KK Article

Research Article
Microwave-Assisted Development of Orally Disintegrating Tablets by Direct
Compression
Kishor V. Kande,1
Darsheen J. Kotak,1
Mariam S. Degani,1
Dmitry Kirsanov,2,3
Andrey Legin,2,3
and Padma V. Devarajan1,4
Received 12 October 2016; accepted 29 November 2016
ABSTRACT. Orally disintegrating tablets (ODTs) are challenged by the need for simple
technology to ensure good mechanical strength coupled with rapid disintegration. The
objective of this work was to evaluate microwave-assisted development of ODTs based on
simple direct compression tableting technology. Placebo ODTs comprising directly com-
pressible mannitol and lactose as diluents, super disintegrants, and lubricants were prepared
by direct compression followed by exposure to >97% relative humidity and then microwave
irradiation for 5 min at 490 W. Placebo ODTs with hardness (>5 kg/cm2
) and disintegration
time (<60 s) were optimized. Palatable ODTs of Lamotrigine (LMG), which exhibited rapid
dissolution of LMG, were then developed. The stability of LMG to microwave irradiation
(MWI) was confirmed. Solubilization was achieved by complexation with beta-cyclodextrin
(β-CD). LMG ODTs with optimal hardness and disintegration time (DT) were optimized by
a 23
factorial design using Design Expert software. Taste masking using sweeteners and
flavors was confirmed using a potentiometric multisensor-based electronic tongue, coupled
with principal component analysis. Placebo ODTs with crospovidone as a superdisintegrant
revealed a significant increase in hardness from ∼3 to ∼5 kg/cm2
and a decrease in
disintegration time (<60 s) following microwave irradiation. LMG ODTs had hardness >5 kg/
cm2
, DT < 30s, and rapid dissolution of LMG, and good stability was optimized by DOE and
the design space derived. While β-CD complexation enabled rapid dissolution and moderate
taste masking, palatability, which was achieved including flavors, was confirmed using an
electronic tongue. A simple step of humidification enabled MWI-facilitated development of
ODTs by direct compression presenting a practical and scalable advancement in ODT
technology.
KEY WORDS: Lamotrigine; microwave irradiation; orally disintegrating tablet; taste masking; β-
cyclodextrin.
INTRODUCTION
Orally disintegrating tablets (ODTs) rapidly disintegrate
in the mouth to provide an in situ dispersion enabling ease of
administration. ODTs have thereby created a revolution as
patient-friendly alternatives to the conventional tablets and
capsules, especially for geriatric patients and the dysphagic
(1,2). Balancing two opposing requirements, namely, rapid
disintegration time (DT) and adequate hardness, coupled
with good palatability is the major challenge in ODT
development. Lyophilization was among the first processes
reported for ODT development, wherein freeze drying of
aqueous dispersions filled into blister alveoli cavities enabled
the formation of porous tablets (3–5). Vacuum drying
followed as an alternative to freeze drying (6). Nonetheless,
while rapid disintegration was achieved, both processes
resulted in porous fragile structures. An adapted cotton
candy process produced floss-like rapidly dissolving crystal-
line structures, which enabled ODTs with rapid DT, but could
not overcome the limitation of poor strength (7). This
process, moreover, involved high temperatures, further limit-
ing drug candidates that could be incorporated (8).
Wet molding technology, which involves moistening the
powder blend with a hydroalcoholic solvent followed by
1
Department of Pharmaceutical Sciences and Technology, Institute of
Chemical Technology, Deemed University, Elite Status and Centre
of Excellence (Maharashtra), N.P. Marg, Matunga (E), Mumbai,
400019, Maharashtra, India.
2
Institute of Chemistry, St. Petersburg State University,
Universitetskaya nab. 7/9, Mendeleev Center, 199034, St. Peters-
burg, Russia.
3
Laboratory of Artificial Sensory Systems, ITMO University,
Kronverkskiy pr., 49, 197101, St. Petersburg, Russia.
4
To whom correspondence should be addressed. (e-mail:
pvdevarajan@gmail.com)
AAPS PharmSciTech (# 2016)
DOI: 10.1208/s12249-016-0683-z
1530-9932/16/0000-0001/0 # 2016 American Association of Pharmaceutical Scientists

forcing the wetted mass into mold plates, was also evaluated
for the design of ODTs. While rapid DT was optimized, low
hardness resulted in high breakage during handling. Interest-
ingly, Sano and Itai demonstrated that subjecting wet molded
tablets comprising mannitol and silicon dioxide to drying by
microwave irradiation (MWI) enhanced their hardness,
without compromising on the rapid disintegration (9). The
effects of MWI on the increased porosity enabled by the
water vapor generated aided rapid disintegration. Enhanced
hardness was ascribed to the dissolution of mannitol in the
water vapor, with subsequent solidification coupled with a
change in the polymorphic form. In another study, Sano et al.
demonstrated superior ODT properties with l-HPC as the
disintegrant (10). Wet molding dictates the need for water
during processing, and being a slow process is not readily
adaptable for large-scale manufacture.
Direct compression, on the other hand, is a simple and
cost-effective technique for tablet manufacture (11) adaptable
on high-speed machines, with the added advantage of being a
dry process. ODTs manufactured by direct compression
methods at lower hardness exhibited rapid DT, but high
friability and even tablet rupture during opening of the blister
posed serious issues (12–14). Increasing the hardness resulted
in prolonged DT (15), thereby limiting application of the
direct compression process for ODT manufacture.
In this paper, we present a new approach for the design
of ODTs, adapting direct compression as the first step of
ODT manufacture followed by MWI. Water, a critical
requirement to enable enhanced tablet porosity, was provided
through a simple yet innovative step of humidification of the
directly compressed tablets prior to microwave irradiation.
Using this approach, placebo ODTs of high hardness (>5 kg/
cm2
) and rapid disintegration (<60 s) were successfully
developed. The method was then successfully adapted for
optimization of palatable ODTs of Lamotrigine (LMG),
which exhibited rapid dissolution by design of experiment
(DOE) approach.
MATERIAL AND METHODS
Materials
Ac-Di-Sol (FMC Biopolymers), crospovidone
(Kollidon® CL-SF, BASF), directly compressible mannitol
(Perlitol-200), beta-cyclodextrin (β-CD) and sodium stearyl
fumarate (Roquette Pharma), lactose DC (Meggle Pharma),
sodium starch glycolate (Primogel, DFE Pharma), and pre-
gelatinized starch (UNI-PURE WG 220, National Starch
Food Innovation) were received as gifts. Potassium sulfate
was purchased from S. D. Fine Chemicals, Ltd. Lamotrigine
was a gift sample (Cipla Pvt. Ltd., India).
Preparation of ODTs
Direct Compression
Placebo ODTs were prepared by mixing diluents, binder,
and superdisintegrants, followed by mixing with the lubri-
cants, sodium stearyl fumarate and magnesium stearate, in a
polyethylene bag. The blend was compressed on a rotary
Table I. Placebo ODT Formulation Batches
Ingredients (mg/tablet) DC1 DC2 DC3 DC4 DC5 DC6
DC mannitol 147 147 147 155 153 152
DC lactose 40 40 40 40 40 40
Pre-gelatinized starch – – – – – –
Ac-Di-Sol 10 – – – – –
SSG – 10 – – – –
Crospovidone – – 10 2 4 5
PVP K-25 2 2 2 2 2 2
Sod. stearyl fumarate 1 1 1 1 1 1
Mg stearate – – – – – –
Total wt. (mg) 200 200 200 200 200 200
RH exposure time
Hardness (kg/cm2
) Initial 3 3.2 2 3 3 3
After MWI 3.2 3.2 3.5 3.3 3.5 3.7
30 min + MWI – – – 5 5.2 5.2
2 h + MWI 4.4 4.2 5.2 – – –
3 h + MWI 4.5 4.2 5.3 – – –
DT (s) Initial 175 177 57 154 130 122
After MWI 160 162 26 148 123 114
30 min + MWI – – – 90 67 48
2 h + MWI 135 130 14 – – –
3 h + MWI 130 117 14 – – –
Table II. Independent Variables and Levels for DOE
Parameters Low level (−1) High level (+1)
A: Crospovidone (%) 2.5 7.5
B: Microwave irradiation time (min) 2 5
C: Humidity exposure time (min) 20 40
Kande et al.

tablet press using 8-mm flat punches to obtain tablets of
approximately 200 mg.
Humidification of Tablets
Humidification of tablets was carried out by exposure of
tablets for various time intervals in a humidity chamber
maintained at 97% relative humidity (RH) using a saturated
solution of potassium sulfate (16)
Microwave Irradiation
The placebo tablets were subjected to microwave
irradiation at 490 W in a microwave oven (Catalyst™ System,
Cata 2R).
Effect of the following variables on tablet hardness and
DT was evaluated:
(a) Microwave exposure time (5, 7, and 10 min)
(b) Effect of initial tablet hardness (2 and 3 kg/cm2
)
(c) Effect of superdisintegrant type and concentration
(Ac-Di-Sol, sodium starch glycolate, and
crospovidone)
(d) Effect of humidification time prior to microwave
irradiation (30 min, 2 h, and 3 h)
The various tablet batches evaluated are described in
Table I.
Development of LMG ODTs
Effect of Microwave Irradiation on LMG Stability
LMG as a powder was exposed to microwave irradia-
tion for 5 min at 490 W. A sample of about 10 mg of the
MWI sample was accurately weighed and transferred to a
100 mL volumetric flask. Methanol (5 mL) and volume were
made up to 100 mL with double distilled water filtered
through a 0.22-μm membrane filter (stock I, 100 μg/mL).
One milliliter of stock I solution was further diluted to
10 mL with mobile phase filtered through a 0.22-μm
membrane filter to obtain a solution of 10 μg/mL. Analysis
was performed by HPLC at room temperature (25°C) using
a Jasco Instrument (PU-980, Japan) equipped with a Waters
Spherisorb® 250 × 4.6-mm column and a Jasco photodiode
array detector at 210 nm. The mobile phase comprised of
phosphate buffer pH 3/acetonitrile/methanol/THF
(64:15:20:1) at a flow rate of 1 mL/min. The sample
(100 μL) was injected into the system and the concentration
of LMG was extrapolated from a standard plot in the
concentration range 2–10 μg/mL prepared in a manner
similar to the sample preparation.
Phase Solubility Study
A phase solubility study was carried out using the
method reported by Higuchi and Connors (17). Increasing
concentrations of β-CD of 1, 2, 4, 6, 8, and 10 mM were
prepared in distilled water and 3 mL filled in glass bottles.
Excess LMG (50 mg) was added to these solutions and the
bottles stoppered and agitated in a constant temperature
shaker water bath at 37 ± 2°C for 72 h. LMG without β-CD
served as the reference. Following equilibrium, the superna-
tant was withdrawn and centrifuged at 10,000 rpm for 15 min
and assayed for LMG content by UV spectrophotometry
(UV1650PC, Shimadzu Corporation, USA) at λmax of
276 nm. Experiments were performed in triplicate. A phase
solubility graph of drug concentration vs. β-CD concentration
was plotted and the apparent stability constant (K1:1) was
Table III. Batches for Taste Masking
Ingredients (mg/tablet) DC7 DC8 DC9 DC10 DC11 DC12 DC13
Pineapple flavor – 2 2 2 – – –
Vanilla flavor – – – – 2 2 2
Sucralose – – 2 4 – 2 4
Fig. 1. HPLC chromatograms of LMG. a Standard LMG. b LMG after MWI indicating stability
MWI-Enabled Development of DC ODT

calculated from the initial straight line portion of the phase
solubility diagram using the following equation:
K1:1 ¼
Slope
Intercept 1−Slopeð Þ
LMG-β-CD Inclusion Complex
The LMG-β-CD inclusion complex was prepared by the
wet kneading method. A mixture of LMG and β-CD in a 1:1
molar ratio was kneaded in a mortar with ethanol–water (1:1)
to obtain a paste-like consistency (18). The paste was dried in
an oven at 50°C, pulverized, passed through a 60-mesh sieve,
and stored in a desiccator until further use.
Characterization of LMG-β-CD Inclusion Complex
FTIR Spectrophotometry. Samples of LMG and the
LMG-β-CD inclusion complex were prepared in the form of
KBr pellets and scanned from 4000 to 400 cm−1
on a FTIR
spectrophotometer (Perkin-Elmer, Model Spectrum RX).
Differential Scanning Calorimetry. Differential scanning
calorimetry (DSC) thermograms were obtained on a differ-
ential scanning calorimeter (Perkin-Elmer, Shelton, USA).
Samples (5 mg) of LMG and LMG-β-CD inclusion com-
plexes were sealed in an aluminum pan and heated from 30 to
300°C at a heating rate of 10°C/min using an empty pan as a
reference under a purge of nitrogen (18 mL/min).
Powder XRD. The powder X-ray diffraction (XRD)
spectra of LMG and LMG-β-CD complexes were recorded
using an X-ray diffractometer (Rigaku Miniﬂex, Japan) with a
copper tube anode at a scanning rate of 5°/min and the
diffraction angle (2θ) in the range 0–80°.
Design of Experiment Approach: LMG ODTs
A two-level full factorial design (23
) with a center point
was adopted using Design Expert® 7 software to analyze the
effect of critical material attributes (A: concentration of
crospovidone) and critical process parameters (B:
microwave irradiation time and C: humidity exposure time)
on the desired critical quality attributes (Y1:disintegration
time and Y2: hardness). The variables and levels are
indicated in Table II.
LMG ODTs
For the preparation of LMG ODTs, the LMG-β-CD
inclusion complex equivalent to 25 mg LMG was mixed with
the diluents, disintegrants, and lubricants and the tablets
compressed as described in BDirect Compression^
Fig. 2. Phase solubility study of LMG in β-CD solution
Fig. 3. FTIR spectra of LMG (a), β-CD (b), and the LMG-β-CD complex (c)
Kande et al.

In Vitro Evaluation of LMG ODTs
ODTs were evaluated for standard tablet properties includ-
ing hardness, DT, weight variation, friability, and dimensions.
Drug content was determined by UV spectrophotometry
(UV1650PC, Shimadzu Corporation) at λmax of 276 nm.
Wetting Time
Wetting time was measured by placing the ODTs on a
tissue paper in a Petri dish (i.d. = 6.5 cm) containing 10 mL of
water and monitoring the time for complete wetting. Three
replicates were performed.
In Vitro Dissolution Study
In vitro dissolution (n = 6) was performed in 900 mL of 0.1 N
HCl maintained at 37 ± 0.5°C using USP type II dissolution
apparatus with sinkers (Electrolab, India) at a paddle speed of
50 rpm. At predetermined time intervals, 10 mL sample was
withdrawn and replaced with fresh medium (37°C). The drug was
quantiﬁed by UV spectrophotometry (UV1650PC, Shimadzu
Corporation) at λmax of 276 nm.
Scanning Electron Microscopy Analysis
ODTs were mounted on metal stubs using double-sided
adhesive tapes and scanned on a scanning electron micro-
scope (JSM-6510, Jeol, Japan). ODTs were evaluated before
and after microwave irradiation.
Taste-Masked LMG ODT Using an Electronic Tongue
ODT batches with ﬂavors (pineapple and vanilla) and
sweeteners are reported in Table III. Taste masking was optimized
using an electronic tongue. Placebo ODTs (labeled as DC7P–
DC13P, respectively) and the plain drug, LMG, served as reference.
Multisensor System
The potentiometric multisensor system employed in this
study contained 18 potentiometric membrane sensors and
Fig. 4. XRD patterns for Lamotrigine (a) and the LMG-β-CD complex (b)
Fig. 5. DSC thermograms of LMG and the LMG-β-CD complex

standard pH glass electrode (ZIP, Gomel, Belorussia). Ten
sensors were PVC-plasticized anion-sensitive electrodes and
six sensors were PVC-plasticized anion-sensitive electrodes
based on various ion exchangers and similar to those
employed earlier (19). Two sensors were based on
chalcogenide glass membranes with pronounced RedOx
sensitivity (a sensor sensitive to the reduction/oxidation
process on the electrode surface). All sensors were produced
in the Laboratory of Chemical Sensors of Saint Petersburg
State University. Sensor potentials were measured against a
Table IV. Experimental Design Model
Run order Parameters Response 1: DT
(s)
Response 2: hardness
(kg/cm2
)
A: Crospovidone
(%)
B: Microwave drying
(min)
C: Humidity exposure
(min)
1 −1 −1 −1 67.333 ± 1.52 3.066 ± 0.11
2 −1 +1 +1 50.666 ± 1.15 5.533 ± 0.11
3 +1 +1 −1 59.666 ± 0.57 6.533 ± 0.05
4 +1 −1 −1 15 ± 0.1 2.566 ± 0.11
5 +1 +1 +1 20.666 ± 1.15 5.933 ± 0.11
6 +1 −1 +1 24.333 ± 0.2 2.6 ± 0.1
7 −1 −1 +1 80.333 ± 0.57 2.533 ± 0.05
8 −1 +1 −1 110.33 ± 1.52 6.1 ± 0.45
9 0 0 0 20.666 ± 1.52 5.533 ± 0.05
* n = 3; 0 indicates center point
Fig. 6. Response surface plots of hardness as a function of the concentration of crospovidone (a), microwave irradiation
time (b), and humidity exposure time (c)
Kande et al.

Ag/AgCl reference electrode (Izmeritelnaya Tehnika, LLC
Moscow, Russia) with 0.1 mV precision using a high-
impedance multichannel digital mV-meter HAN-32 (Sensor
Systems, LLC, St. Petersburg, Russia). The mV-meter was
connected to a PC for data acquisition and processing.
Data Processing
Principal component analysis (PCA) is the method of
data dimensionality reduction and visualization of the hidden
data structure. Nowadays, it is widely employed in different
studies, and detailed descriptions of the mathematical calcu-
lations behind the PCA are available (20). Briefly, the PCA
algorithm looks for orthogonal directions of maximal vari-
ance in the initial multidimensional space and projects the
points on this new coordinate axis (principal components).
The main outcomes of PCA are so-called score and loadings
plots, visualizing similarity of the studied samples and the
information contained in the employed variables (sensor
responses in our case).
Stability Evaluation
LMG ODTs were packed in sealed HDPE bottles and
subjected to 40 ± 2°C/75% RH ± 5% and 30 ± 2°C/65 ± 5% as
per the ICH guidelines for 3 months. Samples were with-
drawn at 1, 2, and 3 months and evaluated for appearance,
hardness, DT, and drug content.
Fig. 7. Response surface plots of disintegration time as a function of the concentration of crospovidone (a), microwave
irradiation time (b), and humidity exposure time (c)
Table V. Regression Analysis
Term Tablet hardness (kg/cm2
) Disintegration time (s)
Coefficient p value Coefficient p value
A 0.050 0.1976 −21.79 <0.0001
B 1.68 <0.0001 4.96 0.0159
C −0.20 0.0330 −11.37 <0.0001
AB – – 1.62 0.3925
BC – – 0.29 <0.0001
AC – – −13.29 0.8767
ABC – – 4.88 0.0175
Constant 4.46 32.46
R2
= 0.9353 R2
= 0.9345

Statistical Analysis
All values are expressed as the mean ± SD of at least three
independent experiments. Statistical analysis was performed
using one-way ANOVAwith Dennett’s test and Student’s t tests.
P < 0.05 was the criterion for statistical significance.
RESULTS
Preparation of ODTs
Placebo ODTs
The various placebo ODT batches are reported in
Table I. It is evident from the table that exposure to humidity
prior to MWI reflected a significant change in both hardness
and DT. Although humidity exposure time did not influence
hardness, DT was significantly affected and inversely related
to the exposure time. The superdisintegrant, however, had a
significant role and influenced both hardness and DT. While
an increase in hardness was seen with all three
superdisintegrants, this increase was substantial with
crospovidone as the disintegrant. Interestingly, crospovidone
also reflected a very low DT of 14 s (DC3), while the DTs
seen with Ac-Di-Sol (DC1) and SSG (DC2) were significantly
greater than 60 s. Nevertheless, tablets with 10%
crospovidone (DC3) revealed a rough surface. A decrease
in crospovidone concentration resulted in an acceptable
appearance with a significant increase in hardness and a DT
of less than 1 min. Moreover, this was achieved with just
30 min of exposure to high humidity (D6).
ODT of LMG
The HPLC chromatogram following microwave irradia-
tion revealed no additional peaks, confirming the stability of
LMG to MWI, as shown in Fig. 1.
Phase Solubility Study of LMG-β-CD
The phase solubility plot revealed a linear increase in the
aqueous solubility of LMG as a function of β-CD concentra-
tion up to 10 mM (Fig. 2). The linear host–guest correlation
coefficient was r2
> 0.97 and the slope < 1, with a stability
constant K of 524.72/M.
Characterization of the LMG-β-CD Inclusion Complex
FTIR Interaction of β-CD with LMG in Solid State. The
FTIR spectra of LMG and the LMG-β-CD complex are shown
in Fig. 3. The infrared spectrum of LMG (Fig. 3a) is
characterized by vibration peaks at 3450 cm−1
(N–H aromatic),
3317 and 3213 cm−1
(C–H aromatic), 1630 cm−1
(C=N), and
1556 cm−1
(C=C). The FTIR spectra of β-CD (Fig. 3b) shows
peaks at 3377 cm−1
(O–H), 2926 cm−1
(C–H), 1157 cm−1
(C–H),
and 1080 cm−1
(C–O). The FTIR spectra of the LMG-β-CD
inclusion complex (Fig. 3c) shows broadening and reduction of
peak intensities of aromatic N–H, C–H, and C=N groups,
indicating interaction between LMG and β-CD.
Powder X-Ray Diffraction Analysis. The X-ray diffrac-
tion profile of LMG revealed a crystalline nature (Fig. 4a).
The XRD pattern of the LMG-β-CD (Fig. 4b) complex
exhibited peaks with a decrease in the intensity of peaks.
DSC Study. The DSC thermogram of LMG revealed a
sharp endothermic peak at 221°C which corresponds to the
Fig. 8. Design space overlay plot
Table VI. Optimization and Statistical Validation
Predicted
value
Observed
value
%
Deviation
T a b l e t
hardness
(kg/cm2
)
5.05 5.23 0.127
Disintegration
time (s)
23.44 22 1.018
Parameters: A = 5.5%, B = 3.5 min, and C = 30 min
Kande et al.

melting point of LMG (Fig. 5). This endotherm was not
exhibited by the LMG-β-CD complex.
DOE Approach
The design of experiment approach was applied to arrive
at the optimum LMG ODT formulation with rapid disinte-
gration and good hardness as the response parameters.
Crospovidone concentration, microwave irradiation time,
and humidity exposure time were selected as the variables.
The hardness and DT of the LMG ODTs are depicted in
Table IV. The main and interaction effects of the concentra-
tion of crospovidone, microwave irradiation time, and hu-
midity exposure time on the selected responses were
evaluated. Regression analysis was carried out and a p value
less than 0.05 was considered statistically significant. Stan-
dardized regression coefficients represent the positive or
negative effects of each parameter and their interactions on
each of the tablet properties. The coefficient of determination
(r2
), which was doubly adjusted with degrees of freedom, was
employed as an indicator of the model fit. The contour plots
revealed the effect of the variables on the hardness (Fig. 6)
and DT (Fig. 7) of the LMG ODTs. Values of 0.9353 and
0.9345 for the correlation coefficient R2
suggested good
correlation between the observed and model-predicted values
of hardness and DT, respectively (Table V). The overlay plot
(Fig. 8) depicts the design space representing optimal values
of the three variables to arrive at LMG ODTs with desirable
properties of DT < 30 s and hardness > 5 kg/cm2
.
We considered the following optimized conditions::A
(concentration of crospovidone) = 5.5%; B (microwave irradia-
tion time) = 3.5 min; and C (humidity exposure time) = 30 min,
as shown in Table VI. Our results confirm that both responses
were consistent with the predicted values, validating the
appropriateness of the experimental design. Optimized LMG
ODTs revealed that crospovidone exerted no effect on hard-
ness. A linear increase in hardness with an increase in
microwave irradiation time and a decrease with an increase in
humidity exposure time were observed. Concentration of
crospovidone and humidity exposure time revealed a negative
effect on DT, whereas microwave irradiation time exhibited a
positive effect. A negative interaction effect was seen between
crospovidone (A) and humidity exposure time (C).
Furthermore, friability of <1% was an indication of the
good mechanical resistance of the tablet. The thickness was in
Fig. 9. Tablet wetting time images at various stages
Fig. 10. Scanning electron microscope images of the internal surface of untreated (a) and
microwave-treated (b) tablets (arrows indicate porosity)

the range of 2.24 ± 0.07 mm, and the drug content was
99.13%, which was within acceptable limits. Tablets exhibited
complete wetting in 16 s (Fig. 9). SEM images of the tablet
surface before and after microwave irradiation are depicted
in Fig. 10. A porous surface was clearly evident in the
microwave-irradiated tablets (Fig. 10b).
In Vitro Drug Release
The dissolution profiles of LMG and the optimized LMG
ODTs are shown in Fig. 11. While the optimized LMG ODTs
released nearly 100% of the drug within 5 min, LMG
exhibited a release of barely 50% at 30 min.
Taste Masking
Figure 12 shows the PCA score plot obtained for all
analyzed samples. The score plot provides a clear separation of
LMG and LMG ODTs from the placebo ODTs along the PC1
axis. All placebo samples are located on the left part of the plot
and have negative score values on PC1; all samples with LMG are
on the right side of the plot. The observed separation can be
attributed to the sensitivity of the sensor array towards the
studied drug. Separate PCA analysis of all active pharmaceutical
ingredient (API) samples reveals that certain separation of
formulations with different taste masking is also possible using a
potentiometric multisensor system. The PCA score plot shown in
Fig. 13 suggests that formulations DC7, DC9, DC10, and DC12
are more similar to LMG in terms of sensor responses indicating
bitterness compared to formulations DC8, DC11, and DC13. The
data also suggested that good taste masking was achieved simply
by the addition of vanilla flavor without the need for sucralose
(DC 11), confirming the role of β-CD in taste masking.
Stability Study
Optimized ODT formulation was evaluated for stability.
No significant difference in appearance, disintegration time,
hardness, weight variation, and drug content was observed,
confirming the stability of LMG ODTs (Table VII).
DISCUSSION
Development of ODTs presents a delicate balance of
high mechanical strength with low disintegration time. Direct
compression as a process for the manufacture of ODTs has
manifold advantages, including scalability, high capacity, and
being a solvent-free process. The excipients that impart
hardness usually increase the disintegration time. Hence,
MWI was evaluated as a strategy to increase hardness with a
corresponding decrease in DT. Mannitol is an excipient of
choice for ODTs due to its negative heat of solution and
pleasant taste. It is available as α-, β-, and δ-crystalline
polymorphs (21). Furthermore, the effect of microwave
irradiation on mannitol results in the conversion of the δ-
form to the stable β-form, with a corresponding increase in
the hardness of the tablets, and no compromise on DT is
demonstrated (10). We therefore selected mannitol as the
diluent in our study. As tablets with mannitol alone exhibited
high friability, we arrived at a diluent combination of
mannitol and lactose for the development of ODTs.
The effects of MWI on tablet hardness and porosity are
related entirely to the water vapor generated. Microwave
irradiation causes vibrations in water molecules at high
velocities, resulting in partial conversion to water vapor.
While the dissolution of mannitol in this water vapor and
subsequent solidification enabled the formation of solid
bridges to increase the hardness, the water vapor-induced
expansion of the tablet mass facilitated enhanced porosity
and, hence, low DT. It is therefore evident that water is a
crucial requirement in ODT development using MWI. To
adapt the advantage of MWI to direct compression, a dry
Fig. 11. Dissolution profiles of LMG ODT and for LMG drug
Fig. 12. PCA score plot for analyzed samples (API-containing
samples are marked with filled points, while placebo samples are
marked with empty points)
Fig. 13. PCA score plot for API samples
Kande et al.

process, we proposed one simple additional step, that of
exposure of ODTs to controlled humidity (>95%RH) for
predetermined time periods prior to microwave irradiation.
The increased hardness and the decrease in DT observed
confirmed the effects of MWI on the ODTs.
The significant decrease in DT seen with crospovidone
is attributed to the high capillarity and the resulting rapid
water absorption (22). On the other hand, the swelling
disintegrants Ac-Di-Sol and SSG exhibited core formation,
which hampered disintegration (23–25). A decrease in
crospovidone concentration favored good appearance with
desired DT. The successful exploitation of MWI in the
development of placebo ODTs triggered us to design LMG
ODTs.
LMG is a low-molecular-weight (256 g/mol) BCS class II
drug which exhibits poor solubility and also has a bitter taste.
β-CD is a good solubilizer, stabilizer, and a known taste
masking agent specifically for low-molecular-weight drugs
which can readily be entrapped in the β-CD cavity. A stable
inclusion complex of LMG/β-CD at a 1:1 ratio, which
correlated with the Higuchi and Connors linear model
relationship, was obtained, as confirmed by the high K value
(17). Interaction of LMG with β-CD, as seen in the FTIR
spectra, is indicative of solubility enhancement, while inter-
actions specifically involving N groups also suggest taste
masking (26). The DSC thermogram and XRD spectra, which
indicated a significant decrease in crystallinity with possible
partial amorphization, also proposed an enhanced dissolution
rate (27).
LMG ODTs were successfully optimized by DOE to
obtain LMG ODTs with hardness of 5.23 kg/cm2
and DT of
22 s. The positive interaction effect seen between the
concentration of crospovidone, microwave irradiation time,
and humidity exposure time on DT proposed that all three
variables were critical. The enhanced dissolution rates
confirmed the role of β-CD as a solubilizer for LMG, with
improvement in LMG wettability and formation of readily
soluble complexes in the dissolution medium enabling
enhanced dissolution (28).
The added difficulty with LMG was its bitter taste.
Various strategies like ion exchange resin (29,30), complexa-
tion with cyclodextrin (31,32), microencapsulation (33,34),
film coating (35), flavors and sweeteners (36,37), and
rheological modification (38) have been used to mask the
bitter taste of drug. The potentiometric multisensor system
coupled with principal component analysis confirmed that the
LMG-β-CD inclusion complex in combination with vanilla
flavor enabled successful taste masking of LMG ODTs.
CONCLUSION
We present an innovative yet simple and green approach
for the preparation of ODTs by direct compression coupled
with MWI. This technology is versatile, scalable, and adapt-
able to a range of drugs. More importantly, this approach was
successfully extrapolated for the design of LMG ODTs which
also exhibited good palatability with rapid dissolution of the
drug.
ACKNOWLEDGEMENTS
The authors are thankful to the University Grants
Commission, Government of India, Department of Science
& Technology (DST), Government of India and Russian
Foundation for Basic Research (grant INT/RUS/RFBR/P-195
and RFBR no. 15-53-45105), and DST Prime Ministers
Fellowship for financial support. Dmitry Kirsanov and
Andrey Legin acknowledge partial financial support from
Government of Russian Federation (grant 074-U01).
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