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Original Article
HME-assisted formulation of taste-masked dispersible tablets of
cefpodoxime proxetil and roxithromycin
Prathamesh S. Patil, M. Pharm
a
,
b
, Sushank J. Suryawanshi, M. Pharm
b
,
Sharvil S. Patil, M. Pharm, Ph.D.
a
and Atmaram P. Pawar, M. Pharm, Ph.D.
a
,
*
a
Department of Pharmaceutics, Bharati Vidyapeeth (Deemed to be University), Poona College of Pharmacy, Pune,
Maharashtra, India
b
STEERLife India Pvt. Ltd, Bengaluru, Karnataka, India
Received 3 June 2023; revised 10 November 2023; accepted 13 December 2023; Available online 21 December 2023
ﺍﻟﻤﻠﺨﺺ
ﺃﻫﺪﺍﻑﺍﻟﺒﺤﺚ:ﺍﻟﻤﻀﺎﺩﺍﺕﺍﻟﺤﻴﻮﻳﺔﻫﻲﺍﻷﺩﻭﻳﺔﺍﻷﻛﺜﺮﺷﻴﻮﻋﺎﺑﻴﻦﺍﻟﻤﺮﺿﻰ
ﺍﻷﻃﻔﺎﻝ.ﻭﻣﻊﺫﻟﻚ،ﻓﻲﻣﻌﻈﻢﺍﻷﺣﻴﺎﻥ،ﻳﺼﺒﺢﺇﻋﻄﺎﺀﺍﻟﺠﺮﻋﺔ
ﺍﻟﺪﻗﻴﻘﺔﻟﻸﻃﻔﺎﻝ
ﻣﺸﻜﻠﺔﺑﺴﺒﺐﻣﺬﺍﻗﻪﺍﻟﻤﺮﻟﻠﻐﺎﻳﺔ.ﻳﻌﺪﺳﻴﻔﺒﻮﺩﻭﻛﺴﻴﻢﺑﺮﻭﻛﺴﻴﺘﻴﻞﻭﺭﻭﻛﺴﻴﺜﺮﻭﻣﻴﺴﻴﻦ
ﺃﺣﺪﺍﻟﻤﻀﺎﺩﺍﺕﺍﻟﺤﻴﻮﻳﺔﺍﻟﺘﻲﺗﻮﺻﻒ
ﻏﺎﻟﺒﺎﻟﻸﻃﻔﺎﻝﻭﻟﻬﺎﻃﻌﻢﻣﺮﻳﺮ.ﺍﻟﺘﺮﻛﻴﺒﺎﺕ
ﺍﻟﻤﺴﻮﻗﺔﻟﻬﺬﻩﺍﻷﺩﻭﻳﺔﻫﻲﻣﻌﻠﻖﺟﺎﻑﻭ/ﺃﻭﺃﻗﺮﺍﺹ.ﻣﻦﺍﻟﻤﻌﺮﻭﻑﺃﻥﻃﺮﻳﻘﺔ
ﺍﻟﺘﺠﻔﻴﺪﺗﺘﻀﻤﻦﺧﻄﻮﺍﺕ
ﻣﺨﺘﻠﻔﺔﻭﺑﺎﻟﺘﺎﻟﻲﻓﻬﻲﺗﺴﺘﻐﺮﻕﻭﻗﺘﺎﻃﻮﻳﻼﻭﻣﻜﻠﻔﺔ.ﻛﺎﻥ
ﺍﻟﻬﺪﻑﻣﻦﻫﺬﻩﺍﻟﺪﺭﺍﺳﺔﻫﻮﺇﺧﻔﺎﺀﺍﻟﻄﻌﻢﺍﻟﻤﺮﻟﺴﻴﻔﺒﻮﺩﻭﻛﺴﻴﻢﺑﺮﻭﻛﺴﻴﺘﻴﻞ
ﻭﺭﻭﻛﺴﻴ
ﺜﺮﻭﻣﻴﺴﻴﻦﺩﻭﻥﺍﻟﻤﺴﺎﺱﺑﺎﻟﺬﻭﺑﺎﻥﻭﺷﻜﻞﺇﻃﻼﻕﺍﻟﺪﻭﺍﺀﻋﻨﺪﻣﻘﺎﺭﻧﺘﻪ
ﺑﺎﻟﺘﺮﻛﻴﺒﺎﺕﺍﻟﻤﺴﻮﻗﺔ.ﺑﺎﻹﺿﺎﻓﺔﺇﻟﻰﺍﻟﺘﻐﻠﺐﻋﻠﻰﺍﻟﻌﻴﻮﺏﺍﻟﻤﺮﺗﺒﻄﺔﺑ
ﺘﻘﻨﻴﺔﺍﻟﺘﺠﻔﻴﺪ
ﺍﻟﻤﺴﺘﺨﺪﻣﺔﺣﺎﻟﻴﺎ.
ﻃﺮﻳﻘﺔﺍﻟﺒﺤﺚ:ﺗﻢﺍﺳﺘﺨﺪﺍﻡﺗﻘﻨﻴﺔﺍﻟﺒﺜﻖﺑﺎﻟﺬﻭﺑﺎﻥﺍﻟﺴﺎﺧﻦﻟﻤﻌﺎﻟﺠﺔﺳﻴﻔﺒﻮﺩﻭﻛﺴﻴﻢ
ﺑﺮﻭﻛﺴﻴﺘﻴﻞﻭﺭﻭ
ﻛﺴﻴﺜﺮﻭﻣﻴﺴﻴﻦﺑﺸﻜﻞﻓﺮﺩﻱﺑﺎﺳﺘﺨﺪﺍﻡﺑﻮﻟﻴﻤﺮﻳﻮﺩﺭﺍﺟﻴﺖﺇﻳﺒﻮ.ﺗﻢ
ﺗﺸﺨﻴﺺﺍﻟﺒﺜﻘﺎﺕﺍﻟﺘﻲﺗﻢﺍﻟﺤﺼﻮﻝﻋﻠﻴﻬﺎﺑﻮﺍﺳﻄﺔﺍﻟﺘﺤﻠﻴﻞﺍﻟﻄﻴﻔﻲﻟﻸﺷﻌﺔ
ﺗﺤﺖ
ﺍﻟﺤﻤﺮﺍﺀﻟﺘﺤﻮﻳﻞﻓﻮﺭﻳﻴﻪ،ﻭﻗﻴﺎﺱﻧﻤﻂﺍﻟﺤﻴﻮﺩﻟﻠﻤﻮﺍﺩﺍﻟﺒﻠﻮﺭﻳﺔﻭﻗﻴﺎﺱﺍﻟﺴﻌﺮﺍﺕ
ﺍﻟﺤﺮﺍﺭﻳﺔﺑﺎﻟﻤﺴﺢﺍﻟﺘﻔﺎﺿﻠﻲ.ﺗﻤﺖﺻﻴﺎﻏﺔﺍﻟﺒﺜﻘﺎﺕ
ﺍﻟﻤﺴﺤﻮﻗﺔﻛﺄﻗﺮﺍﺹﻗﺎﺑﻠﺔﻟﻠﺘﺸﺘﺖ
ﻭﺗﻢﺗﻘﻴﻴﻤﻬﺎﻣﻦﺣﻴﺚﻛﻔﺎﺀﺓﺇﺧﻔﺎﺀﺍﻟﻄﻌﻢﺩﺍﺧﻞﺍﻟﻤﺨﺘﺒﺮﻭﻓﻲﺍﻟﺠﺴﻢﺍﻟﺤﻲ.
ﺍﻟﻨﺘﺎﺋﺞ:ﺃﻇﻬﺮﺕﺍﻷﻗﺮﺍﺹﺍﻟﻤ
ﺤﻀﺮﺓﻓﻲﻫﺬﻩﺍﻟﺪﺭﺍﺳﺔﻣﻼﻣﺢﺫﻭﺑﺎﻥﻗﺎﺑﻠﺔ
ﻟﻠﻤﻘﺎﺭﻧﺔﻭﻟﻜﻦﺗﻢﺗﻌﺰﻳﺰﻛﻔﺎﺀﺓﺇﺧﻔﺎﺀﺍﻟﻄﻌﻢﺑﺸﻜﻞﻛﺒﻴﺮﻋﻨﺪﻣﻘﺎﺭﻧﺘﻬﺎﺑﺎﻷﻗﺮﺍﺹ
ﺍﻟﻤﺴﻮﻗﺔﻣﻦﺳﻴ
ﻔﺒﻮﺩﻭﻛﺴﻴﻢﺑﺮﻭﻛﺴﻴﻞﻭﺭﻭﻛﺴﻴﺜﺮﻭﻣﻴﺴﻴﻦ.ﻭﻛﺎﻧﺖﻧﺘﺎﺋﺞﺗﻘﻴﻴﻢﺇﺧﻔﺎﺀ
ﺍﻟﻄﻌﻢﺍﻟﺒﺸﺮﻱﺩﺍﺧﻞﺍﻟﺠﺴﻢﻣﺘﻔﻘﺔﺃﻳﻀﺎﻣﻊﺩﺭﺍﺳﺎﺕﺇﺧﻔﺎﺀﺍﻟﺘﺬﻭﻕﺩﺍ
ﺧﻞﺍﻟﻤﺨﺘﺒﺮ.
ﺍﻻﺳﺘﻨﺘﺎﺟﺎﺕ:ﻭﺑﺎﻟﺘﺎﻟﻲﻓﺈﻥﺍﻟﻌﻤﻞﺍﻟﺤﺎﻟﻲﻗﺪﻗﺪﻡﺗﻜﻨﻮﻟﻮﺟﻴﺎﺍﻟﺒﺜﻖﺑﺎﻟﺬﻭﺑﺎﻥﺍﻟﺴﺎﺧﻦ
ﺍﻟﺨﺎﻟﻴﺔﻣﻦﺍﻟﻤﺬﻳﺒﺎﺕﻭﺍﻟﻘﺎﺑﻠﺔ
ﻟﻠﺘﻄﻮﻳﺮﻭﺍﻟﻤﺴﺘﻤﺮﺓﻟﻤﻌﺎﻟﺠﺔﻣﺸﻜﻼﺕﺍﻟﻄﻌﻢﺍﻟﻤﺮﻓﻲ
ﺳﻴﻔﺒﻮﺩﻭﻛﺴﻴﻢﺑﺮﻭﻛﺴﻴﺘﻴﻞﻭﺭﻭﻛﺴﻴﺜﺮﻭﻣﻴﺴﻴﻦ.ﻋﻼﻭﺓﻋﻠﻰﺫﻟﻚ،ﺗﻢﺍﻟﺘﻐﻠﺐﻋﻠﻰ
ﺍﻟﻌﻴﻮ
ﺏﺍﻟﻤﺮﺗﺒﻄﺔﺑﺘﻘﻨﻴﺔﺍﻟﺘﺠﻔﻴﺪﺍﻟﻤﺴﺘﺨﺪﻣﺔﺣﺎﻟﻴ
ً
ﺎﻣﻦﺧﻼﻝﺗﻄﻮﻳﺮﺍﻟﺘﺮﻛﻴﺒﺎﺕ
ﺑﺎﺳﺘﺨﺪﺍﻡﺗﻘﻨﻴﺔﺍﻟﺒﺜﻖﺑﺎﻟﺬﻭﺑﺎﻥﺍﻟﺴﺎﺧﻦ.
ﺍﻟﻜﻠﻤﺎﺕﺍﻟﻤﻔﺘ
ﺎﺣﻴﺔ:ﺇﺧﻔﺎﺀﺍﻟﻄﻌﻢ؛ﺃﻗﺮﺍﺹﻗﺎﺑﻠﺔﻟﻠﺘﺸﺘﺖ؛ﺍﻟﺒﺜﻖﺑﺎﻟﺬﻭﺑﺎﻥﺍﻟﺴﺎﺧﻦ؛
ﻳﻮﺩﺭﺍﺟﻴﺖﺇﻳﺒﻮ؛ﺍﻟﺬﻭﺑﺎﻥ
Abstract
Objectives: Antibiotics are the most commonly adminis-
tered medications among pediatric patients. However
most of the time, accurate dose administration to children
becomes a problem due to the extremely bitter taste.
Cefpodoxime proxetil (CP) and roxithromycin (ROX) are
antibiotics often prescribed to the pediatric population
and have a bitter taste. Marketed formulations of these
drugs are dry suspension and/or tablets. The lyophiliza-
tion method involves various steps and thus is time
consuming and expensive. The objective of this study was
to mask the bitter taste of CP and ROX without
compromising the solubility and drug release profile
compared to marketed formulations, as well as to over-
come the disadvantages associated with the currently
used lyophilization technique.
Methods: Hot melt extrusion (HME) technology was
used to process CP and ROX individually with Eudragit
E PO polymer. The extrudates obtained were character-
ized by Fourier transform infrared spectroscopy, powder
*Corresponding address: Department of Pharmaceutics, Bharati
Vidyapeeth (Deemed to be University), Poona College of Phar-
macy, Pune, Maharastra, India.
E-mail: atmaram.pawar@bharatividyapeeth.edu (A.P. Pawar)
Peer review under responsibility of Taibah University.
Production and hosting by Elsevier
Taibah University
Journal of Taibah University Medical Sciences
www.sciencedirect.com
1658-3612 Ó2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.jtumed.2023.12.004
Journal of Taibah University Medical Sciences (2024) 19(2), 252e262
X-ray diffraction, and differential scanning calorimetry.
The powdered extrudates were formulated as dispersible
tablets and evaluated for in vitro and in vivo taste-
masking efficiency.
Results: The tablets prepared in this study showed com-
parable dissolution profiles but the taste-masking effi-
ciency was significantly enhanced compared to the
marketed tablets of CP and ROX. The results of in vivo
human taste-masking evaluation were also in agreement
with the in vitro taste-masking studies.
Conclusion: The current work presents solvent-free,
scalable, and continuous HME technology for address-
ing the bitter taste issues of CP and ROX. The disad-
vantages associated with the currently used lyophilization
technique were overcome by developing the formulations
using HME technology.
Keywords: Dispersible tablets; Dissolution; Eudragit EPO;
Hot melt extrusion; Taste masking
Ó2023 The Authors. Published by Elsevier B.V. This is an
open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Antibiotics are the most commonly administered medica-
tions in the pediatric population, and are reportedly prescribed
to one in five pediatric patients.
1
The main problem associated
with the administration of such medications is that they are
very bitter in taste, making them aversive to children and in
turn difficult for parents to administer the required dose.
Additionally, some widely used antibiotics have low
bioavailability due to their poor aqueous solubility. There are
several techniques including cyclodextrin complexation,
microencapsulation, granulation, formulation of beads, solid
dispersion with polymers having pH-dependent solubility,
and formulation of nanoparticles to address the bitter taste and
solubility issues of drugs.
2e4
Among these techniques, solid
dispersion is the most widely used due to its advantages such
as conversion into amorphous form; improved surface area
by particle size reduction; and improved wettability, porosity,
and dispersion into an inert polymer or matrix, which in turn
enhance the solubility and oral bioavailability of
Biopharmaceutical Classification System (BCS) class II
drugs. Furthermore, the dispersion of bitter tasting drugs
into the polymer matrix also has taste-masking effects.
5
Solid
dispersion of drug and polymer can be achieved by methods
such as solvent, melting, melt extrusion, and lyophilization
methods.
Cefpodoxime proxetil (CP) is a broad-spectrum third-
generation cephalosporin antibiotic, which is a prodrug that
is hydrolyzed to its active metabolite cefpodoxime. It acts by
binding to the penicillin-binding proteins of bacteria,
impairing bacterial cell wall synthesis. It is mainly prescribed
for upper respiratory tract and urinary tract infections. CP is
slightly alkaline, amorphous in nature, and absorbed from
the gastrointestinal tract after oral administration. It has low
bioavailability due to its poor aqueous solubility (0.103 mg/
mL), gelation behavior in an acidic environment, and
luminal metabolism.
6e11
Furthermore, CP is highly
hygroscopic and unstable in water and hence it is given in
the form of dry powder for reconstitutable suspension. The
reconstituted suspension once produced, needs to be stored
in the refrigerator and used within 1 week. It is well known
that such reconstitutable suspensions are formulated by the
lyophilization technique. Nevertheless, the lyophilization
method has disadvantages, including extended handling
and processing time, the necessity for a sterile diluent
during reconstitution, the use of expensive equipment, and
significantly, its batch nature, which leads to longer
production times and higher costs for the final product due
to reduced output for the manufacturing company.
12
The second antibiotic roxithromycin (ROX) is a semi-
synthetic macrolide derived from erythromycin containing a
14-membered lactone ring. It acts by binding to the 50S ribo-
some, thereby inhibiting protein synthesis in both gram-
positive and gram-negative bacteria. ROX is extremely bitter
in taste and has poor bioavailability due to poor aqueous sol-
ubility (0.187 mg/mL).
13e16
Hot melt extrusion (HME) is an
emerging technology due to its scalable, continuous, and
solvent-free process and multiple applications such as taste
masking, stabilizing the active ingredients, solubility enhance-
ment, delayed or controlled release formulations, and fabri-
cation of implants. HME is a process that leads to formation of
a homogeneous mixture of drug and polymer by the applica-
tion of heat and pressure.
17
Furthermore, HME has been
efficiently used for taste masking bitter drugs. CP and ROX
used in the present study are bitter in nature.
The objective of the present study was to address the
bitter taste and low aqueous solubility issues of CP and ROX
using commercially viable HME technology. Furthermore,
development of the HME processing technique for these two
antibiotics individually would lead to a reduction in the
processing cost associated with the currently used lyophili-
zation technique and associated packaging. Considering the
same, the preparation of dispersible tablets of CP and ROX
individually using HME was attempted, which would pro-
vide ease of handling, taste-masking efficiency, and patient
acceptability.
Materials and Methods
Materials
CP and roxithromycin were donated by Lupin Ltd.
(Pradesh, India) and Century Pharmaceuticals Ltd. (Vado-
dara, India), respectively. Eudragit EPO (E-EPO) was ob-
tained as a gift sample from Evonic India Pvt. Ltd. (Mumbai,
India). All other excipients such as polyethylene glycol 6000
(PEG 6000), stearic acid, mannitol, crospovidone, silicon
dioxide, magnesium stearate, and flavoring were purchased
from Sigma Aldrich (St. Louis, MO, USA). All chemicals
used were of analytical grade.
P.S. Patil et al. 253
Methods
Preformulation studies
Drug excipient compatibility study using Fourier transform infrared
spectroscopy.
Fourier transform infrared spectroscopy
(FTIR) spectra of CP, ROX alone, E-EPO, and their phys-
ical mixture were obtained using the Jasco IR Spectropho-
tometer (FT/IT-4100; Jasco Inc., Easton, MD, USA) to
investigate if there was any interaction between the drug and
excipients. FTIR spectrum of the extruded batch was also
recorded to analyze the degradation of the drug molecules.
The powder samples were triturated with potassium bromide
and filled into the die of an equipment to examine the sam-
ples by infrared spectroscopy within the range of 400e
4000 cm
1
.
Analytical method for CP
Analysis of CP for its assay, solubility, drug release, and
in vitro taste-masking assessment was done with an ultravi-
olet (UV) spectrophotometer at different wavelengths. To
study the assay, methanol was used as a solvent. Serial di-
lutions of CP in different media such as methanol, glycine
buffer (pH 3), and simulated salivary media (pH 6.8) were
prepared and the absorbance was recorded at
l
max
of 235 nm
for methanol and 259 nm for glycine buffer and simulated
salivary media. The recorded absorbance was plotted against
concentration to calculate the standard regression equation
and regression coefficient (R
2
).
High-performance liquid chromatography for roxithromycin
For the analysis of roxithromycin, high-performance
liquid chromatography (HPLC) was used. The Jasco chro-
matographic system with a UV detector was used. The
Kromasil C18 HPLC Column (150 4.6 mm; Kromasil,
Bohus, Sweden) with the mobile phase consisting of aceto-
nitrile and ammonium dihydrogen phosphate (4.8% w/v)
buffer pH adjusted to 5.3 at a ratio of 3:7 was used. The UV
detection wavelength was 205 nm. The column temperature
was maintained at 25
C.
Preparation methods
Optimizing the parameters for HME using placebo.
Extrusion was
done with only E-EPO and EPO with plasticizers in different
concentrations to optimize the parameters such as barrel
temperature, screw speed, feed rate, and amount of plasti-
cizer to be added for obtaining clear, plastic, and uniform
extrudates using a co-rotating twin screw extruder (10 mm,
Steer omicron 10P; STEERLife India Pvt. Ltd., Bangalore,
India). The barrel temperature was in the range of 80
Ce
110
C and the screw speed was in the range of 100e300 rpm
while keeping the feed rate constant at 2 g/min. To reduce the
processing temperature and obtain plastic extrudates, E-
EPO was extruded with varying amounts of plasticizer PEG
6000 in varying ranges of 2%e10%.
Preparation of hot melt extrudates of CP
CP and E-EPO with PEG 6000 (5%) as a plasticizer was
first blended using the geometric blending method in a pol-
ybag followed by passing the blend from sieve mesh #40. The
drug-loading amount varied from 10% to 40%, keeping the
quantity of plasticizer constant. The uniformly blended and
mesh-passed mixtures of drug and polymer were extruded
using a co-rotating twin screw extruder at 75
C with a screw
speed of 150 rpm. The extrudates were further milled using a
ball mill and passed from sieve mesh #60 before further
processing.
Preparation of hot melt extrudates of roxithromycin
Roxithromycin, E-EPO, PEG 6000, and stearic acid (5%
each) were first blended using a geometric blending method
in a polybag followed by passing the blend from sieve mesh
#40. The drug-loading amount varied from 10% to 40%,
keeping the quantity of plasticizer and stearic acid constant.
The uniformly blended and mesh-passed mixtures of drug
and polymer were extruded using a co-rotating twin screw
extruder at 100
C with a screw speed of 150 rpm. The
extrudates were further milled using a ball mill and passed
from sieve mesh #60 before further processing.
Optimizing drug loading using solubility studies
All of the batches processed in different concentrations
were studied for solubility to finalize the drug loading. The
solubility of CP and ROX was assessed in their standard
prescribed media glycine buffer (pH 3) and phosphate buffer
(pH 6), respectively. The excess quantity of samples of
different batches was added to 100 mL of each dissolution
media and kept in a mechanical shaker water bath main-
taining the temperature of 37 0.5
C. Samples were
collected at various time points of 15, 30, 60, 120, and
240 min, and 24 h. The filtered samples (0.45
m
m syringe
filter) were analyzed spectroscopically for CP and by HPLC
for ROX.
Powder X-ray diffraction
The physical form of the drug (CP and ROX), excipients,
their physical mixture, and milled extrudates was determined
using powder X-ray diffraction (PXRD). The study was
performed with the Thermo Scientific ARL EQUINOX 100
Powder X-ray Diffractometer (Thermo Fisher Scientific,
Waltham, MA, USA) at room temperature using CuK
a
ra-
diation at 15 mA and 30 kV, 4
C min
1
. The samples were
scanned in the range of diffraction angles (2
q
)of1e100
.
Differential scanning calorimetry
The physical state, thermal and melting behavior of active
pharmaceutical ingredients (API) alone (CP and ROX), ex-
cipients, their physical mixtures, and milled extrudates were
examined by differential scanning calorimetry (DSC) (Met-
tler-Toledo 823e; Mettler Toledo, Columbus, OH, USA). A
small quantity of sample (2e3 mg) was placed in pierced
aluminum pans and heated from 30 to 200
C at a heating
rate of 10
C min
1
in a nitrogen atmosphere.
Preparation and evaluation of dispersible tablets
Flow properties of granules.
Milled extrudates or granules were
evaluated for their flow properties and compressibility.
Micromeritic properties such as bulk density, tapped density,
Hausner’s ratio, Carr’s compressibility index, and angle of
repose of milled extrudates were investigated using the
Electrolab Tap Density Tester ETD-1020X and Electrolab
Manual Powder Flow Tester ETF-01 (Electrolab, Mumbai,
India). All granules taken for the evaluation were passed
through mesh #60. Bulk density (
r
B
) was calculated by the
equation
r
B
¼M/V
B
, by placing 30 g (M ¼the mass of
Dispersible tablets of CP and ROX254
granules) of the granules in a 100 mL graduated measuring
cylinder to measure the bulk volume (V
B
). Tap density (
r
T
)
was calculated by the equation
r
T
¼M/V
T
, by placing 30 g of
the granules in a 100 mL graduated measuring cylinder fol-
lowed by tapping 100 times with the tap density apparatus,
after which the volume (V
T
)was recorded. Hausner’s ratio
was calculated with the formula
r
T
/
r
B
, while Carr’s
compressibility index was calculated with the formula
CI ¼(
r
T
r
B
)/
r
T
100.
Drug content
To determine the actual drug content in the respective
extrudates, the assay was performed in a methanol and sol-
vent mixture for CP and ROX, respectively, as given in the
Indian Pharmacopoeia (IP). The solvent mixture for ROX
was acetonitrile and ammonium dihydrogen phosphate
(4.8% w/v) buffer pH adjusted to 5.3 at a ratio of 3:7. Then
333.33 and 500 mg milled extrudes or granules of fixed drug
content equivalent to 100 mg were dissolved in their
respective solvents, diluted appropriately, and analyzed for
drug content using the previously reported analytical
methods.
Preparation of dispersible tablets of CP and ROX
For the preparation of CP tablets, a 30% drug-loading
batch was selected based on the solubility and taste-
masking efficiency. Similarly, for ROX tablets, a 20%
drug-loading batch was finalized. All tablets were prepared
by the direct compression method. The quantity of milled
extrudates was decided based on calculating % assay along
with maintaining the standard dose of respective drugs
(348.99 mg for CP and 387.37 mg for ROX). Other excipients
such as crospovidone, silicon dioxide (aerosil), mannitol,
magnesium stearate, and flavor were optimized by taking
trials with varying concentrations of crospovidone in the
range of 1%e5% and within the minimum required amount
(Table 1). The uniformly mixed blend was passed through
mesh #40, and tablets were punched with adjusting
compression force as per the requirement (18e24 kN) in
hardness, thickness, and disintegration time.
Tablet characterization
The prepared tablets were evaluated in different physical
aspects such as hardness, thickness, friability, disintegration
time, and uniformity of dispersion. Hardness was determined
with the ERWEKA hardness tester (ERWEKA GmbH,
Langen, Germany), the thickness was determined with a
digital vernier caliper (Insize Co., Ltd., Suzhou, China),
friability was determined with the Electrolab friabilator
(Electrolab), and disintegration time was assessed with the
Electrolab disintegration apparatus (Electrolab). For the
uniformity of dispersion test, as per IP, two tablets of CP and
ROX each were dispersed in 100 mL distilled water at 25
C
with gentle stirring until they were completely dispersed. A
smooth dispersion was obtained, which was passed through
sieve mesh #22.
In vitro taste-masking evaluation
To study the taste-masking efficiency of tablets in vitro,
the amount of drug release in the simulated salivary fluid (pH
6.8) was recorded. Simulated salivary media was prepared
according to the composition previously reported.
5
The test
was performed at a temperature of 37 0.5
C, 50 rpm,
and 150 mL media. The study was done for only 120 s
considering the residence time in the mouth. The samples
were collected at predetermined time intervals of 10, 20, 30,
60, 90, and 120 s and drug concentration was estimated
using previously described analytical instruments.
In vivo taste-masking evaluation
For the confirmatory test of taste-masking efficiency, the
CP and ROX tablets were analyzed in vivo with human taste
panel studies. In vivo taste-masking evaluation of formulated
and marketed tablets of both CP and ROX was performed
according to the Code of Ethics of the World Medical As-
sociation (Declaration of Helsinki). Considering the in vitro
taste-masking efficiency of the prepared tablets and the
holding time of 60 s in the mouth, the study did not require
approval; however, written consent from the participating
volunteers was obtained. Six healthy volunteers were selected
randomly within the same age group (18e45) of either sex
(i.e., three males and three females). After properly training
the volunteers, they were given the formulated tablets indi-
vidually and told to hold them in their mouths for 60 s and
then spit them out followed by rinsing their mouth with
water. The taste-masking efficiency or bitterness was recor-
ded by obtaining the score by volunteers from 1 to 5 (i.e., 1, 2,
3, 4, and 5 indicate bitterness of none, slightly bitter,
moderately bitter, bitter, and strongly bitter, respectively).
The same procedure was repeated for the marketed tablets to
compare the bitterness.
In vitro dissolution study of dispersible tablets
The dissolution study of the tablets was conducted in
900 mL medium glycine buffer (pH 3.0) for CP and phos-
phate buffer (pH 6.8) for ROX tablets. The USP Type II
Electrolab Dissolution Test Apparatus (Electrolab) was used
with a media temperature of 37 0.5
C at 100 rpm for
120 min. The samples were withdrawn at time points of 5, 15,
30, 45, 60, 90, and 120 min and analyzed for their content
with the Shimadzu UV Spectrophotometer (Shimadzu,
Columbia, MD, USA) for CP and the Waters HPLC-UV
system (Waters, Milford, MA, USA) for ROX. Sink condi-
tions were maintained throughout the dissolution test.
Results
Preformulation studies
Polymer selection
To accomplish the primary objective of taste masking
selected drugs, it was necessary that the polymer used release
the minimum amount of drug in the mouth (i.e., saliva without
compromising solubility at another gastric pH).
18
Considering
the same from the literature survey, we pointed out that the E-
EPO could be the polymer of choice to mitigate the set
objective. Once theoretically finalized, it is important to
analyze the compatibility of APIs and excipients before
proceeding with formulation development. To this end,
FTIR studies were performed.
P.S. Patil et al. 255
Drug excipient compatibility study using FTIR
The FTIR spectra of CP depicted % transmittance bands
at wavelengths of 2988.16 cm
1
and 2938.02 cm
1
corre-
sponding to CeH stretching, 1782.87 cm
1
for C]O
stretching, 1677.77 cm
1
for NeH stretching, 1618.95 cm
1
for C]N vibration, 1531.2 cm
1
for NeO vibration,
1275.68 cm
1
for CeN vibration, and 1035.59 cm
1
for CeO
vibration
19
(Figure 1). Similarly, the FTIR spectra of
Figure 1: FTIR spectra of CP API, EPO, CP physical mixture (CP PM), CP formulation (CP-F), ROX API, ROX physical mixture (ROX
PM) and ROX formulation (ROX F).
Table 1: Composition of dispersible tablets.
Cefpodoxime proxetil Roxithromycin
Ingredients Quantity (mg) Quantity (%) Ingredients Quantity (mg) Quantity (%)
CP Granules 385 84.4 ROX Granules 417 84.4
Crospovidone 20 4.38 Crospovidone 25 5.1
SiO
2
4 0.98 SiO
2
51
Mannitol 25 5.5 Mannitol 25 5.1
Flavor 20 4.35 Flavor 20 4
Mg. Stearate 2 0.49 Mg. Stearate 2 0.4
Total 456 100 Total 456 100
CP, cefpodoxime proxetil; Mg, magnesium; ROX, roxithromycin; SiO
2
, silicone dioxide.
Dispersible tablets of CP and ROX256
ROX showed characteristic bands at 3582.13 cm
1
,
3522.34 cm
1
, and 3460.63 cm
1
corresponding to free e
OH groups and intramolecular hydrogen bonding between
eOH groups, 1729.83 cm
1
(C]O stretching),
1630.52 cm
1
(NeH stretching), 1460.81 cm
1
(CeH
bending), and 1282.43 cm
1
(CeN vibration).
20
FTIR
spectra of E-EPO showed characteristic peaks at
1724.05 cm
1
(C]O stretching), 1463.71 cm
1
(CeH
bending), 1272.79 cm
1
(CeN stretching), and
1062.59 cm
1
(CeO vibration).
21
To investigate the
interaction (if any) between API and Eudragit, physical
mixtures of CP and E-EPO and of ROX and E-EPO were
prepared and subjected to FTIR spectroscopy. It was
observed that all of the characteristic peaks associated with
drug and polymer was retained in the FTIR spectra of the
physical mixture, and no new peak was identified.
Analytical method for CP and ROX
The analytical methods used for CP were found to be
linear in the concentration range of 10e20 ppm. The
regression analysis of calibration curves generated standard
equations with R
2
values nearer to 1 for CP in methanol,
glycine buffer (pH 3), and simulated salivary media (pH 6.8).
Similar results were recorded for ROX, which showed line-
arity in the range of 50e100 ppm in the solvent mixture,
dissolution media, and simulated salivary media. The
regression equations generated were used to compute drug
content, assay, and in vitro drug release study (data not
shown).
HME process
The processing parameters (temperature, screw speed,
and feed rate) in the HME process were optimized using
plain polymer E-EPO with varying ratios of plasticizers. The
plasticizer content was optimized based on trials with an
increase in its amount from 1% to 5% until an uninterrupted
continuous extrusion process was observed with clear plastic
extrudates at the desired temperature (minimum). Plastic
extrudates made the further milling process easy and
convenient. Elastic extrudates were obtained at a lower
concentration of plasticizer, which could not be milled easily.
Finally, 5% w/w plasticizer was optimized for the study. In
the preliminary studies, we tried to optimize the extrusion
temperature for both CP and ROX batches based on the
extrusion process and morphology of the extrudates with
HME parameters of 100
C extrusion temperature, 300 rpm
screw speed, and 2 g/min feed rate based on the clarity of
extrudates, plasticity, and smooth flow through the extruder.
These parameters were then used for processing batches
containing CP. The primary batches executed with CP were
analyzed using UV spectroscopy to investigate the degra-
dation of the drug (if any). Surprisingly, the UV spectro-
scopic analysis showed a shift in the characteristic
l
max
of
CP. To investigate this further, we performed HPLC analysis
according to the reported method in IP to confirm if there
was degradation of CP after HME processing. HPLC spectra
showed characteristic peaks corresponding to S and R epi-
mers of CP at Rt value of 9 and 10 min, respectively. How-
ever, HPLC analysis also showed an extra peak at Rt 8.456,
Figure 2: HPLC chromatogram of (a) degraded batch of CP (b)
optimized batch of CP.
Figure 3: A) Extrudates of CP-F batch B) extrudates of ROX-F batch.
P.S. Patil et al. 257
which could be attributed to the degradation of CP and/or
impurity compared with the HPLC spectra of the reference
standard (Figure 2a). To address this issue, placebo batches
were taken again by changing the plasticizer, their amount,
and processing temperature. Finally, for CP, the HME
process was set as plasticizer PEG 6000 (5%), extrusion
temperature of 75
C, and screw speed of 150 rpm, keeping
the feed rate the same. The processing batch of CP with
these optimized parameters showed characteristic peaks of
CP of its S and R epimers (Figure 2b) with an absence of
any extra peak confirming the prevention of CP
degradation. Figure 3A depicts the CP extrudates obtained
after processing with optimized parameters, which were
used for further processing.
In the case of batches executed with ROX, we did not
observe any degradation of ROX; however, in preliminary
studies we observed lack of taste-masking efficiency. Thus, it
was decided to process batches of ROX after the addition of
stearic acid as a wax to coat the drug efficiently and to pass it
easily from the oral cavity (tongue) minimizing taste sensa-
tion. Thus, the processing of ROX batches was done as per
previously optimized parameters with the addition of 5%
stearic acid. Figure 3B depicts the ROX extrudates obtained
after processing with optimized parameters. The extrudates
were cooled to room temperature, milled, and passed
through sieve #60 for further evaluation.
Optimizing drug loading using solubility studies
It is known that while designing taste, masked formula-
tion solubility of an API is of prime importance. In our case,
there was no significant enhancement in the solubilities of
both CP and ROX after the HME process (Table 2). Thus,
we utilized the taste-masking efficiency to optimize the
drug loading into final formulations along with the solubility
data. In the case of CP, the taste masking was efficient up to
the drug loading of 30%, whereas in the case of ROX, it was
up to 20% after addition of stearic acid. Hence, based on
these considerations CP drug loading was confirmed to be
30% and ROX 20% with stearic acid.
PXRD
The PXRD graphs of CP alone, CP Physical Mixture (CP
PM), and CP Formulation (CP-F) showed broad diffraction
peaks. Similarly, E-EPO also did not show sharp diffraction
peaks (Figure 4A). In the case of ROX, ROX alone showed
characteristic sharp diffraction peaks at 2
q
¼7.20
, 10.92
,
11.76
, 12.83
, 13.52
, 18.8
, and 22.3
.
16
Furthermore, the
PXRD graph of ROX PM showed all of the peaks of ROX
(Figure 4B). However, PXRD analysis of ROX-F dis-
played a reduction in the intensity of ROX upon HME
processing.
DSC
The DSC thermogram of CP alone showed a blunt peak
at about 100
C supporting our observation of its existence
as an amorphous form (Figure 5A). Similar behavior was
observed in the DSC thermogram of E-EPO. DSC
thermograms of PEG 6000 and stearic acid showed sharp
melting endotherms at temperatures of 62
C and 71
C,
respectively. Similarly, the DSC thermogram of ROX
alone showed a sharp melting endotherm at 120
C
(Figure 5B).
22
Preparation and evaluation of disintegrating tablets
Flow properties of granules
The drug-loaded batch of CP (30% w/w) and ROX (20%
w/w) with stearic acid was considered to be optimized, which
Table 2: Saturation solubility and torque value generated by the HME machine for CP and ROX tablets.
CP batches Drug
loading
Torque
(Nm)
Solubility in glycine
buffer pH 3.0
ROX
batches
Drug
loading
Torque
(Nm)
Solubility in
phosphate buffer pH 6.0
F1 10% 0.28 0.02 0.19 0.02 F1 10% 0.32 0.03 0.24 0.03
F2 20% 0.31 0.03 0.21 0.03 F2 20% 0.43 0.02 0.31 0.02
F3 30% 0.39 0.01 0.25 0.02 F3 30% 0.48 0.03 0.27 0.01
F4 40% 0.46 0.02 0.22 0.01 F4 40% 0.54 0.04 0.25 0.04
n¼3 Data are presented as the mean standard deviation.
Figure 4: A) X-ray crystallographs of (a) CP formulation (b) CP PM (c) PEG 6000 (d) E-EPO (e) CP-API (f) sample holder. B) X-ray
crystallographs of a) ROX formulation (b) ROX PM (c) stearic acid (d) PEG 6000 (e) E-EPO (f) ROX-API (g) sample holder.
Dispersible tablets of CP and ROX258
was further processed by their milling and passing through
sieve #60 to obtain uniform free-flowing granules. These
granules were analyzed for flow properties with different
evaluating parameters such as bulk density, tap density,
Carr’s index, Hausner’s ratio, and angle of repose and those
were found to be within the range of 0.55e0.58 g/mL, 0.48e
0.5 g/mL, 12.2e15.5%, 1.14e1.18, and 31e33
, respectively,
for both CP and ROX. The assessment of all parameters
suggested that the prepared granules had good flow
properties.
Drug content
The drug content of the granules of CP and ROX was
investigated and found to be 95.3% 0.8% and
96.7% 1.3%, respectively. Considering these drug content
values, the final amount of granules for processing into
tablets with the desired dose was 100 and 75 mg for CP and
ROX, respectively.
Tablet preparation and characterization
Dispersible tablets of CP and ROX were prepared and
evaluated physically with parameters including hardness,
thickness, disintegration time, friability, drug content, and
uniformity of dispersion and the results were found to be
within the range of 3e3.5 kg, 4.5e5 mm, 30e40 s, 0.74%e
0.78%, 95%e105%, respectively, and the uniformity of
dispersion test passed and complied as per IP.
In vitro taste-masking evaluation
In vitro taste-masking studies were performed for the
prepared tablets of CP-F and ROX-F, which were compared
with the marketed tablets OPOX DT and Roxid DT,
respectively (Figure 6).
23,24
The prepared tablets showed
3.21% 0.6% of CP and 5.3% 0.8% of ROX release in
simulated salivary media (pH 6.8) within the first 2 min.
However, the marketed tablets OPOX DT and Roxid DT
showed 20.35% and 18.25% of CP and ROX release,
respectively. It is always preferred to evaluate the
Figure 5: A) DSC thermograms of (a) CP formulation (b) CP PM (c) PEG 6000 (d) E-EPO (e) CP-API. B) DSC thermograms of (a) ROX
formulation (b) ROX PM (c) stearic acid (d) PEG 6000 (e) E-EPO (f) ROX-API.
Figure 6: Comparative in vitro taste-masking evaluation study of
formulated tablets with marketed tablets of CP and ROX.
Table 3: Bitterness score obtained from human volunteers.
Name of sample Scores given by volunteers for respective samples Average bitterness value
CP(F) 1111111
CP (M) 4 5 5 4 5 4 4.5
ROX (F) 1 1 2 1 2 1 1.33
ROX (M) 5 5 5 5 5 5 5
P.S. Patil et al. 259
formulation efficiency in vivo. Accordingly, the prepared
tablets along with their marketed counterparts were
evaluated in human volunteers for taste-masking efficiency.
In vivo taste-masking evaluation
From the data obtained from volunteers (Table 3), the
average bitterness score of the prepared tablets of CP was
found to be 1 and that for ROX was found to be 1.3.
25
Similarly, the bitterness scores of the marketed tablets of
CP and ROX were found to be 4.5 and 5, respectively.
In vitro dissolution study of dispersible tablets
An in vitro dissolution study was performed in glycine
buffer (pH 3) and phosphate buffer (pH 6) for the prepared
and marketed tablets of CP and ROX, respectively.
26
Both
(i.e., formulated and marketed) showed drug release in the
range of 96e98% within 120 min (Figure 7). To evaluate
whether the drug release profiles of prepared and marketed
tablets were similar, F2 (similarity factor) values were
evaluated. The prepared tablets of CP and ROX showed
F2 values of 54.52 and 64.09, respectively, which suggested
that the drug release profiles of the prepared tablets were
similar.
Discussion
E-EPO is chemically a cationic copolymer consisting of
dimethyl aminoethyl methacrylate, butyl methacrylate, and
methyl methacrylate in a ratio of 2:1:1.
27
It displays pH-
dependent solubility releasing most of the entrapped drug
at an acidic pH below 5. E-EPO has a glass transition tem-
perature (T
g
)of57
C, which makes the extrusion process
easy at lower temperatures. Additionally, there are reports
highlighting the role of E-EPO in enhancing the aqueous
solubility of poorly water-soluble drugs.
5,28
Moreover, E-
EPO provides a moisture-protective coating and also cre-
ates a physical barrier to the drug toward taste buds,
enhancing the taste-masking efficiency of the formulation.
FTIR studies confirmed the processing compatibility be-
tween drug (CP or ROX) and E-EPO, as there were no new
peaks observed in the FTIR spectra of the physical mixtures
and formulations of both drugs with the retention of all of
the characteristic peaks of drug and polymer. As stated
previously, formulating solid dispersion of drugs with EPO
for taste-masking purposes also enhances their aqueous
solubility as a result of strong intermolecular interactions
such as hydrogen bonding or electrostatic interaction. The
solid dispersion of mefenamic acid with E-EPO has been
prepared using HME for taste masking wherein the authors
claimed to significantly enhance the solubility of the drug due
to the intermolecular interaction (hydrogen bonding) be-
tween the C]O group (proton-donating) of mefenamic acid
and the amino alkyl group (proton-accepting) from E-EPO
as per the FTIR spectra of the formulation.
5
In our case,
there were no such intermolecular interactions observed
between the drug and polymer (Figure 1), which might be
the reason for no change in the solubility of CP and ROX
after HME processing.
It is well known that the amorphous form of solids do not
show sharp diffraction peaks in PXRD. Thus, in the present
work, the amorphous nature of CP was confirmed by PXRD
and it was retained even after HME processing. The reduc-
tion in the peak intensities of ROX-F as reflected by PXRD
patterns suggests the possibility of its partial amorphiza-
tion.
29
DSC studies confirmed the crystalline nature of ROX.
Surprisingly, DSC thermograms of CP PM, CP-F, ROX
PM, and ROX-F did not show melting endotherms for CP
and ROX. This could be due to the solubilization of drugs in
the already molten mass of excipients. Such results have
previously been reported. The in vitro drug release study of
CP-F and ROX-F tablets in the acidic medium showed a
delay in the drug release in the initial time period, which
could be attributed to the magnesium stearate that was used
as a lubricant during compression of the tablet. It has been
reported in the literature that magnesium stearate delays the
drug dissolution rate from a tablet in acidic medium, due to
the fact that stearic acid released by the magnesium stearate
in acidic medium has detrimental effects on the drug release
characteristics of dispersible tablets.
30
Furthermore, the
results of in vitro taste-masking studies have confirmed that
the prepared tablets have better taste masking compared to
marketed tablets. The pH of media used for the test was 6.8;
however, as stated earlier, E-EPO reportedly releases the
drug below pH 6 due to its pH-dependent solubility char-
acteristics. This could be the reason for better taste-masking
efficiency by the prepared tablets compared to marketed
Figure 7: Comparative in vitro dissolution study of CP-F and ROX-F formulated tablets with marketed tablets.
Dispersible tablets of CP and ROX260
ones. Additionally, ROX tablets have stearic acid, which
might have retarded ROX release and thus displayed taste-
masking efficiency over its marketed counterpart. More-
over, the results of in vivo studies were in agreement with the
in vitro taste-masking efficiency studies, confirming the
accomplishment of the set objective of the present work.
Conclusion
To conclude, taste-masked dispersible tablets of CP and
ROX were successfully prepared with E-EPO for pediatric
administration using HME technology. The current work
presented solvent-free, scalable and continuous HME tech-
nology to address the bitter taste issues of CP and ROX.
Furthermore, the disadvantages associated with the
currently used lyophilization technique were overcome by
developing the formulations using HME technology.
Source of funding
Sharvil Patil and Atmaram Pawar are thankful to Bharati
Vidyapeeth (Deemed to be University), Pune for finacial
assistance in terms of BVDU Minor Research Project for this
work.
Conflict of interest
The authors have no conflict of interest to declare.
Ethical approval
There is no ethical issue with the study performed in the
present work.
Authors contributions
PP and SS performed the work and characterization of
the prepared formulation as described in the manuscript. SP
conceptualized the idea and wrote the manuscript. AP
reviewed the written draft of the manuscript. All authors
have critically reviewed and approved the final draft and are
responsible for the content and similarity index of the
manuscript.
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How to cite this article: Patil PS, Suryawanshi SJ, Patil
SS, Pawar AP. HME-assisted formulation of taste-
masked dispersible tablets of cefpodoxime proxetil
and roxithromycin. J Taibah Univ Med Sc 2024;19(2):252
e262.
Dispersible tablets of CP and ROX262
