%, 26.0%, 14.5%, and 12.2% of the overall variability,
respectively, and the sum of these PCs accounted for 85% of the total. Points gathered
together indicated correlation, and points located opposite to each other indicated that
Pearson1 they had negative relationships. Pearson1
1.000 1.000Sheet1
Contact angle 1.000
Bulk density Pearson1
Dissolution at 60min
True denstiy Tapped density
1.000
+1
Granule size atD[4,3]
Dissolution 45min
Granule size atD[3,2]
Dissolution 30min
True density
Granule
0.6190 size D90 Contact angle
0.6100
Granule sizeDissolution
Dissolution at D50 at 60min
15min 0.6190
Granule size
Dissolution D10
at 10min
0.6300
Angle of repose Dissolution at 45min +0.5
Dissolution
Granule at 5min
strength
Carr's
0.2380 index
Tablet CU 0.2200
Intrinsic dissolution rate 0.2380
Granule uniformity
Contact Dissolution
angle at 10min 0.2600
Dissolution
Granule at 10h at 5min
strength
Dissolution
Dissolution
Tapped
at 3h
density
0
Dissolution atGranule 1h strength
Gel-0.1430
strength at
Bulk density5h size D[4,3]
Granule -0.1700
-0.1100
Gel strength at 3h size D[3,2] -0.1430
Granule
Ribbon density
Gel strength at 1h
Mass loss at D Granule
5h size D90
[4,3]
Mass loss at 3h size D50
D Granule
[3,2]
-0.5
Mass
-0.5240
loss atGranule
1h size D10 -0.4800
-0.5600
Weight gain atD90 5h -0.5240
Weight gain atD50 3hBulk density
Weight gain at Angle 1h of repose
Swelling property atD10
Intrinsic 5h
dissolution rate
Swelling property atrate
3h -1
Intrinsic dissolution -0.8500
Swelling -0.9050
property at 1h -0.9500
at strength
repose
density
angle
1hD10
5hD50
1hD90
D[3,2]
D[4,3]
density
density
at 3h5min
at 30min
at 45min
at 60min
rate
-0.9050
D [3,2]
[4,3]
strength
D10
D50
D90
Bulk density
angle
density
density
uniformity
TabletatCU
at 5min
15min
45min
60min
rate
Granule strength
Contact angle
Angle of repose
Granule size D[3,2]

Granule size D[4,3]
Carr's index
Granule size D10

Granule size D50
Granule size D90
True denstiy
Bulk density
Intrinsic dissolution rate
at 1h
atof3h
5h
3h
5h
1h
strength
of repose
at 1h
Swelling property at 3h
Swelling property at 5h
3h
at D10
D50
size D90
at 10h
Contact angle
rate
index
True denstiy
Bulk density
D[3,2]
Granule size D[4,3]
dissolution
D size
at size
at size
Contact
size
size
True
Granule sizeTapped
Weight gainBulk
dissolution
Dissolution
at
at
at
Granuleat
at
Granule
Granule
Granule
Granule
Dissolution
Dissolution
AngleDissolution
GranuleContact
Angle
Long Name
at
at
Intrinsic dissolution
Granule
size
size
Tapped
MassRibbon
Dissolution
gain
Weight gain
Dissolution
Dissolution
Gel strength
Gel strength
Gel strength
property
Mass loss
loss
Mass loss
Granule
Carr's
Dissolution
Dissolution
Dissolution
Dissolution
Granule
Intrinsic
Granule
Granule
Granule
Weight
Intrinsic
Figure 3. Pearson correlation coefficient of the high-shear wet granulation process. Bulk: bulk
Swelling
density; True: true density; A.O.R.: angle of repose; G.S.: granule strength; Carr’s: Carr’s index; IDR:
Figure 3. Pearson correlation coefficient of the high-shear wet granulation process. Bulk: bulk den-
intrinsic dissolution rate; Contact: contact angle; Diss.: dissolution; Gel.: gel strength; M.L.: mass
(b)
sity; True: true density; A.O.R.: angle of repose; G.S.: granule strength; Carr’s: Carr’s index; IDR:
loss;dissolution
intrinsic W.G.: weight gain;
rate; SWE.:contact
Contact: swelling property.
angle; Diss.: dissolution; Gel.: gel strength; M.L.: mass
loss; W.G.: weight gain; SWE.: swelling property.
Figure 4a shows the loading plot with PC1 and PC2 of high-shear wet granulation.
As is shown in Figure 4a, the granule size, contact angle, weight gain, granule strength,
Figure 3 shows the correlation between IQAs and CQAs in the high-shear wet gran-
gel strength at 5 h, and swelling property at 5 h have positive loading values in PC1.
ulation process. According to Figure 3, we confirmed that dissolution had a positive cor-
In contrast, the intrinsic dissolution rate, gel strength at 1 h and 3 h, swelling property at
relation with the intrinsic dissolution rate, Carr’s index, bulk density, and angle of repose.
1 h and 3 h, bulk density, dissolution, angle of repose, Carr’s index, and mass loss have
On the other hand, dissolution had a negative correlation with granule strength, granule
negative loading values in PC1. In addition, dissolution and granule size, which are located
size, and true density. In particular, the relationship between D10 and dissolution at 1 h
opposite to each other, have a negative correlation. In the case of PC2, granule size, bulk
and the relationship between bulk density and dissolution at 1 h were strongly correlated.
density, swelling property at 5 h, and true density near the zero line indicate that they have
This means that as the granule size decreases, dissolution and bulk density increase. In
a smaller effect on PC2. Dissolution, Carr’s index, angle of repose, mass loss, swelling
addition, as is shown in Figure 3, the bulk density and granule size have a negative corre-
property at 1 h, and granule size have negative values in PC2. In addition, the intrinsic
lation.
dissolution rate, weight gain, contact angle, granule strength, swelling property at 3 h,
To evaluate
gel strength the
at 1relationship between
h and 5 h, and IQAs and
true density hadCQAs, PCA
positive wasin
values conducted
PC2. using the
SIMCA© software (Sartorius Stedim Biotech., version 15, Umeå, Sweden). The first, sec-
ond, third, and fourth PCs explained 32.3%, 26.0%, 14.5%, and 12.2% of the overall varia-
bility, respectively, and the sum of these PCs accounted for 85% of the total. Points gath-
ered together indicated correlation, and points located opposite to each other indicated
that they had negative relationships.
Figure 4a shows the loading plot with PC1 and PC2 of high-shear wet granulation.
As is shown in Figure 4a, the granule size, contact angle, weight gain, granule strength,
gel strength at 5 h, and swelling property at 5 h have positive loading values in PC1. In
0.4 0.5
W.G. 5h Gel. 3h
W.G. 1h
0.3 Gel. 1h W.G. 3h 0.4 G.S.
Gel. 5h
Pharmaceutics
0.2
2021, 13, x Contact 0.3 SWE. 3h 22 of 28
SWE. 3h True
Diss. 3h
Gel. 3h 0.2 Bulk
0.1 G.S. SWE. 5h W.G. 3h
True 0.1
Bulk M.L. 3h Gel. 1h
D10
Diss. 3h DD[3,2]
[4,3]
PC2
PC4
0 D50 W.G. 1h D50 D10 Carr’s
Carr’s Diss. 10h SWE.5h D10 Gel. 5h D10
0.4 Diss. 1h D [3,2] 0 D[4,3]D
90 D[3,2]
-0.1 0.5 D [4,3]

Mass loss at 5h Diss. 1h
W.G. 5h -0.1 W.G. 5h D [3,2] Gel.
M.L.3h 5h
W.G. 1h D90
A.O.R IDR 0.4 G.S. M.L. 1h
0.3 Gel. 1h W.G. 3h SWE. 1h IDR
-0.2 -0.2
Gel. 5h Diss. 10h
SWE. 3h A.O.R
M.L. 1h Contact 0.3
0.2 SWE. 3h SWE. 1h True
-0.3 M.L. 5h -0.3 Diss. 3h
M.L. 3h Gel. 3h 0.2 Contact Bulk
0.1 G.S. SWE. 5h
-0.4 -0.4 W.G. 3h
True 0.1-0.5 0.5
Bulk Diss. 3h 0.1 0.2 D10
DD[3,2]
[4,3]0.3 -0.4 -0.3 -0.2 -0.10 3h0.1 Gel.0.2
1h 0.3 0.4 0.5
0-0.3 -0.2 -0.1 0
PC2
PC4
M.L.
D50 W.G. 1h D50 PC3 D10 Carr’s
Carr’s Diss. 10h PC1 SWE.5h D10 Gel. 5h D10
Diss. 1h R2X[2]= 0.26 D [3,2] 0 D[4,3]D
90 D[3,2]
R2X[1]= 0.323, D [4,3]
Mass
R2X[3]= loss at 5h
0.145, R2X[4]=M.L.
0.122 Diss. 1h
-0.1 -0.1 W.G. 5h D [3,2] 5h
D90
A.O.R IDR M.L. 1h
SWE. 1h IDR
-0.2 (a) -0.2 (b) Diss. 10h
M.L. 1h A.O.R
SWE. 1h
-0.3 M.L. 5h -0.3
Figure 4. Figure
Score 4. Score scatter
scatter plot ofplot of high-shear
high-shear
M.L. 3h
wetwet granulation:(a)
granulation: (a) PC1
PC1 and
-0.4 lines located opposite to each other, indicate a negative correlation.
andPC2,
PC2, (b)(b)
PC3PC3
andand
PC4.PC4.The groups
Contact
The groupswithin the gray the gray
within
dotted -0.4 The groups within
-0.5 -0.4 -0.3 -0.2 -0.1
the orange dotted
0.3
lines
0.5
dotted lines -0.3
located
indicate
-0.2
opposite
positive
-0.1
correlations
0
to each
PC1
0.1
withother,
0.2
indicate
each other.
0.3
a negative
Bulk: bulk density; correlation. TheA.O.R:
True: true density: groups anglewithin the orange 0.5
0 0.1 0.2 0.4
PC3 of repose; G.S.: granule
dotted lines
R2X[1]= 0.323, R2X[2]= 0.26 R2X[3]= 0.145, R2X[4]= 0.122
indicate positive
strength; correlations
Carr’s: Carr’s with
index;each
IDR: other.
intrinsicBulk: bulk density;
dissolution True:
rate; Contact: true angle;
contact density: A.O.R:
Diss.: angleGel.:
dissolution; of repose; G.S.: granule
gel strength;
strength; M.L.:
Carr’s:mass loss; W.G.:
Carr’s index; (a) gain;
weight
IDR: SWE.:dissolution
intrinsic swelling property.
rate; Contact: contact angle; Diss.: (b) dissolution; Gel.: gel strength;
M.L.: mass loss;4.W.G.:
Figure Score weight gain;
scatter plot SWE.: swelling
of high-shear property.
wet granulation: (a) PC1 and PC2, (b) PC3 and PC4. The groups within the gray
Figure 4b shows the loading plot with PC3 and PC4 of high-shear wet granulation.
dotted lines located opposite to each other, indicate a negative correlation. The groups within the orange dotted lines
According
indicate positive correlations with each to Figure 4b, thedensity;
mass loss, dissolution, intrinsic dissolution rate, angle of re-
Figure
pose,
4bother.
swelling
showsBulk:the
bulk
loading True:
plottrue
withdensity:
PC3 A.O.R:
and angle
PC4 of repose;
of G.S.: granule
high-shear wet granulation.
strength; Carr’s: Carr’s index; IDR: intrinsicproperty atrate;
dissolution 3 h, Contact:
gel strength at 3angle;
contact h, and bulk
Diss.: density had
dissolution; positive
Gel.: values in
gel strength;
According
PC3.
M.L.: mass loss; W.G.: weight
to Figure
InSWE.:
gain; contrast, 4b, granule strength, true density, and swelling property at 5 h wereof repose,
the mass
the property.
swelling
loss, dissolution, intrinsic dissolution rate, angle
swelling
negativeproperty
for PC3. atIn3 addition,
h, gel strengthgranule at size3 h,andand bulkgain,
weight density
whichhad are positive
located near values
the in PC3.
In contrast, line,the
zero Figure granule
indicate
4b shows strength,
thatthethey had atrue
loading density,
smaller
plot witheffect
PC3 onand
andPC3.swelling
PC4 Moreover, property
of high-shear wetatgranulation.
the granule 5h were
size and negative
weight
for PC3. Ingain
According toare
addition, located
Figure 4b,near
granule the
the masssizezero line
loss,
and in PC4, indicating
dissolution,
weight intrinsic
gain, whichthat theylocated
dissolution
are hadrate,
a smaller
near effect
angle of
the re-zero line,
on PC4.
pose, The
swelling contact angle,
property at bulk
3 h, density,
gel angle
strength at of
3 repose,
h, and
indicate that they had a smaller effect on PC3. Moreover, the granule size and bulkand intrinsic
density haddissolution
positive rate
values hadin weight
negative values inthe
PC3. In contrast, PC4. On thestrength,
granule other hand, true thedensity,
granuleand strength, trueproperty
swelling density, gelat 5strength
h were
gain are located near the zero line in PC4, indicating that they had a smaller effect on PC4.
at 3 h, andfor
negative swelling
PC3. Inproperty
addition,atgranule
3 h weresize positive for PC4.
and weight gain, which are located near the
The contact
zero As
angle,
dissolution
line,
bulk
indicate that maydensity, angle ofrelated
be significantly
they had a smaller
repose,
effectto
and
onthe
intrinsic
bioavailability
PC3.
dissolution
Moreover, the of drug
granule
rate
products,hadit negative
size and
valuesis in PC4.
important
weight gain areOn the
to satisfy
located other
the hand,
desired
near the
target
the zero granule
lineofindissolutionstrength, true
in the that
PC4, indicating density,
development gel
they had aofsmaller strength
effect at 3 h,
formulation
and swelling
and
on PC4. The property
manufacturing at 3 hbulk
contact processes
angle, were
[36]. positive
density, anglefor
Therefore, PC4. and
dissolution
of repose, in intrinsic
CQAs was used to establish
dissolution rate had
the
As control
negative strategy
dissolution
values inmay for be
PC4. the high-shear
Onsignificantly
the other hand, wetrelated
granulationto the
the granule process. Based
bioavailability
strength, on the
true density,ofPearson
drug cor-
products,
gel strength it is
relation
at 3 h, coefficient
and swelling and PCA
property results,
at 3 h we
were confirmed
positive that
for PC4.in
important to satisfy the desired target of dissolution in the development of formulation the high-shear wet granulation
process, there was a may
As dissolution strong berelationship
significantly among
relatedgranule
to size, intrinsic dissolution
the bioavailability of drug rate, and
and manufacturing processes [36]. Therefore, dissolution in CQAs wasproducts,
used toitestablish
dissolution
is importantatto1satisfy
h, as well as a strong
the desired relationship
target of dissolutionamong granule
in the size, bulk
development ofdensity,
formulationand
the control
dissolution
strategy for the
at 3 h. Figure
high-shear
5 shows
wet granulation process. Based on the Pearson
and manufacturing processes [36].3D plots representing
Therefore, dissolutionthe in relationships
CQAs was used among D10, in-
to establish
correlation
trinsic coefficient
dissolution
the control and
strategyrate,
for andPCA results,
dissolutionwet
the high-shear we confirmed
at 1granulation that
h, and the relationshipsin the
process. Based high-shear
among
on theDPearsonwet
10, bulk den-
granulation
cor-
process,
sity, there was
andcoefficient
relation a
dissolutionand strong
at 3PCA relationship among granule size, intrinsic
h. results, we confirmed that in the high-shear wet granulation dissolution rate,
and dissolution
process, there at was1 ah,strong
as well as a strong
relationship among relationship
granule size,amongintrinsicgranule
dissolution size,
rate,bulk
and density,
dissolution at at
and dissolution 1 h,3as h.well as a strong
Figure 5 showsrelationship
3D plots among granule size,the
representing bulk density, and among
relationships
D10 , dissolution at 3 h.4 Figurerate,
intrinsic dissolution 8
5 shows and3Ddissolution
plots representingat 1 h,theand relationships among D10,among
the relationships in- D10 , 82
trinsic dissolution rate, and dissolution at 1 h, and the relationships among D10, bulk den-
bulk density, and dissolution at 3 h.
sity, and dissolution at 3 h. 80
Dissolution at 3h
1h
46
D iss olu tio n at
78
44
4 8 76
8 2
470
4
42 0 .0
6
80
7 .5
Dissolution at 3h
1h
Int 46 0 .0
58
rin 7 40 30
eD
10
sic Bu 0 .0 5 6
D iss olu tio n at
lk d siz
dis 6 . 5 30 ens 54 an
ule 78
sol ity 0 .0 20 Gr
uti 6
0
D1
2
on 20 44 0 .05
rat 5 .5 76
e
470
4
42 0 .0
6
Int
7 .5
(a) 0 .0
58
(b)
rin 7 40 30
eD
10
sic Bu 0 .0 5 6
lk d siz
dis 6 . 5 30 ens 54 an
ule
sol ity 0 .0 20 Gr
uti 6
0
on 20 D1 0.0
52
rat 5 .5
e
(a) (b)
Figure 5. 3D plot of high-shear wet granulation process: (a) relationship among D10 , intrinsic dissolution rate, and dissolu-
tion at 1 h, (b) relationship among D10 , bulk density, and dissolution at 3 h.
As is shown in Figure 5a, the dissolution profile at 1 h had a positive correlation

with the intrinsic dissolution rate and a negative correlation with granule size. The intrin-
sic dissolution rate is significantly correlated with the drug product dissolution profile,
which affects bioavailability [22]. The intrinsic dissolution rate refers to the rate of drug
release from a constant surface, and a fast intrinsic dissolution rate indicates that the
dissolution is faster. Therefore, the intrinsic dissolution rate has a positive correlation
with dissolution. Granule size can affect solubility [32–34]. This is because the surface
area varies depending on the granule size. The smaller the granule size, the larger the
surface area, which in turn leads to a faster drug release owing to the larger area available
for the granules and water to come into contact. Therefore, the smaller the granule size,
the faster the drug is released [24], so there is a negative correlation between the granule
size and the dissolution profile. As is shown in Figure 5b, the dissolution profile at 3 h
had a positive correlation with bulk density and a negative correlation with granule size.
This is because small granules have a larger surface area than large granules, thus drug
release is fast [24]. Bulk density refers to the amount of granules that fit in the same volume.
Therefore, smaller-sized granules have a larger bulk density because more can fit in the
same volume. Thus, granule size has a negative correlation with bulk density. This means
that monitoring IQAs in the high-shear wet granulation process can present target CQAs
in real-time, except for the drug product experiments after the process.
3.5.2. Correlation between the IQAs and CQAs of the Roller Compaction Process
Figure 6 shows the correlation between IQAs and CQAs in the roller compaction
process. According to Figure 6, dissolution had a strong positive correlation with the
intrinsic dissolution rate and bulk density and a strong negative correlation with granule
size and ribbon density. In particular, there was strong negative correlation between
granule size and dissolution. This means that as the granule size decreases, dissolution
increases. Additionally, tapped density was less correlated with dissolution, as the value
was approximately 0. The contact angle had a strong positive correlation with the intrinsic
Pharmaceutics 2021, 13, x dissolution rate and bulk density and a strong negative correlation with
24 of granule
28 size and
ribbon
Pearson1 density. Pearson1
Pearson1 1.000 Contact angle
Pearson1
1.000
1.000
Contact atangle
Pearson1 1.000
Dissolution 60min
Tapped density
Pearson1
1.000
+1
Dissolution at 45min 1.000
Tapped density
True density +1
0.6190 True density 0.6100
Contact angle
Dissolution at 15min 0.6100
0.6190 Contactatangle
Dissolution 60min 0.6300
Dissolution atat
Dissolution 60min
45min 0.6300
Dissolution at 10min +0.5
Dissolution at 5min
Dissolution atat
45min
Dissolution 30min +0.5
Dissolution
0.2380
at 5minCU
Tablet 0.2200
Dissolution atat
Dissolution 30min
15min
Tablet
0.2380Granule CU at 15min
uniformity
Dissolution 0.2600 0.2200
Granule uniformity
Granule strength
0.2600
Dissolution at 5min
Granule strength
Dissolution 0
Tapped Granuleatstrength
density 5min
0
Tapped
-0.1430 density
Bulk Granule
Granule strength
density size D[4,3] -0.1700
-0.1100
-0.1430 Bulk density
Granule size -0.1700
Granule
Ribbon density sizeD[4,3]
D[3,2] -0.1100
Granule
Ribbon density size D[3,2]
D Granule
[4,3] size D90
D Granule
[4,3] size D90 -0.5
D Granule
[3,2] size D50
-0.5
-0.5240 D Granule
[3,2] size
Granule sizeD50
D10 -0.4800
-0.5600
D90 -0.4800
-0.5240 Granule size D10 -0.5600
D90 Bulk density
D50
Bulk density
D50Angle of repose
D10 of repose
Angle
Intrinsic
D10dissolution rate -1
Intrinsic dissolution rate -0.8500
-1
Intrinsic-0.9050
dissolution rate -0.9500-0.8500
strength
repose
density
30minangle
D10
size D50
size D90
size D[3,2]
size D[4,3]
True density
density
5min
10min
15min
30min
at 60min
rate
-0.9050 -0.9500
strength
repose
density
angle
D10
size D50
size D90
size D[3,2]
size D[4,3]
density
density
atat5min
10min
15min
at 30min
60min
rate
[3,2]
[4,3]
strength
D10
D50
D90
Bulk density
angle
density
Granuledensity
uniformity
TabletatCU
5min
10min
15min
30min
at 45min
Gel strength at 1h
at 3h
at 5h
Granule strength
angle
of repose
D[3,2]
Granule size D[4,3]
True denstiy
Bulk density
at 1h
at 3h
Carr's index
D10
D50
size D90
at 10h
rate
dissolution
size
[3,2]
[4,3]
strength
D10
D50
D90
Bulk density
Tappedangle
density
Granuledensity
uniformity
at CU
at5min
at 10min
15min
at 45min
60min
strength
angle
of repose
density
size D10
size D50
D90
D[3,2]
D[4,3]
True denstiy
at 10h
Carr's index
Dissolutionrate
Dissolution atContact
at at
at at
dissolution
D size
of of
Tapped
Bulk
dissolution
size size
size size
Dissolution
DissolutionContact
D
Granule D
Granule
Granule
Granule
at
Gel strength
strength
Dissolution
Dissolution
Dissolution
Dissolution
Dissolution
Contact
Angle
Tablet
Contact
True
Bulk
Intrinsic dissolution
Anglesize
Dissolution
at
atat
Bulksize
Dissolution
Granule
Granule
Granule
Granule
Granule
Dissolutionat
Tapped
Ribbon
Dissolution
Dissolution
Dissolution
Dissolution
Contact
Angle
Contact
Dissolution
Dissolution at
Dissolution
Granule
Granule
Granule
Granule
Granule
Dissolution
Dissolution
Dissolution
Tapped
Ribbon
Dissolution
Granule
Granule
Granule
Granule
Granule
Granule
Dissolution
Dissolution
Granule
Intrinsic
Angle
Granule
Granule
Granule
Intrinsic
Gel
Intrinsic
Figure 6. Pearson correlation coefficient of roller compaction process. Contact: contact angle; Diss.:
Figure 6. Pearson correlation coefficient of roller compaction process. Contact: contact angle; Diss.:
(a) dissolution;
dissolution; G.U.:G.U.: granule
granule uniformity;
uniformity; G.S.:
G.S.: granule granule
strength; strength;
Tapped: tappedTapped: tapped
density; Bulk: (b)
bulkdensity; Bulk: bulk
(b)
density; Ribbon:
density; ribbon
Ribbon: density;
ribbon IDR: intrinsic
density; IDR: dissolution rate.
intrinsic dissolution rate.
The first, second, and third PCs explained 65.1%, 13.5%, and 10.3% of the overall var-
iability, respectively, and the sum of these PCs accounted for 88.9% of the total.
Figure 7a shows the loading plot with PC1 and PC2 of roller compaction. According
to Figure 7a, the dissolution, intrinsic dissolution rate, contact angle, bulk density, and
tablet C.U. had positive loading values in PC1. In contrast, the granule size, ribbon den-
sity, granule strength, and granule uniformity, which are located on the other side, had
negative loading values in PC1. The tapped density near zero indicates that it had a lower
Dissolutio
Dissolutio
dissolu
Carr'
D
GranD
a1
ata1
Dissolution atCo3
at 4
Tru6
Intrinsic dissoluti
of
Granule
Granule
dissoluti
T
Granuledsi
strsi
Granule
Granule
Granule
Granule
DissolutionCont
s
size s
size s
True ds
Tappe
Ang
Bul
Dissolut
Granule s
Tap
uni
of r
unifo
a
a
Dissolutionat
str
Tapped
Bulk
Ribbon
Ta
Conta
siz
siz
Anglesiz
Dissolution
Dissolution
Dissolution
Dissolution
Dissolution
Tabl
diss
True
Bulk
Bulk d
Conta
Dissolutio
Bulksiz
Granule siz
Contact
Intrinsic dissolutio
d
Gran
Gran
Dissoluti
Dissoluti
Dissoluti
Dissoluti
Dissoluti
Angle
Gran
Intrinsic dissolutio
Carr's
Dissolutio
Dissolution
at
Dissolution at
Granule
Granule
Granule
Granule
Granule
Dissolution
Dissolution
Dissolution
Dissolution
Tapped
Ribbon
Dissolution
Granule
Granule
Granule
Granule
Granule
Granule
Dissolution
Dissolution
Granule
Intrinsic
Angle
Granule
Granule
Granule
Intrinsic
Intrinsic
Pharmaceutics 2021, 13, 80 Figure 6. Pearson correlation coefficient of roller compaction process. Contact: contact angle;24Diss.:
of 27
a) dissolution; G.U.: granule uniformity; G.S.: granule strength; Tapped: tapped density; Bulk: bulk (b)
(b)
density; Ribbon: ribbon density; IDR: intrinsic dissolution rate.
The first,
first, second,
second,andandthird
thirdPCsPCsexplained
explained65.1%,
65.1%,13.5%,
13.5%,andand
10.3% of the
10.3% of overall var-
the overall
iability, respectively,
variability, respectively, and thethe
and sum
sum of of
these PCs
these accounted
PCs accounted forfor
88.9%
88.9%of of
thethe
total.
total.
Figure 7a shows the loading plot with PC1 and and PC2PC2 of
of roller
roller compaction.
compaction. According
According
dissolution, intrinsic dissolution rate, contact angle, bulk density, and
to Figure 7a, the dissolution, and
C.U. had
tablet C.U. hadpositive
positiveloading
loadingvalues
valuesininPC1.
PC1.InIncontrast,
contrast,thethe granule
granule size,
size, ribbon
ribbon den-
density,
sity, granule
granule strength,
strength, and granule
and granule uniformity,
uniformity, which
which are are on
located located on the
the other other
side, hadside, had
negative
loading
negativevalues
loading invalues
PC1. The tapped
in PC1. The density near zero
tapped density indicates
near that it had
zero indicates that ait lower effect
had a lower
on PC1.
effect onIn addition,
PC1. granule
In addition, size and
granule sizedissolution, whichwhich
and dissolution, are opposite to eachtoother,
are opposite had a
each other,
negative correlation.
had a negative In theIn
correlation. case
theof PC2,
case of granule uniformity
PC2, granule and table
uniformity C.U. C.U.
and table had negative
had neg-
loading valuesvalues
ative loading and ribbon density,density,
and ribbon granulegranule
strength, granule granule
strength, size, dissolution, and intrinsic
size, dissolution, and
dissolution rate had positive loading values.
intrinsic dissolution rate had positive loading values.
0.5 0.7
Ribbon Tapped
0.6
0.4 G.S. Diss. 5min G.U.
D10 Diss. 15min 0.5
0.3 Diss. 10min
D90 IDR 0.4
D[3,2] Diss. 30min 0.3 Bulk
0.2 Diss. 45min
D50 0.2 Diss. 60min
PC2
D90
PC3
Diss. 60min Diss. 45min
Tapped D [4,3] Ribbon Diss. 15min Dissolution at 45min
0.1 Contact 0.1 D50 Dissolution at 15min
Diss. 10min
D[4,3] Bulk 0
D [3,2] Diss. 5minat 5min Dissolution at 10min
Dissolution
IDR
0 Diss. 30min
-0.1 G.S. Tablet CU
Contact
-0.1 -0.2
G.U. Tablet CU
-0.3
D10
-0.2 0.3 -0.4-0.3
-0.2 0.3
-0.3 -0.1 0 0.1 0.2 0.3 -0.2 -0.1 0 0.1 0.2 0.3
PC1 PC1
R2X[1]= 0.651, R2X[2]= 0.135 R2X[1]= 0.651, R2X[3]= 0.103
(a) (b)
Figure 7.
Figure 7. Score
Score scatter
scatterplot
plotofofroller
rollercompaction:
compaction:(a)(a)
PC1 and
PC1 andPC2, (b)(b)
PC2, PC1 andand
PC1 PC3. TheThe
PC3. group within
group the gray
within dotted
the gray lines
dotted
located opposite each other indicate a negative correlation. Contact: contact angle; Diss.: dissolution: G.U.: granule
lines located opposite each other indicate a negative correlation. Contact: contact angle; Diss.: dissolution: G.U.: granule uni-
formity: G.S.: granule strength; Tapped: tapped density; Bulk: bulk density; Ribbon: ribbon density; IDR: intrinsic
uniformity: G.S.: granule strength; Tapped: tapped density; Bulk: bulk density; Ribbon: ribbon density; IDR: intrinsic disso-
lution rate.
dissolution rate.
Figure 7b shows the loading plot with PC1 and PC3 of roller compaction. As is shown
in Figure 7b, the granule uniformity and tapped density had positive loading values in
PC3. Granule size D10 , granule strength, contact angle, and tablet C.U., which are located
on the other side had negative loading values. Granule size D(3,2), dissolution at 5, 10,
and 30 min, and the intrinsic dissolution rate located near zero indicate that they had a
lower effect on PC3. Additionally, the dissolution, bulk density, and intrinsic dissolution
rate had a strong correlation because they aggregated. As granule size and ribbon density
were aggregated, they had a strong correlation.
As was mentioned above, the dissolution in CQAs was used to establish the control
strategy for the roller compaction process. Based on the Pearson correlation coefficient
and PCA, we confirmed that granule size and dissolution profiles had a strong negative
correlation in the roller compaction process. Figure 8 shows the fitted line plot of D90
versus dissolution at 10 min and D90 versus dissolution at 15 min. As is shown in Figure
8a, there was a negative correlation between D90 and dissolution at 10 min. In addition,
the plot indicates a linear relationship with an R2 of 0.99, and an adjusted R2 of 0.98. The
value of the residual sum of squares was 18.4, indicating that the model fit the data. In
addition, as is shown in Figure 8b, D90 has a negative correlation with dissolution at 15
min. The plot shows a linear relationship with an R2 of 0.99, and an adjusted R2 of 0.98.
The value of the residual sum of squares was 9.36, indicating that the model fit the data.
Figure 8 shows that a decrease in granule size increases dissolution. This is because small
granules have a larger surface area than large granules, so drug release is fast [24]. This
means that monitoring IQAs in the roller compaction process can present target CQAs in
real time, except for the drug product experiments after the process.
of the residual sum of squares was 18.4, indicating that the model fit the data. In addition,
as is shown in Figure 8b, D90 has a negative correlation with dissolution at 15 min. The
plot shows a linear relationship with an R2 of 0.99, and an adjusted R2 of 0.98. The value of
the residual sum of squares was 9.36, indicating that the model fit the data. Figure 8 shows
that a decrease in granule size increases dissolution. This is because small granules have
Pharmaceutics 2021, 13, 80 a larger surface area than large granules, so drug release is fast [24]. This means that mon- 25 of 27
itoring IQAs in the roller compaction process can present target CQAs in real time, except
for the drug product experiments after the process.
(a) (b)
Figure 8. FittedFigure
line 8. Fitted
plot of line plotcompaction
roller of roller compaction
process: process: (a) relationshipbetween
(a) relationship between DD 90 and dissolution at 10 min, (b) relation-
90 and dissolution at 10 min, (b) relationship
ship between D90 and dissolution at 15 min. The black point represents experimental data, the red line represents the best-
between D90 and fitteddissolution
regression of at 15the
data, min. The black
red-filled point
line is the 95%represents
C.I. band, andexperimental data,
the pink-filled line the
is the red
95% P.I.line represents the best-fitted
band.
regression of data, the red-filled line is the 95% C.I. band, and the pink-filled line is the 95% P.I. band.
4. Conclusions
In this study, we established a control strategy for a combination drug prepared by
4. Conclusions
the high-shear wet granulation and roller compaction processes using the integrated QbD
approach with MVA. Response surface design was used to obtain the optimal process
In parameters
this study, we established a control strategy for a combination drug prepared by
of high-shear wet granulation and roller compaction. Based on the initial risk
the high-shear wet granulation
assessment, CPPs, and roller
IQAs, and CQAs compaction
were selected, and the processes using
effects of CPPs the integrated
on IQAs and QbD
approach CQAswith
wereMVA. Response
confirmed by coded surface
equations design was used
using ANOVA. to obtain the
After establishing thedesign
optimal process
space,of
parameters wehigh-shear
conducted MontewetCarlo simulationsand
granulation to evaluate
roller the risk of uncertainty
compaction. Based in model
on the initial risk
predictions. The relationship between numerous variables presented in the QbD approach
assessment, CPPs, IQAs,
was confirmed throughand CQAs correlation
the Pearson were selected, and
coefficient andthe
PCA.effects of CPPs
The MVA resultson IQAs and
CQAs were confirmed by coded equations using ANOVA. After establishing the design
space, we conducted Monte Carlo simulations to evaluate the risk of uncertainty in model
predictions. The relationship between numerous variables presented in the QbD approach
was confirmed through the Pearson correlation coefficient and PCA. The MVA results prove
that the relationship between IQAs and CQAs can be a powerful tool to control and predict
CQAs in high-shear wet granulation and roller compaction processes. In high-shear wet
granulation process, IQAs such as granule size, bulk density, and intrinsic dissolution rate
were significantly correlated with CQAs such as dissolution profiles, swelling properties,
and contact angle. In particular, dissolution at 1 h had a strong correlation with the intrinsic
dissolution rate and granule size, and dissolution at 3 h had a strong correlation with bulk
density and granule size. In the roller compaction process, IQAs such as granule size,
intrinsic dissolution rate, ribbon density, and granule strength were significantly correlated
with CQAs such as dissolution profiles, tablet C.U., and contact angle. In particular,
dissolution at 10 min and 15 min was strongly correlated with granule size. Based on
these relationships, we can develop a control strategy for the production of high-quality
drug products. The properties of the intermediate product can be controlled by adjusting
the process parameters. Technologies such as PAT allow the real-time identification of
the characteristics of intermediate products. The results of this study suggest that the
combination of MVA and DoE in pharmaceutical process development can offer a deep
understanding of the relationships among numerous variables, which is one of the most
fundamental concepts for control strategy.
Author Contributions: Investigation, J.Y.K., M.H.C.; writing-original draft preparation, J.Y.K.;

writing-review and editing, M.H.C., D.H.C.; supervision, D.H.C. All authors have read and agreed to
the published version of the manuscript.
Funding: This work was supported by the Basic Science Research Program through the National Re-
search Foundation of Korea funded by the Ministry of Education (grant number 2020R1I1A307373311).
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Björn, I.N.; Jansson, A.; Karlsson, M.; Folestad, S.; Rasmuson, A. Empirical to mechanistic modelling in high shear granulation.
Chem. Eng. Sci. 2005, 60, 3795–3803. [CrossRef]
2. Dumarey, M.; Talwar, S.; Yahyah, M.; Peterson, J. Empirical modelling to support scale up of primary pharmaceutical processes.
In Computer Aided Chemical Engineerin; Elsevier: Amsterdam, The Netherlands, 2016; Volume 38, pp. 2241–2246.
3. Lawrence, X.Y. Pharmaceutical quality by design: Product and process development, understanding, and control. Pharm. Res.
2008, 25, 781–791.
4. Pandey, P.; Bharasdwaj, R.; Chen, X. Modeling of drug product manufacturing processes in the pharmaceutical industry.
In Predictive Modeling of Pharmaceutical Unit Operations; Elsevier: Amsterdam, The Netherlands, 2017; pp. 1–13.
5. Djuris, J.; Djuric, Z. Modeling in the quality by design environment: Regulatory requirements and recommendations for design
space and control strategy appointment. Int. J. Pharm. 2017, 533, 346–356. [CrossRef] [PubMed]
6. Yeom, S.B.; Ha, E.-S.; Kim, M.-S.; Jeong, S.H.; Hwang, S.-J.; Choi, D.H. Application of the discrete element method for manufac-
turing process simulation in the pharmaceutical industry. Pharmaceutics 2019, 11, 414. [CrossRef] [PubMed]
7. Park, M.S.; Choi, D.H. Application of mechanism-based modeling to predict drug quality during the pharmaceutical unit
operations of granulation and compression: A review. J. Pharm. Investig. 2020, 50, 445–467. [CrossRef]
8. Lawrence, X.Y.; Amidon, G.; Khan, M.A.; Hoag, S.W.; Polli, J.; Raju, G.; Woodcock, J. Understanding pharmaceutical quality by
design. AAPS J. 2014, 16, 771–783.
9. Rogers, A.; Ierapetritou, M.; Engineering, C. Challenges and opportunities in modeling pharmaceutical manufacturing processes.
Comput. Chem. Eng. 2015, 81, 32–39. [CrossRef]
10. Stauffer, F.; Vanhoorne, V.; Pilcer, G.; Chavez, P.-F.; Schubert, M.; Vervaet, C.; De Beer, T. Managing active pharmaceutical
ingredient raw material variability during twin-screw blend feeding. Eur. J. Pharm. Biopharm. 2019, 135, 49–60. [CrossRef]
11. Badawy, S.I.F.; Menning, M.M.; Gorko, M.A.; Gilbert, D.L. Effect of process parameters on compressibility of granulation
manufactured in a high-shear mixer. Int. J. Pharm. 2000, 198, 51–61. [CrossRef]
12. Cavinato, M.; Bresciani, M.; Machin, M.; Bellazzi, G.; Canu, P.; Santomaso, A. The development of a novel formulation map for
the optimization of high shear wet granulation. Chem. Eng. J. 2010, 164, 350–358. [CrossRef]
13. Rahmanian, N.; Ghadiri, M.; Jia, X.; Stepanek, F. Characterisation of granule structure and strength made in a high shear
granulator. Powder Technol. 2009, 192, 184–194. [CrossRef]
14. Freitag, F.; Kleinebudde, P. How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials?
Comparison of four magnesium carbonates. Eur. J. Pharm. Sci. 2003, 19, 281–289. [CrossRef]
15. Heiman, J.; Tajarobi, F.; Gururajan, B.; Juppo, A.; Abrahmsén-Alami, S. Roller compaction of hydrophilic extended release
tablets—combined effects of processing variables and drug/matrix former particle size. AAPS PharmSciTech 2015, 16, 267–277.
[CrossRef] [PubMed]
16. Freeman, T.; Vom Bey, H.; Hanish, M.; Brockbank, K.; Armstrong, B. The influence of roller compaction processing variables on
the rheological properties of granules. Asian J. Pharm. Sci. 2016, 11, 516–527. [CrossRef]
17. Huang, J.; Kaul, G.; Cai, C.; Chatlapalli, R.; Hernandez-Abad, P.; Ghosh, K.; Nagi, A. Quality by design case study: An integrated
multivariate approach to drug product and process development. Int. J. Pharm. 2009, 382, 23–32. [CrossRef]
18. Haware, R.V.; Tho, I.; Bauer-Brandl, A. Application of multivariate methods to compression behavior evaluation of directly
compressible materials. Eur. J. Pharm. Biopharm. 2009, 72, 148–155. [CrossRef]
19. Saharan, V.A. Current Advances in Drug Delivery through Fast Dissolving/Disintegrating Dosage Forms; Bentham Science Publishers:
Sharjah, United Arab Emirates, 2017.
20. Greco, K.; Bergman, T.L.; Bogner, R. Design and characterization of a laminar flow-through dissolution apparatus: Comparison of
hydrodynamic conditions to those of common dissolution techniques. Pharm. Dev. Technol. 2011, 16, 75–87. [CrossRef]
21. Choi, D.H.; Kim, K.H.; Park, J.S.; Jeong, S.H.; Park, K. Evaluation of drug delivery profiles in geometric three-layered tablets
with various mechanical properties, in vitro–in vivo drug release, and Raman imaging. J. Control. Release 2013, 172, 763–772.
[CrossRef]
22. Issa, M.G.; Ferraz, H.G. Intrinsic dissolution as a tool for evaluating drug solubility in accordance with the biopharmaceutics
classification system. Dissolution Technol. 2011, 18, 6–13. [CrossRef]
23. Choi, D.H.; Kim, N.A.; Chu, K.R.; Jung, Y.J.; Yoon, J.-H.; Jeong, S.H. Material properties and compressibility using Heckel and
Kawakita equation with commonly used pharmaceutical excipients. J. Pharm. Investig. 2010, 40, 237–244.
24. Han, J.K.; Shin, B.S.; Choi, D.H. Comprehensive study of intermediate and critical quality attributes for process control of high-
shear wet granulation using multivariate analysis and the quality by design approach. Pharmaceutics 2019, 11, 252. [CrossRef]
[PubMed]
25. Choi, D.H.; Lim, J.Y.; Shin, S.; Choi, W.J.; Jeong, S.H.; Lee, S. A novel experimental design method to optimize hydrophilic matrix
formulations with drug release profiles and mechanical properties. J. Pharm. Sci. 2014, 103, 3083–3094. [CrossRef] [PubMed]
26. Thapa, P.; Choi, D.H.; Kim, M.S.; Jeong, S.H. Effects of granulation process variables on the physical properties of dosage forms
by combination of experimental design and principal component analysis. Asian J. Pharm. Sci. 2019, 14, 287–304. [CrossRef]
27. Letellier, P.; Mayaffre, A.; Turmine, M. Drop size effect on contact angle explained by nonextensive thermodynamics. Young’s
equation revisited. J. Colloid Interface Sci. 2007, 314, 604–614. [CrossRef] [PubMed]
28. Abdi, H.; Williams, L.J. Principal component analysis. In Wiley Interdisciplinary Reviews: Computational Statistics; Wiley: Hoboken,
NJ, USA, 2010; pp. 433–459.
29. Wold, S.; Esbense, K.; Geladi, P. Principal companent analysis. Chemom. Intell. Lab. Syst. 1987, 2, 37–52. [CrossRef]
30. Ganti, A. Correlation Coefficient. Corp. Financ. Account. 2020, 9, 145–152.
31. Kassa, W.-E.; Billabert, A.-L.; Faci, S.; Algani, C. Electrical modeling of semiconductor laser diode for heterodyne RoF system
simulation. IEEE J. Quantum Electron. 2013, 49, 894–900. [CrossRef]
32. Wang, C.; Tang, C.-H.; Fu, X.; Huang, Q.; Zhang, B. Granular size of potato starch affects structural properties, octenylsuccinic
anhydride modification and flowability. Food Chem. 2016, 212, 453–459. [CrossRef]
33. Sun, J.; Wang, F.; Sui, Y.; She, Z.; Zhai, W.; Wang, C.; Deng, Y. Effect of particle size on solubility, dissolution rate, and oral
bioavailability: Evaluation using coenzyme Q10 as naked nanocrystals. Int. J. Nanomed. 2012, 7, 5733.
34. Shipar, M.A.H.; Wadhwa, A.; Varughese, C. Affect of granule sizes, types and concentrations of lubricants and compression forces
on tablet properties. Int. J. Pharm. Sci. Res. 2014, 5, 4893.
35. Van den Ban, S.; Goodwin, D.J. The impact of granule density on tabletting and pharmaceutical product performance. Pharm. Res.
2017, 34, 1002–1011. [CrossRef] [PubMed]
36. Jain, S. Quality by design (QBD): A comprehensive understanding of implementation and challenges in pharmaceuticals
development. Int. J. Pharm. Sci. 2014, 6, 29–35.
37. Narendar, D.; Arjun, N.; Someshwar, K.; Rao, Y.M. Quality by design approach for development and optimization of Quetiapine
Fumarate effervescent floating matrix tablets for improved oral bioavailability. J. Pharm. Investig. 2016, 46, 253–263. [CrossRef]
38. Carbinatto, F.M.; de Castro, A.D.; Evangelista, R.C.; Cury, B.S. Insights into the swelling process and drug release mechanisms
from cross-linked pectin/high amylose starch matrices. Asian J. Pharm. Sci. 2014, 9, 27–34. [CrossRef]
39. Lu, Y.; Tang, N.; Lian, R.; Qi, J.; Wu, W. Understanding the relationship between wettability and dissolution of solid dispersion.
Int. J. Pharm. 2014, 465, 25–31. [CrossRef]
40. Dhenge, R.M.; Fyles, R.S.; Cartwright, J.J.; Doughty, D.G.; Hounslow, M.J.; Salman, A.D. Twin screw wet granulation: Granule
properties. Chem. Eng. J. 2010, 164, 322–329. [CrossRef]
41. Davies, W.L.; Gloor, W.T., Jr. Batch production of pharmaceutical granulations in a fluidized bed I: Effects of process variables on
physical properties of final granulation. J. Pharm. Sci. 1971, 60, 1869–1874. [CrossRef]
42. Alkan, M.; Yuksel, A. Granulation in a fluidized bed II Effect of binder amount on the final granules. Drug Dev. Ind. Pharm.
1986, 12, 1529–1543. [CrossRef]
43. Mirza, Z.; Liu, J.; Glocheux, Y.; Albadarin, A.B.; Walker, G.M.; Mangwandi, C. Effect of impeller design on homogeneity, size and
strength of pharmaceutical granules produced by high-shear wet granulation. Particuology 2015, 23, 31–39. [CrossRef]
44. Rahmanian, N.; Ghadiri, M.; Ding, Y. Effect of scale of operation on granule strength in high shear granulators. Chem. Eng. Sci.
2008, 63, 915–923. [CrossRef]
45. Shi, L.; Feng, Y.; Sun, C.C. Massing in high shear wet granulation can simultaneously improve powder flow and deteriorate
powder compaction: A double-edged sword. Eur. J. Pharm. Sci. 2011, 43, 50–56. [CrossRef] [PubMed]
46. Badawy, S.I.; Narang, A.S.; LaMarche, K.; Subramanian, G.; Varia, S.A. Mechanistic basis for the effects of process parameters on
quality attributes in high shear wet granulation. Int. J. Pharm. 2012, 439, 324–333. [CrossRef] [PubMed]
47. Allesø, M.; Holm, R.; Holm, P. Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon
porosity as critical material attribute. Eur. J. Pharm. Sci. 2016, 87, 69–78. [CrossRef] [PubMed]
48. Al-Rabadi, G.J.; Gilbert, R.G.; Gidley, M.J. Effect of particle size on kinetics of starch digestion in milled barley and sorghum
grains by porcine alpha-amylase. J. Cereal Sci. 2009, 50, 198–204. [CrossRef]
49. Schafer, T. Comparison between granule growth in a horizontal and a vertical high speed mixer: I. Granulation of dicalcium
phosphate. Arch. Pharm. Chem. Sci. 1986, 14, 209–224.
50. Nguyen, V.; Nguyen, Q.; Zhang, Y.; Lim, C.; Khoo, B. Effect of particle size on erosion characteristics. Wear 2016, 348, 126–137.
[CrossRef]
51. Goodwin, J.; Sage, W.; Tilly, G. Study of erosion by solid particles. Proc. Inst. Mech. 1969, 184, 279–292. [CrossRef]
52. Zerbe, H.G.; Krumme, M. Smartrix system: Design characteristics and release properties of a novel erosion-controlled oral
delivery system. In Modified-Release Drug Delivery Technology; Marcel Dekker: New York, NY, USA, 2002; pp. 59–76.
53. Woyna-Orlewicz, K.; Jachowicz, R. Analysis of wet granulation process with Plackett–Burman design–case study. Acta Pol. Pharm.
2011, 68, 725–733.
54. Pandey, P.; Tao, J.; Chaudhury, A.; Ramachandran, R.; Gao, J.Z.; Bindra, D.S. A combined experimental and modeling approach to
study the effects of high-shear wet granulation process parameters on granule characteristics. Pharm. Dev. Technol. 2013, 18, 210–224.
[CrossRef]
55. Souihi, N.; Josefson, M.; Tajarobi, P.; Gururajan, B.; Trygg, J. Design space estimation of the roller compaction process. Ind. Eng.
Chem. Res. 2013, 52, 12408–12419. [CrossRef]
56. Meda, U.S.; Rakesh, S.S.; Chandra, L.B. Impact of particle size on content uniformity. Int. J. Innov. Res. Sci. Eng. Technol. 2014, 3, 9369–9374.

Control Strategy For Process Development of High Shear Wet Granulation and Roller Compaction To Prepare A Combination Drug Using Integrated Quality by Design

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Control Strategy For Process Development of High Shear Wet Granulation and Roller Compaction To Prepare A Combination Drug Using Integrated Quality by Design

Uploaded by

Copyright:

Available Formats

pharmaceutics

1 Department of Pharmaceutical Engineering, Inje University, Gyeongnam 621-749, Korea;

Pharmaceutics 2021, 13, 80. https://doi.org/10.3390/pharmaceutics13010080 https://www.mdpi.com/journal/pharmaceutics

QbD in pharmaceutical development focuses on process design, understanding the

2. Materials and Methods

2.2. Experimental Design to Optimize the Manufacturing Process

2.2.2. Experimental Design of Roller Compaction

2.3. Measurement of IQAs and CQAs

2.3.2. Measurement of Granule Properties (Granule Size, Granule Density, Flowability,

2.3.3. Measurement of Swelling Property

2.3.4. Measurement of Weight Gain and Mass Loss

2.3.5. Measurement of Gel Strength

2.3.6. In Vitro Dissolution Test

2.3.7. Measurement of Contact Angle

γSV − γSL − γLY cos θ = 0 (6)

2.4. HPLC Analysis Method

2.5. Multivariate Analysis

2.6. Initial Risk Assessment for the Manufacturing Process Development

Quality Attributes Target Justification Critical

Quality Attributes Target Justification Critical

Quality Attributes Target Justification Critical

3. Results and Discussion

3.1.2. Initial Risk Assessment for Roller Compaction

3.2.2. Effect of CPPs on Granule Size (q2 –q6 )

q2 = 0.7325p1 + 9.47p3 + 1.94p1 2 + 5.01p3 2 (9)

q3 = 10.48p1 + 12.05p2 + 224.23p3 + 51.76p1 p2 + 44.25p2 2 + 161.10p3 2 (10)

q7 = 0.0007p1 − 0.0005p2 + 0.0005p3 − 0.0027p1 p2 + 0.0023p2 p3 (14)

q8 = −0.0008p1 + 0.0001p2 − 0.0014p3 + 0.0025p1 p2 − 0.0023p3 2 (15)

3.2.4. Effect of CPPs on Granule Strength (q11 )

q11 = 0.0900p1 − 0.0400p2 − 0.0725p3 − 0.1400p1 p2 − 0.2200p1 p3 (18)

q12 = −0.3152p1 + 1.07p2 + 0.6223p3 (19)

q13 = −0.4956p1 − 0.7939p2 − 0.8415p3 + 0.4619p1 p2 − 1.22p1 p3 − 1.20p2 p3 (20)

q15 = 1.35p1 − 4.43p2 + 0.5916p3 + 2.92p1 p2 (22)

q16 = 2.06p1 − 5.23p2 + 0.1889p3 + 5.12p1 p2 − 4.58p1 p3 + 2.41p2 p3 (23)

3.2.7. Effect of CPPs on Gel Strength (q21 , q22 , and q23 )

q21 = +1.17p1 − 1.56p2 + 4.05p3 (28)

q22 = −0.1167p1 − 1.49p2 + 0.5977p3 − 0.6932p1 p2 − 2.78p1 p3 − 2.74p2 p3 (29)

3.2.8. Effect of CPPs on Dissolution (q24 , q25 , and q26 )

q24 = −0.2500p1 + 0.4275p2 + 0.6700p3 − 1.03p1 p2 − 1.87p1 p3 − 1.20p2 p3 (31)

q25 = −0.9363p1 + 0.1425p2 + 0.7788p3 − 1.40p1 p3 − 3.18p2 p3 (32)

3.2.9. Effect of CPPs on the Contact Angle (q27 )

q27 = −0.7754p1 − 0.6704p2 + 0.3488p3 + 2.13p1 p2 + 2.00p2 p3 (34)

3.3. Effect of CPPs on the IQAs and CQAs of Roller Compaction

d1 = −0.009c1 − 0.0023c3 (35)

3.3.2. Effect of CPPs on Granule Size (d2 –d6 )

d2 = 0.4225c1 − 0.0075c2 + 0.0900c3 + 0.7075c2 c3 (36)

d3 = 2.12c1 − 1.23c2 + 1.33c3 (37)

d7 = 0.1037c1 − 0.0163c2 + 0.0100c3 (41)

d8 = −0.0016c1 − 0.0008c2 − 0.0021c3 + 0.0027c3 2 (42)

d9 = 0.0001c1 − 0.0003c2 − 0.0001c3 − 0.0002c1 c2 − 0.0008c2 c3 + 0.0008c1 2 + 0.0005c2 2 + 0.0012c3 2 (43)

d10 = 0.1094c1 + 0.0406c2 (44)

d11 = 0.1575c1 − 0.0350c2 + 0.3025c3 + 1.17c2 c3 (45)

3.3.5. Effect of CPPs on Tablet C.U. (d12 )

3.3.6. Effect of CPPs on Dissolution (d13 –d15 )

d13 = −3.93c1 − 12.98c3 (47)

d14 = −4.17c1 − 12.43c3 (48)

3.3.7. Effect of CPPs on the Contact Angle (d16 )

Pharmaceutics 2021, 13, 80 19 of 27

Impeller speed (rpm) Impeller speed (rpm)

0.5 0.5 0.5

3.5. Multivariate Analysis between IQAs and CQAs

Granule size D[3,2]

Granule size D10