pharmaceutics

Article
Effects of Formulation and Process Variables on
Gastroretentive Floating Tablets with A High-Dose
Soluble Drug and Experimental Design Approach
Prakash Thapa and Seong Hoon Jeong *
College of Pharmacy, Dongguk University-Seoul, Gyeonggi 10326, Korea; thapap139@gmail.com
* Correspondence: shjeong@dongguk.edu; Tel.: +82-10-5679-0621




Received: 2 August 2018; Accepted: 12 September 2018; Published: 17 September 2018


Abstract: To develop sustained release gastro-retentive effervescent floating tablets (EFT),

a quality-based experimental design approach was utilized during the composing of a hydrophilic
matrix loaded with a high amount of a highly water-soluble model drug, metformin HCl. Effects
of the amount of polyethylene oxide WSR 303 (PEO), sodium bicarbonate, and tablet compression
force were used as independent variables. Various times required to release the drug, tablet tensile
strength, floating lag time, tablet ejection force, and tablet porosity, were selected as the responses.
Polymer screening showed that PEO had the highest gel strength among the various tested polymers.
Sodium bicarbonate had the most significant effect on the release rate and floating lag time by
retarding the rate from the hydrophilic matrices, whilst tablet compression force and PEO exerted the
greatest influence on tablet properties (p < 0.0001). The design space was built in accordance with the
drug release profiles, tensile strength, and floating lag time, following failure probability analysis
using Monte Carlo simulations. The kinetic modeling revealed that the release mechanism was best
described by the Korsmeyer-Peppas model. Overall, the current study provided a perspective on the
systematic approach of gastro-retentive EFT, loaded with highly water-soluble drugs by applying
quality by design concepts.

Keywords: polyethylene oxide; sodium bicarbonate; gel strength; floating lag time; drug release
kinetics; experimental design

1. Introduction
Even though oral drug delivery is the most convenient and preferable route of drug administration,
there are still challenges to overcome. Bioavailability of active pharmaceutical ingredients (APIs) is
subject to change, depending on their physicochemical properties, including pH-dependent solubility
and stability, and a narrow absorption window [1–3]. Therefore, formulation scientists are continuously
engaged in developing new approaches to improve oral drug delivery systems. Recently, gastroretentive
systems, with strategies to extend gastric residence time, have drawn considerable attention as an
alternative approach to improve bioavailability of drugs with a narrow absorption window, stability at
intestinal pH, local activity in the stomach, and solubility at low pH [4–6]. The gastric residence time can
affect the drug absorption, as the longer the drug stays in contact with the absorbing membrane, the more
the rate and extent of absorption [3,7]. However, residence time in the upper part of the gastrointestinal
tract is short due to fast gastric emptying lasting about 2–3 h [3,8]. To overcome the limitation, controlled
drug delivery systems with prolonged residence time in the stomach can be utilized.
Various pharmaceutical approaches have been applied to prolong the gastric retention time of
dosage forms, including floating systems, bioadhesive/mucoadhesive systems, expandable systems,
high density systems, superporous hydrogel systems, and magnetic systems [6,9–12]. However, among

Pharmaceutics 2018, 10, 161; doi:10.3390/pharmaceutics10030161 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2018, 10, 161 2 of 25

the gastroretentive systems, floating systems offer promising and practical means of achieving prolong
gastric residence time [2,5,6,8,12]. The floating systems are categorized into non-effervescent systems and
effervescent systems. In the case of non-effervescent systems, highly swellable cellulose derivatives or
gel-forming polymers are used, which is preferable for potent drugs [13–15]. However, in effervescent
systems, gas generating agents, such as sodium bicarbonate and calcium carbonate are used, which generate
CO2 gas upon contact with gastric fluid, and eventually reduce the bulk density of tablets [16–19].
It is often challenging to maintain tablet buoyancy in high-dose tablets due to their high bulk density;
therefore, the non-effervescent technique may not be feasible for such tablets. Effervescent floating tablets
(EFTs) have better potential for improved buoyancy [20–22]. The selection of a suitable polymer, a gas
generating agent, and process variables might be necessary for high-quality EFT development. A large
amount of polymer is required to achieve sustained release profiles in highly water-soluble high-dose
tablets, which in turn increases the weight of tablets [21,23–25]. Hydrophilic polymers have long been
used in floating systems to create sustained release profiles. Among various hydrophilic polymer types
(cationic, anionic, and non-ionic polymer), the non-ionic hydrophilic polymers, such as hydroxypropyl
methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO), are commonly
used in controlled release tablets because these polymers are not affected by pH [13,26]. As a result,
drug release and floating behavior of tablets are also not influenced by the pH of gastric fluid [13,26].
In addition, non-ionic hydrophilic polymers are non-toxic, economic, and safe to use for EFT [27–29].
Therefore, these types of polymers have potential in designing the floating tablet. Moreover, other
factors, including amount of polymer and polymer viscosity grade and molecular weight may influence
the drug release rate and tablet buoyancy, as well as other physicochemical properties, such as tablet
tensile strength, porosity, hydration rate, and gel strength [30].
In the effervescent system, sodium bicarbonate improves tablet buoyancy in gastroretentive
floating systems containing hydrophilic polymer combinations. However, no systematic investigation
has yet been performed to explore the influence of sodium bicarbonate on drug release kinetics.
Therefore, it is important to investigate its influence on the drug release kinetics of highly water-soluble
drugs in the EFTs. From the perspective of pharmaceutical technology, tablet compression force
has the potential to affect tablet density and this could alter tablet buoyancy, as tablet density
>1.004 mg/cm3 prevents floating in the gastric fluid [3]. Therefore, optimization of tablet compression
force might overcome issues of table buoyancy, as well as friability and mechanical properties. In the
present study, we also investigated the impact of compression force on tablet buoyancy and other
physiochemical properties.
Formulation scientists often experience the challenges of identifying the appropriate combination
of formulation and process variables to produce a high-quality product [13,31–33]. However, with the
application of quality-based experimental design tools, the variables can be more easily analyzed and
understood. Among the various experimental design tools, Box-Behnken design (BBD) is a popular tool
for formulation and process optimization, which utilizes the treatment combination at midpoint of the
edge and center of the experimental space. The main advantage of BBD, compared to central composite
design (CCD), D-optimal design, and 3-level factorial design, is that it requires fewer experimental
runs, less time for optimization of the process, and is more cost effective. In addition, BBD does not
have axial points and it can assure that all the design points fall within safe operating zones, whereas
CCD usually has axial points outside the cube, which may not be in the region of interest, or may be
beyond safe operating limits [33,34]. In the present study, a Box-Behnken design was used to study
the impact of formulation variables (PEO, sodium bicarbonate) and a process variable (compression
force) on response variables, including drug release rate, floating lag time (FLT), tablet tensile strength,
tablet porosity, and tablet ejection force. In addition, other physical properties, such as medium uptake
(swelling ratio), tablet erosion rate, and gel strength of floating tablets, were also investigated.
Pharmaceutics 2018, 10, 161 3 of 25

2. Materials and Methods

2.1. Materials
The model drug, metformin HCl, was obtained from Farmhispania (Catalonia, Spain).
Hydroxypropyl methylcellulose (Hypromellose USP, substitution type 2208), HPMC 100SR (viscosity
100 mPa.s), HPMC 4,000SR (viscosity 4000 mPa.s), and HPMC 100,000SR (viscosity 100,000 mPa.s)
were obtained from Shin-Etsu (Tokyo, Japan). Hydroxypropyl cellulose, HPC M (viscosity 300 mPa·s),
and HPC H FP (viscosity 3000 mPa·s) were supplied from Nippon Soda Co., Ltd. (Tokyo, Japan).
Polyethyleneoxide WSR 303 (PEO, average molecular weight 7,000,000) was purchased from Dow
Chemical (Midland, MI, USA). Lactose monohydrate (FlowLac 100) was obtained from Meggle
Pharma Tech., Ltd. (Wasserburg, Germany), microcrystalline cellulose (MCC, Avicel PH 101) was
supplied from Daejung Pharmaceuticals. (Seoul, Korea), dicalcium phosphate anhydrous (A-Tab)
was purchased from Whawon Co. Ltd. (Seoul, Korea), and sodium bicarbonate was purchased from
Sigma-Aldrich (St. Louis, MO, USA). Magnesium stearate (S-Mg) was obtained from Faci Asia (Jurong
Island, Singapore).

2.2. Screening of Hydrophilic Polymers

To select the polymer matrix for the floating tablets, gel strength of six different hydrophilic
polymers viz. HPC M, HPC H FP, HPMC 100SR, HPMC 4000SR, HPMC 100,000SR, and PEO
were evaluated using a texture analyzer. Then, 400 mg of each polymer was added to 10 mL of
deionized water in a glass vial and stirred in a water bath at 37 ◦ C, until the polymer was completely
hydrated. Samples of hydrated or swollen polymer were stored at room temperature for 24 h, prior
to analysis [35,36]. The gel strength was measured using a texture analyzer (TA.XT Express, Stable
Micro Systems, Surrey, UK). An analytical probe of 10 mm diameter was penetrated into the hydrated
sample to a depth of 8 mm, at speed of 0.5 mm/s [35,36]. Each experiment was performed in triplicate.

2.3. Box-Behnken Experimental Design

A BBD with three factors, three levels, and 15 runs was selected for the characterization and
optimization (Table 1). The amount of PEO per tablet (X1 ), the amount of sodium bicarbonate per
tablet (X2 ), and tablet compression force (X3 ) were selected as input variables, whilst the time taken
to release 25% of drug (T25%, Y1 ), 50% of drug (T50%, Y2 ), 80% of drug (T80%, Y3 ), FLT (Y4 ), tablet
ejection force (EF, Y5 ), tablet tensile strength (Y6 ), and tablet porosity (Y7 ) were selected as dependent
variables. Statistical analysis and optimization were carried out using MODDE® software, version
12.0.1 (Sartorius Stedim biotech, Malmö, Sweden). The effects of input variables could be described
mathematically, and the response variables could be predicted for each set value of input variables.
The non-linear quadratic equation generated using the experimental design was as follows [37]:

Yi = b0 + ∑ bi Xi + ∑ bii Xii2 + ∑ bij Xi X j (1)

where, Yi is the responses, Xi and X j are the independent variables; b0 is a constant term, and bi , bii ,
and bij are the coefficients of the linear, quadratic, and interaction terms, respectively.

2.4. Preparation of Floating Tablets

Metformin, lactose monohydrate, and MCC were passed through a #30 mesh sieve, and PEO
was passed through a #20 mesh sieve to remove any aggregates. Sodium bicarbonate was milled in
a mortar and pestle for 10 min and passed through a #40 mesh sieve. Metformin and the excipients
except S-Mg were mixed using the motor and pestle for 10 min, to obtain a well-dispersed mixture.
S-Mg (sieved through a #40 mesh sieve) was added to the above mixture, and then blended for 5 min.
Then, 1000 mg of the mixture was loaded into a die and compressed on a hydraulic laboratory press
(Carver Press, Wabash, IN, USA) using a 13 mm set of flat face punches at different compression
Pharmaceutics 2018, 10, 161 4 of 25

forces, as shown in Table 1. The dwell time for each tablet compression was 5 s. To compare the drug
release profiles of tablets containing sodium bicarbonate, tablets without sodium bicarbonate were
also prepared. F0 represents the formulation with a low amount of polymer, i.e., 50 mg PEO and 90 mg
sodium bicarbonate. Likewise, F2 and F15 contained 100 mg and 200 mg PEO, respectively, and 90 mg
of sodium bicarbonate in each formulation. Moreover, additional formulations of F0*, F2*, and F15*
without sodium bicarbonate were also prepared. They contained various PEO amounts of 50 mg,
100 mg, and 200 mg, respectively.

2.5. In vitro Drug Release Studies

In vitro dissolution tests were conducted according to the US Pharmacopeia dissolution apparatus
2 (paddle method with a paddle speed of 50 rpm), with 900 mL dissolution medium of simulated gastric
fluid (pH 1.2), maintained at 37 ± 0.5 ◦ C (Varian 705 DS, Varian, Cary, NC, USA). The tablet was placed
in the stationary basket to prevent the tablet from floating or sticking to the inner surface of dissolution
vessels. Samples were withdrawn at predetermined time intervals (0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h)
from the dissolution vessels, and then replaced with the fresh medium. The aliquots were filtered
through a 0.45 µm membrane filter, suitably diluted, and analyzed with a UV spectrophotometer at a
wavelength of 233 nm to determine the amount of metformin released over time. The percentage drug
released (%), was calculated and provided as the mean value of four tablets.

2.6. In Vitro Floating Behavior

Floating behavior of the tablets was determined in similar conditions as those used in the in vitro
drug release studies. Time required for the tablets to rise on the surface of the medium was considered
as floating lag time (FLT), and the total duration of tablet floating on the medium was considered as
floating time. Each experiment was conducted in triplicate.

2.7. Medium Uptake and Mass Loss of Tablets

Medium uptake and mass loss of the prepared matrix tablets were evaluated using the dissolution
apparatus. Briefly, a pre-weighed tablet (W1 ) was transferred into 900 mL of the simulated gastric fluid
(pH 1.2, 37.0 ± 0.5 ◦ C), at a rotation speed of 50 rpm. At predetermined time intervals, the swollen
tablet was removed from the medium and blotted with a tissue paper to remove the excess medium
on the tablet surface, and weighed (W2 ) in an analytical balance [24,25,38,39]. Then, the swollen tablet
was dried in an oven at 50 ◦ C, until a constant weight was obtained (W3 ). Each experiment was
performed in triplicate. The percentage of medium uptake and mass loss of the tablet were calculated
using the following Equations (2) and (3), respectively.

W2 − W1
% Medium U ptake = × 100% (2)
W1

W1 − W3
% Mass Loss = × 100% (3)
W1
Pharmaceutics 2018, 10, 161 5 of 25

Table 1. Box Behnken experimental design with three independent variables (control factors), and dependent variables of drug release at different time points, floating
lag time, tablet ejection force, tablet tensile strength, and tablet porosity.

Independent Variables Dependent Variables

X1 X2 X3 Y1 Y2 Y3 Y4 Y5 Y6 Y7
Run
PEO WSR Sodium Compression T25% T50% T80% FLT Ejection Tensile Strength Tablet
(mg) Bicarbonate (mg) Force (kN) (min) (min) (min) (s) Force (N) (N/cm2 ) Porosity (%)
1 200 60 6 70 229 528 5 445 342 18.7
2 100 90 6 72 238 516 1 625 179 20.0
3 300 30 6 61 224 529 165 390 524 16.4
4 100 30 6 44 143 391 26 600 207 20.7
5 200 60 6 69 228 531 7 430 330 18.6
6 200 90 4 79 254 580 1 350 188 21.9
7 300 60 4 80 260 612 6 280 271 19.7
8 100 60 4 59 193 461 1 360 90 23.4
9 100 60 8 57 194 459 19 680 260 17.8
10 300 90 6 87 281 655 33 410 441 17.5
11 300 60 8 81 259 610 128 450 690 14.7
12 200 30 8 55 183 444 138 620 503 16.4
13 200 30 4 53 181 450 10 330 200 21.8
14 200 60 6 69 228 525 13 440 336 18.6
15 200 90 8 79 252 575 6 587 430 16.7
Pharmaceutics 2018, 10, 161 6 of 25

2.8. Total Fwork of Penetration

Total work of penetration profiles can give useful information about the gel strength of the
hydrated tablet [40,41]. Therefore, mechanical gel strength of the hydrated tablets was evaluated using
the texture analyzer equipped with a 5 kg load cell and the software texture expert. The tablets were
placed in dissolution vessels under similar conditions as in the in vitro drug release study. The hydrated
tablets were removed at different time points, patted lightly with a tissue paper, and subjected to
texture profiling, to determine the total work of penetration [15,38,42]. Force-displacement profiles
associated with the penetration of a 2 mm round-tipped steel probe into the swollen tablet were
monitored [15,38,41,43,44]. All measurements were carried out in triplicate at each time point. When
the trigger force reached 0.001 N, signal recording was initiated, and the probe was advanced into
the sample at a speed of 0.5 mm/s, until the maximum force of 60 N was attained. The total work of
penetration, which is a measure of gel strength and resistance to probe penetration, was determined
from textural profiles. In Equation (4), F is applied force and D is distance travelled.
Z
Total work o f penetration = FdD (4)

2.9. Tablet Ejection Force

Tablet ejection force was measured using the texture analyzer, immediately after compression.
The die containing the compressed tablet was placed on a sample holder, and a 9 mm cylindrical
probe was adjusted to be at the center of the die. The probe was advanced into the die at the test
speed of 10 mm/s. When the trigger force reached 0.1 N, signal recording begun and the probe was
consistently advanced at a test speed of 4 mm/s and stopped when the tablet was released from the
die. The ejection force was determined by the total probe displacement value (D) and the force applied
(F), using Equation (5). Z
Tablet ejection f orce = FdD (5)

2.10. Tablet Tensile Strength and Porosity

The tablet tensile strength was determined by fracturing the tablet diametrically, on an Ewerka
hardness tester at a speed of 0.5 mm/s (Erweka TBH 125, Heusenstamm, Germany). The tensile
strength was calculated from the maximum crushing strength, tablet diameter, and tablet thickness,
in accordance with Fell and Newton’s method described in Reference [45], in which the tablet tensile
strength (σx ) is represented as follows using the Equation (6),

2x
σx = (6)
πdt
where, x, d, and t are the breaking force, tablet diameter, and thickness, respectively.
Tablet dimensions were measured using a micrometer caliper with a precision of 0.01 mm
(Mitutoyo, Japan). The true densities of materials were determined using a helium pycnometer
(AccuPyc 1330, Micrometrics instruments Co., Norcross, GA, USA). The accuracy of the pycnometer
was evaluated using a standard steel sphere before measurements. The experimental sample was
accurately weighed and loaded into the sample cell. Sample volume was calculated by measuring
pressure, filling the sample chamber with high purity helium gas, followed by discharging the gas
into a second empty chamber. The measurements were repeated for five cycles. The percentage tablet
porosity (ε) was calculated using the Equation (7),
 
D
ε (%) = 1 − tablet × 100 (7)
Dtrue
Pharmaceutics 2018, 10, 161 7 of 25

where ε, Dtablet , and Dtrue are the tablet porosity, tablet density, and true density of the
formulation, respectively.

3. Results and Discussion

3.1. Risk Assessment

Quality by design (QbD) is an efficient, risk-controlled, and systematic approach to improve the
quality of pharmaceutical products. It can be applied to the entire pharmaceutical production processes
or to certain unit operations, and in initial research and development phases [46–48]. The International
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q8
(R2) guideline considers the quality target product profile (QTPP) an essential element of the QbD
approach [49]. It helps to sort out the critical material attributes (CMAs) and critical process parameters
(CPPs), that influence critical quality attributes (CQAs). The QTPP for the controlled release EFT is
listed in Table 2.
In the present study, the objective of risk assessment was to identify the most important risk
factors that needed further investigation. The risk assessment was performed based on the results of
screening experiments, prior knowledge, and experience, as well as information regarding effervescent
floating systems in previous reports. For the assessments, quantitative risk priority values were
mapped into three categories (high, medium, and low), as shown in Table 3. The high-risk factors were
introduced as control factors in the experimental design to establish their relationship with response
variables, and the low-risk factors were not investigated further, because they have minimal influence
on the outcomes.

Table 2. Quality target product profiles (QTPP) of effervescent floating tablets.

QTPP Target Justification

Controlled release Metformin is well absorbed from the upper part of the
Dosage form effervescent small intestine
floating tablet Short half-life and highly water-soluble
Route of administration Oral Designed for oral administration
Dose strength 500 mg/Tablet Commonly accepted strength
Softer tablet could chip or break during packaging and/or
Tablet TS 500 N/cm2 shipping, unacceptable for controlled release formulations.
High tablet hardness can increase FLT.
100% w/w of label Assay variability will affect safety and efficacy. Process
Assay
claim variables could affect product assay.
Failure to meet dissolution specifications can impact
Product quality Sustained release
Dissolution bioavailability. Amount of polymer and effervescence will
attributes up to 12 h
impact drug release rate.
FLT As low as possible Prevent gastric emptying
Tablet should continuously float in medium. If not, gastric
Floating
12 h emptying of the tablet is likely to occur, which can be
time
considered failure.
Tablet
Minimize tablet defects and improve product quality and
ejection As low as possible
production output.
force
Pharmaceutics 2018, 10, 161 8 of 25

Table 3. Initial risk assessment for formulation and process variables in controlled release effervescent floating tablets.

Formulation Variables Process Variables

Drug Product CQAs
Type/Viscosity Sodium Lactose Compression
PEO WSR 303 MCC Dwell Time
Grade of Polymer Bicarbonate Monohydrate Force
Drug release: T25%, T50% and T80% High High High Low Low Low Low
Assay Low Low Low Low Low Low Low
Floating lag time Medium Medium High Medium Low High Medium
Tensile strength High High Low Medium Low High Medium
Gel strength High High Low Low Low Medium Low
Ejection force High High Low Medium Medium High Low
Low: Broadly acceptable risk. No further investigation needed; Medium: Risk acceptable. Further investigation may need to reduce the risk; High: Risk unacceptable. Further investigation
needed to reduce the risk.
Pharmaceutics 2018, 10, 161 9 of 25

3.2. Polymer Screening

Various hydrophilic gel-forming polymers were investigated to select the most appropriate one for
the metformin EFT, in terms of providing controlled release, high mechanical gel strength, minimum
FLT, and high swelling rate. Among the polymers, PEO showed the highest gel strength, whereas
HPC M had the lowest strength (Figure 1a). Likewise, among the various viscosity grades of HPMC,
HPMC 100,000SR showed the highest gel strength, suggesting that viscosity grade has an impact on the
mechanical strength of the gel layer. Higher gel strength may indicate the formation of a stronger gel
barrier layer in matrices. Moreover, stronger gel layer of EFT controls the release of the drug, as well
as provides mechanical integrity to the matrices [15,41]. However, the tablet might get damaged in
the stomach if the outer gel layer is not strong enough and does not resist the external environment.
Similarly, EFTs prepared from different polymers suggested that PEO EFT had the lowest FLT and
quick penetration of dissolution medium into the matrices (data not shown).

(b)
(a)
800 100
Gel Strength (mN.mm)

80
600 HPC-M
Drug release (%)

HPC-H FP
60
400 HPMC-100SR

40 HPMC -4000SR

200 HPMC -100000SR

20
PEO 303

0 0
0 3 6 9 12 15 18 21 24
Time (h)

Figure 1. (a) Gel strength (mN·mm) of various hydrophilic using the Texture analyzer after being
Figure 1. in water at 37 ◦ C. (b) Comparison of drug release profiles of the effervescent floating tablets
swollen
(EFTs) with different hydrophilic polymers.

The in vitro drug release studies of metformin EFT prepared from the polymers are shown in
Figure 1b. PEO showed the lowest drug release rate among the studied polymers, whereas HPC M
showed the highest rate followed by HPMC 100SR. The decrease in drug release rate might be due to
the quick gel-forming capability of PEO, whilst the high release rate from HPC M might be associated
with poor hydration rate due to low polymer viscosity. Moreover, in the low viscosity polymers,
polymer chains are quickly detangled and the polymer can be eroded eventually leading to rapid drug
release [30]. Based on the results, PEO was selected for further optimization studies.

3.3. Evaluation of Medium Uptake, Mass Loss, and Gel Strength

Medium uptake and mass loss were evaluated by comparing the weights of swollen and dried
tablets. In the controlled release EFT, hydration capability of the polymer may govern drug release
kinetics, as well as tablet buoyancy efficiency [13,26]. As shown in Figure 2a, higher medium uptake
was observed in the tablets with higher amounts of PEO, irrespective of compression force in the
experimental range. This could suggest that the compression force may not be a critical factor for the
medium uptake by PEO. Moreover, the polymer’s capability to absorb the test medium might be due to
the presence of hydrophilic groups [50]. Interestingly, at the low level of PEO, sodium bicarbonate did
not influence the hydration extent (F2, F4, F8, and F9). However, at the high level, sodium bicarbonate
showed a tendency to retard the medium uptake.
Pharmaceutics 2018, 10, 161 10 of 25

Figure 3a–c show the erosion rates of swollen tablets with experimental formulations. Formulations
containing higher amounts of PEO (F3, F7, F10, and F11) had low erosion rates, compared to those
containing lower amounts of PEO. As shown earlier, high PEO contents in matrices resulted in
rapid uptake of dissolution medium and formation of a gel barrier to control drug release. Similarly,
formulations containing high amounts of sodium bicarbonate inhibited the erosion rate, which might
be attributed to the presence of CO2 gas bubbles in the gel layer [17]. Moreover, correlations between
the drug release rate and mass loss at 2 h and 8 h, are provided in Figure 3d. The R2 value at 2 h and 8 h
was 0.89 and 0.93, respectively, suggesting high correlation between the drug release rate and mass loss.
Textural profiles provide better understanding of the dynamics of gel strength and movement
of gel boundaries. To evaluate the gel strength of the swollen tablets, total work of penetration was
calculated from the area under the force-displacement curve. As shown in Figure 4, the work of
penetration of the tablet sharply decreased with an increase in exposure time due to the increase in
the size of polymer molecules, as a consequence of the entry of a medium might decrease the glass
transition temperature (Tg) [24,51]. As the hydration proceeded, the polymer might have changed
from a crystalline state to a rubbery state, and undergone relaxation [15,51]. It was also noticeable that
tablets containing higher amounts of PEO (F3, F7, F10, and F11) showed high work of penetration,
compared to those with lower PEO amounts. This might be attributed to the formation of a strong gel
layer in high PEO matrices.

(a) (b)

300
300
F3 F11
250
250 F10
Medium uptake (%)

Medium uptake (%)

F7
200 F13
200 F1
F12
150 F5 150
F14
F6
100 100 F15
F4 F9
50 50
F2 F8
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Time (h) Time (h)

Figure 2. Plots of degree of swelling (medium uptake) vs. time profiles of various formulations based
on the Box-Behnken design (BBD) experimental design, (a) F1–7 and (b) F8–15.
Figure 2.
Pharmaceutics 2018, 10, 161 11 of 25

(a) (b)
80 80 0.5 h
0.5 h
1h 1h

60 2h 2h
60
Mass Loss (%)

3h

Mass Loss (%)

3h
5h 5h
40 40
8h 8h

20 20

0 0
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10

(c) (d)
80 100 y = 0.8161x + 30.567
0.5 h R²= 0.9303
1h
80
60 2h
Drug release (%)
Mass Loss (%)

3h
5h 60
y = 0.6195x + 17.76
40 8h R²= 0.8909
40

20 2h
20
8h

0 0
F11 F12 F13 F14 F15 0 20 40 60 80
Mass Loss (%)

Figure 3. Plots
Figure 3. of tablet matrix erosion (% mass loss) vs. time of various formulations based on the
BBD experimental design, (a) F1–5, (b) F6–10, and (c) F11–F15). (d) Correlation between drug release
rate and mass loss in different time points.

(a) (b)

36
20 F1
Total work penetration (N.mm)

Total work penetration (N.mm)

F9
F2
30
16 F3 F10

F4 24 F11
12
F5 F12
18
F6
F13
8
F7 12
F14
F8
4 F15
6

0 0
0 2 4 6 8 0 2 4 6 8
Time (h) Time (h)

Figure 4.4. Total work of penetration vs. time profiles of various formulations based on the BBD
Figure
experimental design, (a) F1–8 and (b) F9–15.

3.4. Evaluation of Drug Release Kinetics

In vitro drug release profiles of the experimental tablets (F1–F15), and tablets without sodium
bicarbonate (F0*, F2*, and F15*), are provided in Figure 5a–c. Likewise, Table 1 depicts the time
required for 25% of drug release (T25%), 50% of drug release (T50%), and 80% of drug release (T80%)
Pharmaceutics 2018, 10, 161 12 of 25

in the experimental formulations. Initially (up to 1 h), burst release of metformin was observed
in the formulations containing low amounts of polymer and sodium bicarbonate (F4, F8, and F9).
This might be ascribed to insufficient time to form a gel barrier at the lower polymer levels, and the
high metformin contents in the EFTs. However, with the progression of medium uptake, the polymer
might form a gel layer retarding drug molecule transport through the matrix. Moreover, the drug
release rate was significantly retarded in formulations containing sodium bicarbonate, compared to
the formulations without it (Figure 5c). In the tablets containing sodium bicarbonate, CO2 bubbles
were liberated extensively when they reacted with the dissolution medium. These CO2 bubbles might
be entrapped in the gel layer and obstructed diffusion paths, eventually retarding the transport of
both drug and dissolution medium through the matrix. This suggests that sodium bicarbonate has
a potential role in retarding drug release rates of highly water-soluble drugs in combination with a
hydrophilic polymer.
To investigate the release kinetics of metformin EFTs in all the experimental formulations, as well
as in F0, F0*, F2*, and F15*, the model equations were fitted to the data of in vitro release profiles [52–55]:
Zero-order equation (Equation (8)), the Korsmeyer-Peppas model (Equations (9)), and the Higuchi
model (Equation (10)),
Mt = M0 + k0 t (8)

log( Mt /M∝ ) = log k + n log t (9)

√
Mt = k H t (10)

where t is the time, Mt is the amount of drug released at time t, M0 is the initial amount of the drug in
solution, Mt /M∝ is the fraction of drug released at time t (drug loading was considered as M∝ ), k0 is
the zero-order rate constant, k is the Korsmeyer-Peppas rate constant, n is the release exponent, and kH
is the Higuchi constant.
As shown in Table 4, correlation coefficients (R2 ) in the Korsmeyer Peppas model,
the Higuchi model, and the zero-order kinetics equation were determined. Among the models,
the Korsmeyer-Peppas model showed the highest linearity, followed by the Higuchi model and the
zero-order equation, proposing that in vitro drug release in the formulations was best explained using
the Korsmeyer-Peppas model. Furthermore, the n value in the Korsmeyer-Peppas equation could
be used to explain the drug release mechanism: n < 0.5 indicates diffusion transport, whilst n value
between 0.5–1.0 indicates non-Fickian or anomalous diffusion (i.e., drug release controlled by both
diffusion and erosion) [51]. The n values of the formulations, including those of F0, F0*, F2*, and F15*
were in the range of 0.474–0.701 (Table 4). The formulations except F0, F4, F0*, and F2* showed a
non-Fickian or anomalous diffusion, suggesting that drug release was governed by both diffusion and
erosion (0.5 < n < 1.0). This could be due to the blockade of diffusion by CO2 bubbles, as described
earlier. However, the formulations of F0, F4, F0*, and F2* showed a diffusion transport (n < 0.5).
Overall, it could be concluded that formulations containing high levels of both polymer and sodium
bicarbonate showed anomalous transport.
Pharmaceutics 2018, 10, 161 13 of 25

(a) 100

F1

Drug release rate (%)

80
F2
60 F3
F4
40 F5
F6
20 F7
F8
0
0 4 8 12 16 20 24
Time (h)
(b) 100
Drug release rate (%)
80
F9
F10
60
F11

40 F12
F13
20 F14
F15
0
0 4 8 12 16 20 24
Time (h)

(c) 100

80
Drug release (%)

F15

60 F15*
F2
40 F2*
F0
20 F0*

Figure 5. Metformin
0
0 4 8 12 16 20 24
Time (h)

Figure 5. In vitro dissolution profiles of various formulations based on the BBD experimental design,
(a) F1–8 and (b) F9–15. (c) Comparison of drug release profiles of tablets with sodium bicarbonate
(F0, F2, and F15), and those without sodium bicarbonate (F0*, F2*, and F15*).

Table 4. Correlation coefficient (R2 ) values for the dissolution profiles plugged into various release models.

Zero-Order Higuchi Korsmeyer-Peppas

Run
R2 R2 R2 n k
F1 0.9355 0.9970 0.9999 0.575 0.375
F2 0.9413 0.9959 0.9991 0.599 0.234
F3 0.9229 0.9957 0.9996 0.567 0.376
F4 0.8871 0.9979 0.9876 0.490 0.633
F5 0.9401 0.9977 0.9995 0.584 0.370
F6 0.9469 0.9944 0.9986 0.639 0.158
F7 0.9408 0.9962 0.9990 0.612 0.210
F8 0.9222 0.9961 0.9987 0.534 0.478
F9 0.9238 0.9959 0.9969 0.535 0.488
F10 0.9450 0.9940 0.9937 0.702 0.100
F11 0.9415 0.9956 0.9987 0.632 0.210
F12 0.9132 0.9945 0.9983 0.554 0.450
F13 0.9167 0.9934 0.9984 0.541 0.452
F14 0.9307 0.9969 0.9983 0.577 0.373
F15 0.9475 0.9946 0.9945 0.641 0.160
F0 0.7702 0.9936 0.9675 0.485 0.730
F0* 0.8333 0.9985 0.9825 0.474 0.792
F2* 0.8174 0.9947 0.9740 0.481 0.744
F15* 0.8787 0.9937 0.9838 0.512 0.600
Pharmaceutics 2018, 10, 161 14 of 25

3.5. Statistical Analysis and Summary of Fit

A quadratic statistical model, including linear, interactive, and polynomial terms, was used to
investigate the influence of control factors on the responses. Table 5 summarizes the coefficients
of model terms and associated p values for Y1 –Y7 . If the p value was less than 0.05 (p < 0.05),
the factor could be considered to affect the responses significantly. To simplify the regression model,
the non-significant terms (p > 0.05) were not considered (Equations (11)–(17)). A positive or negative
coefficient indicated an increase or decrease in the corresponding response, respectively, to the increase
in the level of the factor or factors involved in that term.
To evaluate the validity of the experimental design, analysis of variance (ANOVA), R2 , adjusted
R , and predicted R2 were determined (Table 5). The high values of R2 , adjusted R2 , and predicted R2
2

indicated good data fitting of the investigated responses. In addition, p values of regression models of
Y1 –Y7 were below the significance level (p < 0.05), suggesting that the studied response variables were
not influenced by any of the control factors. p values of lack of fit of Y1 –Y7 were 0.0508, 0.064, 0.397,
0.108, 0.073, 0.251, and 1.000, respectively, which were greater than 0.05 for all responses, suggesting
that model errors were not significant.

3.6. Effect of Control Factors on Drug Release Profiles

The actual model R2 , adjusted R2 , and R2 predicted value for Y1 (T25%) were 0.9702, 0.9653,
and 0.9493, respectively. Similarly, the actual model R2 , adjusted R2 , and R2 predicted value for Y2
(T50%) were 0.9984, 0.9973, and 0.9910, respectively, and for Y3 (T80%) were 0.9980, 0.9972, and 0.9952,
respectively. The similarity of these values was suggestive of the goodness of fit. Likewise, the p-value
of model equation of Y1 , Y2 , and Y3 were <0.0001. The reduced regression equations in coded terms for
Y1 , Y2 , and Y3 , are shown in Equations (11)–(13).

Y1 = 67.66 + 9.62X1 + 13.00X2 (11)

Y2 = 229.000000 + 32.000000X1 + X2 36.750000 − 0.000003X3 − 9.500040X1 X2

(12)
−8.000020X22 − 2.999980X32

Y3 = 527.08 + 72.38X1 + 64.00X2 + 9.12X12 − 14.13X22 (13)

As shown in Table 5, the amount of PEO (X1 ) and sodium bicarbonate (X2 ) had a significant effect
on Y1 , Y2 , and Y3 . Coefficients of X1 and X2 were positive for Y1 − Y3 , suggesting that the dependent
variables increased with the increase of PEO and sodium bicarbonate. In addition, coefficients of X12 for
Y3 were positive, suggesting a synergistic effect on drug release response, whilst negative coefficients
of X22 for Y2 and Y3 indicated an antagonist effect on drug release response. Furthermore, in case of Y2
and Y3 , the coefficient of X1 X2 had a negative effect, which indicated that the X1 X2 interaction term
had a reciprocal relation with Y2 and Y3 . This can be explained on the basis that as the amount of
sodium bicarbonate increased in the tablet, more CO2 was generated, which was entrapped in the gel
layer and obstructed diffusion, thereby reducing drug transport through the matrix. In the previous
studies, polymer content in the matrix was highlighted as an important variable in controlling release
rate [10,13,38]. However, in case of highly water-soluble drugs loaded at high levels, a large amount
of polymer is required in the formulation to extend release rate, which often poses challenges for
formulation scientists [56,57]. However, our finding suggests that sodium bicarbonate could contribute
to controlling the release rate of highly water-soluble drugs, and potentially reduce the polymer
amount in the formulation.
In addition, a contour plot (Figure 6) was used to visualize the influence of tablet compression
force and the concentrations of PEO and sodium bicarbonate on Y1 , Y2 , and Y3 . The plot showed that
the time required for drug release from the EFT, significantly increased with the sodium bicarbonate
level. This might be attributed to the increased release of CO2 bubbles at the high levels of sodium
bicarbonate, when reacted with the dissolution medium. As suggested earlier, the liberated CO2
Pharmaceutics 2018, 10, 161 15 of 25

bubbles may interfere the transport of drug and water through the matrix. Likewise, at a constant
sodium bicarbonate level, an increase in PEO concentration increased Y1 , Y2 , and Y3 . Increase in
PEO concentration may cause the dissolution medium to penetrate quick into the tablet and form a
thick gel layer. As a result, the diffusion path length would be increased, retarding the drug release
rate. In addition, at high PEO levels, PEO tortuosity might increase, facilitating entanglement of the
polymer chains [56,58].

(a)

(b)

(c)

Figure 6. 6. Contour plots showing the effects of hydrophilic polymer (PEO) and sodium bicarbonate on
Figure
the drug release responses (Y1 –Y3 ): (a) T25% (Y1 ), (b) T50% (Y2 ), and (c) T80% (Y3 ).
Pharmaceutics 2018, 10, 161 16 of 25

Table 5. Regression coefficients and associated p values for the responses.

T25% T50% T80% FLT Tablet Ejection Force Tablet Tensile Strength Tablet Porosity
Terms (Y 1 ) (Y 2 ) (Y 3 ) (Y 4 ) (Y 5 ) (Y 6 ) (Y 7 )
Coefficient p Value Coefficient p Value Coefficient p Value Coefficient p Value Coefficient p Value Coefficient p Value Coefficient p Value
Constant 67.667 <0.0001 229.000 <0.0001 527.077 <0.0001 12.230 0.04712 440.714 <0.0001 332.733 <0.0001 18.633 <0.0001
X1 9.625 <0.0001 32.000 <0.0001 72.375 <0.0001 35.625 <0.0001 −91.875 <0.0001 148.750 <0.0001 −1.700 <0.0001
X2 13.000 <0.0001 36.750 <0.0001 64.000 <0.0001 −37.250 <0.0001 4.0000 0.6248 −24.500 0.0001 0.1000 0.001
X3 – – 0.0000 1.0000 – – 34.125 <0.0001 127.1200 <0.0001 141.750 <0.0001 −2.650 <0.0001
X1 *X2 – – −9.500 <0.0001 – – 26.750 0.0019 – – −13.750 0.0239 −0.450 <0.0001
X2 *X3 – – – – – – −30.750 0.0010 – – −15.250 0.0150 0.050 0.0408
X1 *X3 – – – – – – 26.000 0.0022 −37.5000 0.0140 62.250 <0.0001 0.150 0.0004
X1 2 – – – – 9.115 <0.0001 23.346 0.0045 – – 9.5000 0.0010 −0.141 <0.0001
X2 2 – – −8.000 <0.0001 −14.134 0.0011 23.596 0.0043 48.2856 0.0043 – – 0.158 <0.0001
X3 2 – – −3.000 0.0180 – – – – – – – – 0.408 <0.0001
R2 0.9702 0.9984 0.9980 0.9859 0.9747 0.9978 0.9999
R2 (Adj) 0.9653 0.9973 0.9972 0.9670 0.96.07 0.9962 0.9998
R2 (Pred) 0.9493 0.9910 0.9952 0.8668 0.9135 0.9896 0.9998
– indicates the insignificant term (p > 0.05).
Pharmaceutics 2018, 10, 161 17 of 25

3.7. Effect of Control Factors on Floating Lag Time (FLT)

FLT is the time required for the tablet to float on the surface of dissolution medium, after its
introduction into the medium. Dosage form density might be associated with floating behavior.
Previous studies showed that tablets with density greater than 1.004 g/cm3 could not float on gastric
fluid [3,59]. In the floating system, a shorter FLT is preferable. It is generally assumed that as FLT
increases, the tablet may attach to the lower part of the stomach and be unable to float, leading to
an increase in the chances of gastric emptying. Therefore, FLT may be an important factor affecting
gastric retention time, requiring minimization.
Figure 7a shows the FLT values of the experimental formulations. The actual model R2 , adjusted
R , and R2 predicted, for FLT (Y4 ) were 0.9859, 0.9670, and 0.8668, respectively, and were close to 1.
2

The similarity of these values was suggestive of the goodness of fit. The reduced regression equations
in coded terms for FLT Y1 , are shown in Equation (14).

Y4 = 12.23 + 35.63X1 − 37.25X2 + 34.12X3 − 26.75X1 X2 + 26.00X1 X3 − 30.75X2 X3

(14)
+23.35X12 + 23.60X22

As shown in Table 5, linear, interaction, and polynomial terms of the control factors had a
significant influence on the FLT. The coefficients of X1 , X3 , X1 X3 , X12 , and X22 were positive, whilst
coefficients of X2 , X1 X2 , and X2 X3 were negative (Equation (14)). This suggested that FLT increased
with the increasing amount of PEO and/or compression force but decreased with the increase in
sodium bicarbonate.

(a) (b)

200 700

600
160
500
Ejection Force (N)
FLT (s)

120 400

300
80
200
40 100

0
0
F10
F11
F12
F13
F14
F15
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
F13
F14
F15
F1
F2
F3
F4
F5
F6
F7
F8
F9

(d)
(c)

800 750
y = -62.394x + 1508.7
Tensile strength (N/cm2)

700 R²= 0.872

600
600
Tensile Strength (N/cm2)

500 450
400
300
300
200
150
100
0 0
12.5 15.0 17.5 20.0 22.5 25.0
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
F11
F12
F13
F14
F15

Tablet porosity (%)

Figure 7.
Figure 7. Evaluation of tablet properties of the BBD experimental formulations (a) floating lag time
(FLT (s)), (b) tablet ejection force (N), (c) tablet tensile strength (N/cm2 ), and (d) correlation between
tablet tensile strength and tablet porosity (%).
Pharmaceutics 2018, 10, 161 18 of 25

Figure 8a shows the influence of PEO and sodium bicarbonate on the FLT at low, moderate,
and high level of compression force. FLT increased significantly with an increase in the compression
force. As compression force increased, tablet density would increase because of decreased tablet
porosity. To float on the surface of the gastric fluid, tablet density would need to be less than that
of the gastric fluid. At all compression force values, increase in the amount of sodium bicarbonate
resulted in a reduction in FLT, whilst an increase in the PEO amount led to an increase in FLT; a high
level of sodium bicarbonate may lower tablet density by quickly releasing CO2 upon contact with
the dissolution medium. However, increase in PEO could reduce tablet porosity and increase tablet
density, increasing the FLT. Furthermore, at a higher PEO level, an outer gel layer may form quickly
upon contact with the simulated gastric fluid, and retard its exposure to sodium bicarbonate, further
delaying the FLT.

8. Contour
FigureFigure 8. plots showing the effects of hydrophilic polymer (PEO) and sodium bicarbonate on
(a) floating lag time, (Y4 ), (b) tablet ejection force, (Y5 ), (c) tablet tensile strength, (Y6 ), and (d) tablet
porosity (Y7 ).

3.8. Effect of Control Factors on Tablet Properties

Process development and formulation design of tablet dosage forms, need a thorough understanding
of physicochemical properties and the deformation nature of API and excipients. These properties
have a significant impact on compaction behavior during tableting. During the tablet compression,
various factors, such as mechanical interlocking, solid bridging, particle fragmentation, and van der
Waals’ forces, contribute to packing and bonding of pharmaceutical materials [60]. Tablet compression
Pharmaceutics 2018, 10, 161 19 of 25

involves several stages, including particle rearrangement, deformation, fragmentation, decompression,

and ejection. A high tablet ejection force may indicate a high frictional force at the tablet-die wall
interface, which could damage the tablet and reduce tooling life due to wear [61]. In general, brittle
materials produce tablets with a rough surface increasing the frictional force at the interface of the
die wall and tablet, eventually increasing tablet ejection force. Even though lubricants can be used
to reduce the frictional force during tablet compression, use of a lubricant in excessive amounts in
tablets could have adverse effects on tablet quality, including low tablet tensile strength [62], increased
tablet friability [63], and reduced dissolution rate [64]. One approach of reducing tablet ejection force
is the use of both brittle and plastic deforming materials in the formulation, as the deforming nature
of powder including brittle, plastic, and elastic deforming could influence tablet properties, such as
ejection force, tensile strength, and porosity [32,39].

3.8.1. Effects of Control Factors on Tablet Ejection Force

Tablet ejection force of different experimental runs ranged from 270 to 680 N, as shown in Figure 7b.
A regression equation with control factors affecting the ejection force used to generate the empirical
model is described by Equation (15)

Y5 = 440.71 − 91.87X1 + 4.00X2 + 127.13X3 − 37.5X1 X3 + 48.29X22 (15)

As shown in Table 5, p value < 0.05 for any of the factors, represents a significant effect of
the corresponding factors on tablet ejection force. The coefficients of X2 , X3 , and X22 were positive,
while the coefficients of X1 and X1 X3 were negative, suggesting that tablet ejection force decreased
with the increase in PEO level and increased with the increase in compression force. The actual
model R2 , adjusted R2 , and R2 predicted, for tablet ejection force (Y5 ) were 0.9747, 0.9607, and 0.9135,
respectively. The similarity of these values was suggestive of the goodness of fit.
Effects of PEO and sodium bicarbonate amounts on tablet ejection force at low, moderate, and high
compression force, are shown in a contour plot (Figure 8b). As the compression force increased from 4 to
8 kN, ejection force significantly increased. As the ejection force increased, frictional force at the tablet-die
wall interface would increase, eventually increasing the tablet ejection force. At constant compression
force and PEO, tablet ejection force decreased at a low sodium bicarbonate level, but increased at a
moderate level, suggesting a quadratic effect of sodium bicarbonate (nonlinear relation). However,
this effect was not significant (p = 0.62). Moreover, at constant ejection force and sodium bicarbonate,
an increase in PEO amount resulted in a decrease in tablet ejection force. This might be attributed to the
plastic deforming nature of PEO, resulting in a low frictional force at the tablet-die wall interface [32,65].
In addition, decreasing PEO amount in the tablet resulted in an increase in the amount of lactose
monohydrate (used for tablet weight adjustment). As lactose monohydrate is a brittle deforming
excipient, increasing its amount in the tablet could have resulted in a high frictional force at the
tablet-die wall interface, eventually increasing ejection force.

3.8.2. Effect of Control Factors on Tablet Tensile Strength

Mechanical strength of tablets is crucial in controlled release formulations, since tablets with low
mechanical strength could have poor friability causing breakage, and therefore may be unable to resist
stresses during downstream processing, including tablet coating, packaging, and shipping. Therefore,
to ensure sufficient mechanical strength, tablet tensile strength was assessed. Tablet tensile strength of
the experimental formulations ranged from 95 to 690 N (Figure 7c). The actual model R2 , adjusted
R2 , and R2 predicted, for tablet tensile strength (Y6 ) were 0.9978, 0.9962, and 0.9896, respectively.
The similarity of these values was suggestive of the goodness of fit. The reduced regression equations
in coded terms for Y6 , are shown in Equation (16).

Y6 = 332.73 + 148.75X1 − 24.50X2 + 141.75X3 − 13.75X1 X2 + 62.25X1 X3 − 15.25X2 X3 (16)

Pharmaceutics 2018, 10, 161 20 of 25

As shown in Table 5, p value < 0.05 of any of the factors, represents a significant effect of the
corresponding factors on the tensile strength. It was observed using Equation (16), that the coefficients
of X1 , X3 , and X1 X3 were positive, while the coefficients of X2 , X1 X2 , and X2 X3 were negative.
This suggested that PEO content and compression force had a synergistic effect on the tablet tensile
strength, whilst sodium bicarbonate amount had an antagonistic effect. Similarly, the effect of PEO
and sodium bicarbonate levels on the tensile strength at low, moderate, and high compression force
is provided in a contour plot (Figure 8c). At low compression force, increasing the amount of PEO
contributed to a slight increase in the tensile strength. However, at medium and high compression
force, increase in PEO levels resulted in a drastic increase in the tensile strength. This may be attributed
to high mechanical interlocking, van der Waal’s forces, and solid bridging between the particles at
high compression force. In addition, the more ductile behavior of PEO may allow plastic deformation
during tableting, yielding stronger tablets. At constant compression force and PEO, an increase in
the concentration of sodium bicarbonate resulted in a slight reduction in the tablet tensile strength.
This may be due to the poor compaction tendency of sodium bicarbonate.

3.8.3. Effect of Control Factors on Tablet Porosity

Tablet porosity of the experimental formulations ranged from 14.7% to 23.4%. The actual model
R2 , adjusted R2 , and R2 predicted, for tablet tensile strength (Y6 ) were 0.9999, 0.9998, and 0.9998,
respectively. The similarities of these values suggest the goodness of fit. The reduced regression
equation in coded terms for Y7 is shown in Equation (17).

Y7 = 18.63 − 1.70X1 + 0.10X2 − 2.65X3 + 0.44X1 X2 + 0.15X1 X3 + 0.05X2 X3 − 0.14X12 +

(17)
0.15X22 + 0.40X32

As shown in Table 5, p value < 0.05 of any of the factors, represented a significant effect of the
corresponding factors on the tablet porosity. Compression force showed the most significant effect on
the porosity among the studied variables. The coefficients of X1 , X3 , and X12 were negative, while the
coefficients of X2 , X1 X2 , X2 X3 , X1 X3 , X22 , and X32 were positive. This suggested that the amount of
PEO and compression force were inversely proportional to the porosity, whilst the amount of sodium
bicarbonate was directly proportional to the porosity.
A contour plot (Figure 8d) showed the effect of PEO and sodium bicarbonate levels on tablet
porosity at low, moderate, and high compression force. As expected, tablet porosity decreased
significantly with the increase of compression force. At high levels of PEO and compression force,
void space between the particles reduced drastically due to high mechanical interlocking and bonding
forces between the particles. Moreover, PEO was highly compressible due to its plastic deforming
nature, forming strong solid bridging between particles. In contrast, slightly higher porosities were
found at higher sodium bicarbonate amounts due to its poor compressibility. Moreover, tablet porosity
was highly correlated with tablet tensile strength, as shown in Figure 7d, suggesting that tablet tensile
strength decreased with the increase in tablet porosity. Based on the experimental data, a regression
model between tablet porosity and tensile strength can be obtained as y = −62.39x + 1508.7, suggesting
that tablet porosity higher than 20% produces tablets with low tensile strength.

3.9. Design Space and Optimization

Design space (DS) is the multidimensional space of formulation and process setting, where the
predetermined product quality attributes remain within the specification, when formulation and/or
process variables are being changed [66]. To identify the design space, the knowledge space is divided
into smaller subspaces, and the probability of fulfilling the specification within each region is evaluated.
In the present study, design space was generated using a Monte Carlo simulation. The desired
specification in the current investigation was to provide the controlled drug release rate, as well as the
tablet buoyancy for 12 h. Therefore, the design space was explored based on the desired targets for the
Pharmaceutics 2018, 10, 161 21 of 25

drug release rate; T25 (50 ≤ Y1 ≤ 80 min; target, 60 min); T50 (220 ≤ Y2 ≤ 260 min; target, 240 min);
T80 (510 ≤ Y3 ≤ 570 min; target, 540 min); FLT (1 ≤ Y4 ≤ 60 s; target, 20 s); and tablet TS (350 ≤ Y6 ≤
670 N/cm2 ; target, 500 N/cm2 ). The resulting design space is provided in Figure 9a. Furthermore,
a sweet plot was also constructed to explain the influence of control factors on the response variables.
The plots were designed based on the given specifications of drug release rate, FLT, and tablet tensile
strength (Figure 9b). The green region denoted in the color index represents fulfillment of all criteria,
suggesting the appropriate region to obtain the desired outputs (Figure 9b).
Even though design space represents the region of theoretical robustness, experimental robustness
testing provides validation of the design. To obtain a robust point close to the selected optimal point,
robustness testing can be performed. The identified robust point was characterized by the combination
of control factors comprising 221 mg PEO per tablet, 62 mg sodium bicarbonate per tablet, and 7 kN
tablet compression force. The obtained experimental robust points were 65 min, 237 min, 548 min, 32 s,
and 450 N/cm2 for Y1 , Y2 , Y3 , Y4 , and Y6 , respectively.

Figure 9. (a) Sweet spot plots of PEO amount (x1 ) and sodium bicarbonate (x2 ) at low (left), medium
(middle), and high (right), and compression force (x3 ), defined in the specification of time required
for release: 25% (50 ≤ Y1 ≤ 80 min; target, 60 min); 50% (220 ≤ Y2 ≤ 260 min; target, 240 min);
and 80% (510 ≤ Y3 ≤ 570 min; target, 540 min). FLT (1 ≤ Y4 ≤ 60 s; target, 30 s), and tensile strength
(TS) (350 ≤ Y6 ≤ 670 N/cm2 ; target, 500 N/cm2 ). (b) Design space in terms of PEO amount (x1 ) and
sodium bicarbonate (x2 ) at low (left), medium (middle), and high (right), and compression force (x3 ),
defined in the specification of time required for release after the Monte Carlo simulation.
Pharmaceutics 2018, 10, 161 22 of 25

4. Conclusions
Polymers with a high viscosity grade and molecular weight provided high mechanical gel
strength, and retarded drug release rate. Our results showed that PEO contributed significantly to
controlling drug release, improving gel strength, and improved tablet properties. The results also
provided evidence that sodium bicarbonate had a dual function in highly water-soluble drug EFTs,
i.e., it improved tablet floating and enabled controlled release by retarding the drug release rate
from the hydrophilic matrices. The various factors tested were negatively correlated with the tablet
properties. Interestingly, PEO sharply reduced tablet ejection force, which could improve the tablet
preparation process. Overall, the present study provided a perspective on systematically fabricating
EFTs loaded with high doses of highly water-soluble drugs by applying design space, and quality by
design concepts.

Author Contributions: Conceptualization, P.T. and S.H.J.; Methodology, P.T. and S.H.J.; Software, P.T.; Formal
Analysis, P.T.; Investigation, P.T.; Resources, S.H.J.; Writing—Original Draft Preparation, P.T.; Writing—Review &
Editing, S.H.J.; Supervision, S.H.J.; Funding Acquisition, S.H.J.
Funding: This work was supported by the National Research Foundation of Korea(NRF) grant funded by the
Korea government(MSIT) (NRF-2018R1A5A2023127).
Conflicts of Interest: The authors declare no conflicts of interest.

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