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Physicochemical Characterization of Bi-Layered Terbutaline Sulfate Tablets for
Chronotherapeutic Pulsatile Drug Delivery Design Based on Natural and
Synthetic Polymer using Direct...
Article in Research Journal of Pharmacy and Technology · April 2021
DOI: 10.52711/0974-360X.2021.00330
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2. Research J. Pharm. and Tech. 14(4): April 2021
1867
ISSN 0974-3618 (Print) www.rjptonline.org
0974-360X (Online)
RESEARCH ARTICLE
Physicochemical Characterization of Bi-Layered Terbutaline Sulfate Tablets
for Chronotherapeutic Pulsatile Drug Delivery Design Based on Natural and
Synthetic Polymer using Direct Compression Technique
Prasanta Kumar Mohapatra1
*, Janki Manohar2
, Pankaj Singh Patel 1
, Mandeep Kumar Gupta1
,
Bibhuti Prasad Rath3
1
Moradabad Educational Trust Group of Institutions Faculty of Pharmacy, Moradabad,
Uttar Pradesh - 244001, India.
2
Lydia College of Pharmacy, Ravulapalem, Andhra Pradesh - 533238, India.
3
Gayatri Institute of Science and Technology, Rayagada, Odisha- 765022, India.
*Corresponding Author E-mail: mohapatra.kjr@gmail.com
ABSTRACT:
The aim of the strategy to formulate the pulsatile drug delivery system using terbutaline sulfate by direct
compression technique and evaluate the effects of formulation and dissolution medium on the behavior of drug
release, and to clarify the drug release mechanism based on acquiring results. Pulsatile release tablets include a
drug and disintegrating agent-containing core and swellable external layers for slow down drug release, then
rupturing the nearby surrounding outer layer for fast release. Core tablets prepared using disintegrating agent by
direct compression method and coated with polymers like HPMC K100M, ethyl cellulose, karaya gum in
different quantities. Several physical parameters of the tablets evaluated such as stiffness, thickness, friability,
weight variation, disintegration, drug content and dissolution test. Terbutaline sulfate released from bi-layered
tablets with pulsatile behaviors. In-vitro drug release rate readings showed that F3 and F6 are best based on the
less quantity of drug release during the lag time (11% and 14% in 5 h). So, from the result, the F6 has nominated
the best formulation. Thus, by the direct compression method prepared, coated tablets before drug release with
an obvious lag time is possibly useful preparation for the medication of osteoarthritis, rheumatoid arthritis,
dysmenorrhea, asthma which follows a circadian rhythm. It confirmed that eroding, diffusion, and swelling
mechanisms were responsible for drug release. Ultimate pulsatile release activities may be done by modifying
polymeric membrane quantities and proportions to meet the condition of pulsatile activities.
KEYWORDS: Terbutaline sulfate, Pulsatile drug release, Lag time, Direct compression, FTIR.
INTRODUCTION:
The pharmaceutical industry is increasing the cost of
successful drug discovery and development and kept
pressure to keep prices down1
. For the improvement of a
novel drug delivery system (NDDS) and
chronomodulated drug delivery system (ChrDSS) the time
and average cost needed is 3 to 4 y and $20-$50 million.
To improve a new chemical object the which 60%
metabolized by the liver in an average cost needed is
more than the 10-12 y and approximate $500 million.
Received on 31.03.2020 Modified on 10.06.2020
Accepted on 08.07.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(4):1867-1874.
DOI: 10.52711/0974-360X.2021.00330
A current drug molecule can acquire a fresh life and
grow its market value and extend patent life and
competitiveness2
. Nowadays, the interest is increasing
has turned to systems intended to achieve a site-specific
and time-specific (delayed, pulsatile) release of drugs as
compared to modified-release oral dosage forms. For this
mostly, systems for delayed-release will deliver the drug
over a planned period following administration3
.
Subsequently, ChrDSS constructs a quite innovative
class of DSS, the importance of which is essentially
connected with the current improvements in
chronopharmacology4,5,6
. The number of drugs
pharmacokinetics and pharmacodynamics property
follows temporal rhythms, frequently resulting in
variations in circadian along with the symptomatology of

3. Research J. Pharm. and Tech. 14(4): April 2021
1868
numerous pathologies. The possibility of utilizing
delayed-release to implement chronotherapy is quite
interesting for some diseases. The symptoms of which
returned mostly at night-time or in the early morning, for
example, bronchial asthma, angina pectoris, and
rheumatoid arthritis7
. The postponement in the onset of
action has reached through hydrophilic or hydrophobic
layers, osmotic mechanisms, covering a drug-loaded
core and swell-able or erodible masses coating a drug
comprising an insoluble capsule body8,9,10,11
. The drug
release pattern of the conventional drug delivery system
fluctuates or in a sustaining release case, a constant
release rate observed, but it is not always ideal12,13
. Due
to this reason, the latest release pattern of drug delivery
developed, and that fulfilled by a pulsatile drug delivery
system (PDDS). From the maximum DSS, the controlled
release DSS, and the conventional oral DSS, the drug
releases in a constant pattern or fluctuating pattern14
. In a
pulsatile release the drug release rate characterized by a
(lag time) time of very slow release rates, afterward, a
rapid and complete drug release wherein the method
controls the lag time independent of body environmental
influences like GI motility, pH, enzymes15,16
. The system
designed and demand for a time-programmed therapeutic
arrangement, releasing the correct quantity of the drug at
the correct time. The requirement of this pattern of
release achieved by a PDDS, which described by a lag
time that is an interval of a smaller amount of drug
release afterward the drug releases speedily15,17
. The
PDDS is necessary for a verity of diseases similar to
asthma, cancer, diabetes, duodenal ulcer, neurological
disorders, hypercholesterolemia, arthritis, colonic
transport, and diseases like cardiovascular18
. One of the
diseases is asthma, where the PDDS can be suitable and
circadian fluctuations, observed in common lung
function, airway resistance rises in asthmatic patients
gradually at night18,19,20
. A potent β-adrenoreceptor
agonist terbutaline sulfate is usually used in the
treatment of asthma21,22,23
. The drug terbutaline sulfate
absorption from the gastrointestinal tract is inconstant
and absorbed only 33-50% of the total administered an
oral dose and apart from which 60% is metabolized by
the liver under the first-pass metabolism24
. Not only this,
but the drug also undergoes metabolism by the gut
wall25
. For these reasons, 15% of the oral bioavailability
of the drug is found from the total administered dose26
.
And also, the drug is having a small half-life 3-4 h needs
repeated administration27
. Thus, evaluation and
improvement of ChrDSS of terbutaline sulfate have been
undertaken, but also the benefits of this system also
consist of the improved utilization of drugs having small
half-life with expansive first-pass metabolism thereby
producing a better therapeutic result for nocturnal
asthma28
.
MATERIALS:
The pure drug terbutaline sulfate bigheartedly provided
by Matrix Laboratory Limited, Hyderabad, India.
Crospovidone and ethyl cellulose obtained as a gift
sample from S.D. Fine Chemicals, Mumbai, India.
Mannitol and HPMC K100M purchased from Rankem
Lab, Hyderabad, India. Karaya gum and magnesium
stearate were generously supplied by Otto Chemicals,
Pvt Ltd, Mumbai and NR chemicals, Chennai, India. The
obtained analytical grade other reagents and chemicals
were from S.D. Fine Chemicals, Mumbai25,28,29
.
METHODS:
Formulation of the core tablet:
The terbutaline sulfate core tablets mass-produced
through direct compression procedure. The powdered
ingredients like drug terbutaline sulfate and
crospovidone were dry mixed for 20 min afterward,
magnesium stearate added, and the formula shown in
Table I. The powder blends then additionally blended for
10 min and from the subsequent powder blend 50 mg
manually compressed by 16 station rotary tablet punch
instrument comprising 6 mm circular die and punch for
the core tablet formulation16,18,30
.
Table 1: Composition of core tablets
Ingredients (mg) C1 C2 C3 C4 C5 C6
Terbutaline sulfate 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg
Crospovidone 5 mg 5 mg 5 mg 5 mg 5 mg 5 mg
Mannitol 39.25 mg 39.25 mg 39.25 mg 39.25 mg 39.25 mg 39.25 mg
Magnesium stearate 0.75 mg 0.75 mg 0.75 mg 0.75 mg 0.75 mg 0.75 mg
Total weight 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg
Table 2: Composition of press coat tablets
Ingredients (mg) F1 F2 F3 F4 F5 F6
Magnesium stearate 0.75 mg 0.75 mg 0.75 mg 0.75 mg 0.75 mg 0.75 mg
HPMC K100M 200 mg 300 mg 100 mg - - -
Ethyl cellulose 200 mg 100 mg 300 mg 200 mg 300 mg 100 mg
Karaya gum - - - 200 mg 100 mg 300 mg
Total weight 450 mg 450 mg 450 mg 450 mg 450 mg 450 mg
Note: (-) the particular excipient not utilized in the formulation

4. Research J. Pharm. and Tech. 14(4): April 2021
1869
Formulation of press-coated tablet:
The formulations weighed and dry blended around 10
min having compositions ethyl cellulose and HPMC
K100M. The core tablets were press-coated and which
contain around 50mg of weight and specified in Table II.
The accurate weight containing outer layer material 200
mg measured thereafter shifted to 12 mm diameter die
afterward the core tablet was by hand situated at the
center. The residual barrier layer material, exactly 200
mg added into the same die and compressed16,31,32,33
.
Experimental design layout:
Experimental design utilized in the current investigation
for the optimization of excipients concentration, such as
the concentration of HPMC K100M, ethyl cellulose, and
karaya gum taken as X1, X2, and X3 and formulae for all
the experimental batches represented in Table II. Three
levels for the concentration of polymers selected and
coded as (-1=100mg, 0=200mg, +1=300mg). Table III
summarizes a record of the six-formulation examined,
their factor combinations, and the coded levels to the
experimental units utilized during the study6,8,29
.
Table 3: Experimental design layout
Coded
factors and
units
Coded levels
Low level Middle level High level
-1 0 +1
HPMC
K100M
100 200 300
Ethyl
cellulose
100 200 300
Karaya gum 100 200 300
Formulation
code
Coded factors and
their levels
Coded factors and
their actual values
X1 X2 X3 X1 X2 X3
F1 0 0 - 200 200 -
F2 +1 -1 - 300 100 -
F3 -1 +1 - 100 300 -
F4 - 0 0 - 200 200
F5 - +1 -1 - 300 100
F6 - -1 +1 - 100 300
Note: (-) the particular excipient not utilized in the formulation
Evaluation parameters for the pre-compression
tablet:
Bulk density:
Pharmaceutical ingredients or particulate matter and the
granules property, powders, and divided solids
determined by bulk density. It represented a substantial
mass divided by occupied total volume. The total
volume of a substance defined as the addition of inter
and intra-particle void volume to true volume. The bulk
density determined by dividing the powder sample
volume concerning a known mass in a graduated
cylinder18,22,34
.
(Eq. 1)
Where,
ρ
b
= Bulk density
M = Mass of the powder
V0 = Bulk volume of the powder
Limits-The bulk density results having less than 1.2
g/cm3
indicating decent packing and result from over 1.5
g/cm3
specifies poor packing.
Tapped density:
The well-known powder mass poured into a transparent
graduated cylinder and the volume of the powder mass
known as V0. A density determination apparatus fixed to
the cylinder and the cylinder which contains
granules/powder tapped for 500 times than reading
detected. With the help of a measuring cylinder
containing the granules/powder sample, the density
achieved by mechanically tapped18,22,34
.
(Eq. 2)
Where,
ρ
t
= Tapped density
M = Mass of the granules/powder
Vt = Tapped final volume of the granules/powder
Compressibility index:
Carr’s index calculated based on bulk density and tapped
density values. Carr’s index equation represented
below22,33,35
.
(Eq. 3)
Where,
ρ
t
= Tapped density
ρ
b
= Bulk density
Hausner’s ratio:
The flow properties of the powder specified by
Hausner’s ratio and estimated by taking a ratio of tapped
density to the bulk density of the powder or blend18,22
.
(Eq. 4)
Angle of repose:
The knowledge about the flow property of the particles
or powder estimated by the angle of repose. This
represented as the maximum angle achieved between the
powder pile surface concerning the horizontal
plane18,22,33
.
(Eq. 5)
Where,
θ = Angle of repose
h = Height of a pile (2 cm)
r = Radius of pile base
Evaluation parameters for the press-coated tablet:
Thickness and Diameter:
The 10 core tablets, as well as press-coated tablets
thickness and diameters, noted by using a Vernier
caliper18,22
.

5. Research J. Pharm. and Tech. 14(4): April 2021
1870
Weight variation test:
This is a quality control and in-process quality control
test to confirm that the manufacturers control each
compressed tablet comprises the proper amount of drug,
different pharmacopeias stated these weight variation
tests. First, randomly selected 20 tablets average weight
calculated then the same 20 tablets individual weight
calculated with the help of the analytical balance.
Afterward, the ±% limit of average weight compared to
an individual tablet. The ±% average weight limits of
uncoated compressed tablets provided by the USP16,30,36
.
Hardness:
The hardness of a tablet influenced by its particle-
particle bonding and tablet resistance power to capping,
breakage during transportation, and handling. Hardness,
which called crushing strength and it can be regulated by
pressure modification of tablet machine. A too-hard
tablet may not disintegrate in the appropriate time, so
onset time will be more and too soft tablet not be able to
withstand the stress like transportation, handling, coating
and packaging, and easily break. It is the measurement
of strength needed to break the tablet when the force
applied by diametrical direction to the tablet. The in
terms of kg/cm2
average hardness was calculated30,36,37
.
Friability:
Friability test carried out by using 20 tablets. Randomly
from each tablet formulation 20 tablets collected and
weighed by using an analytical balance. The same tablets
kept in a rotary drum and rotated at 25 rpm for 4 min
means a total of 100 revolutions. After 100 revolutions,
the tablets removed from the rotary drum and weighed.
The percentage of weight loss calculated using the
following equation. During transportation, the tablet got
stress like friction and shock and for this reason, the
tablets may chip, break. To appraise the capacity of the
tablet to withstand abrasion during packaging, handling,
and transportation, the friability test led. A weight loss,
an extreme percentage of 20 tablets must not be over 1%
and measured by the apparatus Roche friabilator16,18,22,37
.
Initial weight-Final weight
% Friability = (––––––––––––––––––––––––––) × 100
Initial weight
(Eq. 6)
Disintegration test:
As described in Indian Pharmacopoeia the disintegration
apparatus was used to determine the disintegration time
of the compact mass (tablet). In it, 2 basket assembly
located, and each basket contains 6 glass tubes having 3
inches long is present in a beaker having 1000 ml
capacity. The tubular upper part is open and the lower
part fixed with 10 no mesh. Into each tube, one tablet
kept and pH 7.4 phosphate buffer solvent system used at
temp 37±0.5°C. The time required to disintegrate the
tablet (particles completely pass from the tube into the
beaker through no 10 mesh) was noted18,30,36
.
Uniformity of content:
The test uniformity of content is used to confirm that
each tablet comprises the quantity of drug substance
design with little deviation among tablets within a batch.
The content uniformity test has added to the monographs
due to the need for better-quality awareness of the
physiological availability of entire dosage forms coated
and uncoated tablets plus capsules proposed for the
administration of oral dosage form.
Method:
In this test, randomly selected 30 tablets from the batch,
from that 10 tablets randomly selected and according to
the official assay method, 10 of them assayed
individually. Nine of the 10 tablets must have the
strength within ±15% of the labeled drug content. Only
one tablet may be within the limit of ±25%. If two
tablets within the limit of ±25%, then the remaining 20
tablets drug content must be estimated individually and
none may fall outside ±15% of the labeled content16,30,36
.
Drug excipients compatibility:
In all pharmaceutical dosage forms, the excipients
behave as a dynamic element. To formulate an effective
and stable solid dosage form, it is highly necessary to
select appropriate excipients that should have no
interaction property between them. Which has helped
with easy administration, facilitate prolong release as
well as maintain the bioavailability in the body and to
protect from decline? One of the most exact analytical
techniques to detect functional groups of a drug is FTIR
(FT/IR 4100, Jasco, MD, USA) spectroscopy thus the
pure drug and their formulations subjected to FTIR
studies taken in the range of 4000-500 cm-1
. In the
ongoing study, the conducted technique was a potassium
bromide disc (pellet) technique21,22,25
.
In-vitro dissolution of the press-coated tablet:
The pulsatile delivery press-coated tablets of the
terbutaline sulfate drug release study performed in the
USP Type-II (paddle) dissolution apparatus. The
dissolution medium of pulsatile tablets contains 900 ml
of pH 1.2 for the initial 2 hrs afterward pH 7.4 phosphate
buffer at 37±0.5 °C at 50 rpm rotating speed of the
paddle, the dissolution studies performed. During the
study, 5 ml of the filtrate drug solution withdrawn from
the dissolution basket at a specified time interval and
replaced with the same volume of fresh buffer solution.
The collected dissolution samples absorbance checked at
276 nm in the UV-Visible spectrophotometer. Each
formulation lag time and percentage release determined,
and the graph was plotted18,31,38
.

6. Research J. Pharm. and Tech. 14(4): April 2021
1871
Drug release kinetics:
To look into the drug release mechanism from the
microspheres, the in-vitro release data were gone into
various kinetic models like zero order, first order,
Higuchi’s equations. Further, the drug release
mechanism also analyzed by the Korsmeyer-Peppas
equation39,40
.
RESULTS:
Pre-compression parameters:
Formerly continuing to direct compression method drug
(terbutaline sulfate) along with excipients estimated for
bulk density, tap density, angle of repose,
compressibility index and Hausner’s ratio. The
prominent physical parameters are in Table IV and they
are the bulk density 0.306±0.06 to 0.510±0.02, tap
density 0.353±0.05 to 0.583±0.02, angle of repose:
22.68±0.31 to 26.89±0.92, Compressibility record:
12.46±0.9 to 14.54±1.1, Hausner’s proportion:
1.13±0.02 to 1.17±0.05 determining the tasteful
outcome18,30
.
Table 4: Precompression parameters for formulation batches
Formulations Angle of repose (θ)* Bulk density (g/cm3
)* Tapped density
(g/cm3
)*
% Compressibility
index*
Hausner’s ratio*
F1 22.68 ± 0.31 0.510 ± 0.02 0.583 ± 0.02 12.52 ± 0.8 1.13 ± 0.02
F2 23.73 ± 0.76 0.416 ± 0.04 0.482 ± 0.04 13.69 ± 0.92 1.15 ± 0.03
F3 23.58 ± 0.61 0.423 ± 0.05 0.495 ± 0.03 12.46 ± 0.9 1.14 ± 0.04
F4 25.16 ± 0.56 0.309 ± 0.04 0.353 ± 0.05 13.80 ± 1.6 1.16 ± 0.06
F5 26.89 ± 0.92 0.306 ± 0.06 0.355 ± 0.04 14.54 ± 1.1 1.17 ± 0.05
F6 24.65 ± 0.48 0.322 ± 0.09 0.376 ± 0.03 14.36 ± 1.2 1.16 ± 0.03
*Values were expressed in mean ±SD (n = 3)
Figure 1: 3D Plot shows the compressibility index
Post-compression parameters:
In the tablet's production, the important parameters
according to official specifications for thickness,
hardness, friability, weight variation, drug content, and
in-vitro disintegration time measured and reported in
Table V and VI18,29,30
.
Thickness:
The average thickness of the core and press-coated
tablets (n=3) of batches F1to F6 varied from 1.38±0.13
mm to 1.55±0.15mm and 4.20±0.6mm to 4.51±0.2mm.
The standard deviation values indicated that all the
formulations were within the range.
Weight variation test:
All the tablets fell out of the weight variation test, i.e.,
the average percentage weight variation found within the
pharmacopeia limits of ±5%.
Hardness:
All the formulations hardness or crushing strength of
core tablet hardness varied from 3.6±0.3kg/cm2
to
4.1±0.2kg/cm2
, and for press-coated tablets, the hardness
varied from 6.5 kg/cm2
to 7.4 kg/cm2
possessed
satisfactory mechanical strength with adequate hardness.
Friability:
Core and press-coated tablets friability values from F1 to
F6 varied from 0.328±0.2, to 0.611±0.12, and from
0.398±0.19 to 0.711±0.21 respectively. The obtained
outcomes found to be fit within the approved range
(<1%) in all the manufactured formulations. The
friability test of all the batches passed.
Disintegration test:
Core tablets in-vitro disintegration time from F1 to F6
achieved at pH 7.4 it was from 197±2.3 Sec to 655±1.9
Sec. The least disintegration time displayed in batch F5,
and F6 tabulated in Table V.
Uniformity of content:
The core tablets exhibited drug content in the range from
97.11±0.76 to 100.1±0.85, and similarly press coat
tablets drug content from range 98.11±0.66 to
102.1±0.55. As specified in pharmacopeia the results
were within the limit (±15%).

7. Research J. Pharm. and Tech. 14(4): April 2021
1872
Table 5: Physical evaluation parameters of core tablets
Formulations Hardness
(kg/cm2
)*
Weight uniformity
(mg)*
Friability (%)* Thickness
(mm)*
Uniformity of
content (mg)*
Disintegration
time (sec)*
F1 3.6 ± 0.3 50.52 ± 0.1 0.557 ± 0.2 1.51 ± 0.15 99.77 ± 0.73 432 ± 1.7
F2 3.8 ± 0.4 51.26 ± 0.3 0.435 ± 0.16 1.49 ± 0.083 97.11 ± 0.76 566 ± 2.2
F3 3.9 ± 0.5 49.64 ± 0.4 0.469 ± 0.23 1.38 ± 0.13 99.10 ± 0.89 655 ± 1.9
F4 4.0 ± 0.6 50.36 ± 0.3 0.611 ± 0.12 1.40 ± 0.14 100.1 ± 0.85 368 ± 2.5
F5 4.1 ± 0.2 48.92 ± 0.6 0.328 ± 0.2 1.55 ± 0.15 98.77 ± 0.81 298 ± 2.7
F6 3.9 ± 0.3 49.50 ± 0.2 0.551 ± 0.17 1.39 ± 0.13 100.1 ± 0.78 197 ± 2.3
*Values were expressed in mean ± SD (n = 3)
Table 6: Physical evaluation parameters of press coat tablets
Formulations Hardness
(kg/cm2
)*
Weight uniformity (mg)* Friability (%)* Thickness (mm)* Uniformity of content (mg)*
F1 7.2 ± 0.4 142 ± 0.6 0.552 ± 0.1 4.51 ± 0.2 99.77 ± 0.73
F2 6.9 ± 0.6 146 ± 0.8 0.645 ± 0.2 4.49 ± 0.5 98.11 ± 0.66
F3 7.4 ± 0.7 144 ± 0.4 0.549 ± 0.15 4.38 ± 0.4 99.10 ± 0.89
F4 6.5 ± 0.2 143 ± 0.5 0.711 ± 0.21 4.20 ± 0.6 102.1 ± 0.55
F5 6.8 ± 0.3 147 ± 0.3 0.398 ± 0.19 4.42 ± 0.3 98.77 ± 0.81
F6 7.2 ± 0.6 145 ± 0.2 0.551 ± 0.22 4.33 ± 0.4 100.1 ± 0.78
*Values were expressed in mean ±SD (n = 3)
Figure 2: FTIR graph of terbutaline sulfate pure drug (a) and
optimized formulation (b)
Figure 3: In-vitro drug release of terbutaline sulfate from
formulation
Figure 4: Release kinetics of best formulation F6
DISCUSSION:
Drug excipients compatibility:
The solid pure drug terbutaline sulfate and drug-
excipients mixture compatibility study performed in
FTIR and spectra represented in (Fig. 2). FTIR spectrum
of pure terbutaline sulfate shows prominent peaks at
2845.34 cm-1
, 1316.31 cm-1
, 1158.94 cm-1
, 1037.01 cm-1
corresponds to CH alkanes, CH3 alkanes, S=O
sulfonates, C-N alkyl, stretching respectively. These
peaks may be reflected as characteristic peaks of
terbutaline sulfate were not unnatural and observed in
the FTIR spectra of terbutaline sulfate along with
excipients, which indicated that the interaction between
drug and excipients was not observed21,36
.
In-vitro release studies:
The pulsatile release drug delivery dissolution studies
conducted at pH 1.2 standard buffer 900ml for the initial
2 hrs, afterward phosphate buffer pH 7.4 used
dissolution medium for press-coated tablets6,41
. From the
dissolution data, it concluded that F3 and F6 both

8. Research J. Pharm. and Tech. 14(4): April 2021
1873
selected based on the drug release pattern because of, the
drug release delayed for 5 h and then the drug released
rapidly within 2 h in F3 and 3 h in F6 respectively and
both formulations follow the zero-order kinetic drug
release pattern. It observed that the burst release may be
in F3 due to the use of a 1:3 ratio of HPMC K100M:
ethyl cellulose mixture used as the external layer as well
as ethyl cellulose is a hydrophobic polymer porous
creation in the external layer and the effect of the super
disintegrant. In F6, burst release arises because of 1:3
ratio of ethyl cellulose: karaya gum mixtures in which,
as soon as karaya gum dissolves within 5 h, the drug
releases very quickly detailed in (Fig. 3). In F3 ethyl
cellulose mixed with HPMC K100M and in F6 ethyl
cellulose mixed with karaya gum to modulate the lag
time and hence control the disintegration. HPMC
K100M and karaya gum forms a firm gel, but does not
hydrate quickly while ethyl cellulose is a hydrophobic
polymer and shows erosion type of mechanism.
Therefore, the drug instantly released from the core
tablet as soon as a breakdown of the surrounding
external layer. In the pulsatile tablet, the burst release
carried out as a result of pressure escalation within a
system. This escalation of pressure might be imputed to
the inflow of the dissolution medium by the erosion
effect as a result of the existence of ethyl cellulose in the
external layer. This theory advises that in the external
layer ethyl cellulose might behave as a pore-forming
agent instead of as a gelling agent, therefore enhancing
the penetration of water before rupturing the surrounding
external layer5,28,42
.
In-vitro release kinetic studies:
In Table VII the release exponent values are shown,
representing that the dominant mechanism of drug
release through F3 and F6 types of tablets was due to
swelling and erosion which continually associated with a
diffusion mechanism. The first-order release kinetics
followed by formulation F1, whereas residual F2 to F6
followed a zero-order release mechanism. From the
slope, the release exponent ‘n’ value calculated, and it
describes the mechanism of drug release. The ‘n’ value
obtained for formulations F1, F2, F3, and F6 tablet was
in between (> 0.45 and < 0.89) and recommended that
the drug release monitored non-Fickian anomalous
diffusion because of the hydrophilic polymers have a
greater attraction to water. But the ‘n’ value of
formulation F4 and F5 is greater than > 0.89 so, the
release following the super case II transport
mechanism43,44
.
Table 7: In-vitro drug release kinetic studies of different formulations
Formulations Zero-order First-order Higuchi Hixon Crowell Release exponent
(n)
(R2
)
F1 0.881 0.892 0.888 0.888 0.875
F2 0.968 0.907 0.939 0.936 0.680
F3 0.691 0.589 0.586 0.642 0.516
F4 0.963 0.918 0.895 0.936 0.961
F5 0.923 0.87 0.836 0.89 0.996
F6 0.819 0.687 0.724 0.768 0.782
(R2
= regression coefficient), (n = release exponent).
CONCLUSION:
The FTIR spectra of the pure drug (terbutaline sulfate)
along with excipients evaluated and form the
characteristic peak of the drug with a physical mixture of
the drug and excipients no other suspicious effects
found, and it indicated that the characteristic peak of the
drug has looked in the spectra deprived of any alteration
in the position, henceforth between drug and excipient,
no interaction observed. The conducted all the properties
of micromeritics results were found satisfactory. From
the observed report concluded, the flow property found
excellent, and it proved through bulk density, tapped
density, the angle of repose, Hausner’s ratio, and Carr’s
index. The chronomodulated tablets were inspected for
quality control tests along with appearance, thickness,
weight variation, hardness, friability, uniformity of
content, and indicated that all are within the limits.
Among all core tablets, formulation F3 and F6, press
coat tablets nominated as optimized formulation. From
the directly above results, it displayed that formulation
F6 is the best. From the outcomes, it verified that the
PDDS containing terbutaline sulfate is appropriate for
formulating by direct compression technique in the
treatment of nocturnal asthma.
ACKNOWLEDGEMENTS:
The authors are like acknowledging Matrix Laboratory
Limited, Hyderabad, India for providing the gift sample
drug terbutaline sulfate.
AUTHORS CONTRIBUTIONS:
All the authors have contributed equally.
CONFLICTS OF INTERESTS:
The authors declared a conflict of interest none.
STATEMENT OF HUMAN AND ANIMAL
RIGHTS:
This clause does not contain any studies with human or
animal subjects performed by any of the writers.

9. Research J. Pharm. and Tech. 14(4): April 2021
1874
REFERENCES:
1. Hemalatha V, Kumar PPS, Naidu MRL, Priyanka et al. Formulation and
evaluation of pulsatile drug delivery system of Celecoxib. World Journal of
Pharmaceutical Research. 2016; 5(2): 1110-1119.
2. Hochhaus G, Mollmann H. Pharmacokinetic/pharmacodynamic
characteristics of the beta-2-agonists Terbutaline, Salbutamol and Fenoterol.
International journal of clinical pharmacology, therapy, and toxicology.
1992; 30(9): 342-362.
3. Naik VV, Ankarao A, Anil Babu K, Neelima P.V.A, Anil Babu G et al.
Formulation and evaluation of Valsartan pulsincap drug delivery system.
International Journal of Pharmacy and Analytical Research. 2015; 4(1): 41-
47.
4. Jain D, Raturi R, Jain V, Bansal P, Singh R. Recent technologies in pulsatile
drug delivery systems. Biomatter. 2011; 1(1): 57-65.
5. Nabin K, Biswajit B, Patel J, Patel KM et al. Preparation and evaluation of
pulsatile drug delivery system containing Terbutaline sulphate. International
Research Journal of Pharmacy. 2011; 2(2): 113-119.
6. Nandedkar S.Y, Wagh RD, Bauskar MD et al. Formulation design and
optimization of pulsatile release tablet of Acebrophylline with swelling and
erodiable layers for treatment of nocturnal bronchial asthma. International
Journal of Pharmaceutical Sciences and Research. 2011; 2(12): 3100-3108.
7. Baghel P, Roy A, Chandrakar S, Bahadur S. Pulsatile drug delivery system:
A promising delivery system. Research Journal of Pharmaceutical Dosage
Forms and Technology. 2013; 5(3): 111-114.
8. Mahajan AN, Shah DA, Patel KT et al. Studies in formulation development
of chronotherapeutics dosage of model drug. Scholars Research Library.
2011; 3(4): 227-240.
9. Fatima SN, Mohammed S et al. Formulation and in-vitro evaluation of
meloxicam pulsin cap for pulsatile drug delivery. International Journal of
Innovative Pharmaceutical Sciences and Research. 2017; 5(8): 126-138.
10. Vijaya Vani Ch.S, Rao MV.U, Bhavani D et al. Formulation and evaluation
of Montelukast sodium pulsatile drug delivery system by core in cup
method. International Journal of Pharmacy Review and Research. 2015;
5(1): 15-23.
11. Sudhamani T, Radhakrishnan M, Mallela D, and Ganesan V.
Chronotherapeutic floating pulsatile drug delivery: An approach for time-
specific and site-specific absorption of drugs. Research Journal of Pharmacy
and Technology. 2011; 4(5): 685-690.
12. Gajanan N.P, Borate S, Ranpise A, Mandage Y, Thanki K, Rao M et al.
Design, evaluation and comparative study of pulsatile release from tablet
and capsule dosage forms. Iranian Journal of Pharmaceutical Sciences.
2009; 5(3): 119-128.
13. Gohel MC, Parikh RK, Patel LD, Patel VP Gami SV et al. Design and
evaluation study of pulsatile release tablets of Metoprolol succinate. Pharma
Science Monitor-An International Journal Pharmaceutical Sciences. 2012;
3(2): 171-181.
14. Jadhav TS, Thombre NA, Kshirsagar SJ. Pulsatile drug delivery system
using core-in-cup approach: a review, Pharmaceutical and Biological
Evaluations. 2016; 3(3): 1-9.
15. Seidler FJ, Rahman AA, Tate CA, Nyska A, Rincavage Hl, Slotkin TA,
Rhodes MC et al. Terbutaline is a developmental neurotoxicant: effects on
neuroproteins and morphology in cerebellum, hippocampus, and
somatosensory cortex. The Journal of Pharmacology and Experimental
Therapeutics. 2004; 308(2): 529-537.
16. Thakare VM, Gandhi BR, Tekade BW, Sadaphal KP et al. Formulation and
evaluation of pulsatile drug delivery system for chronobiological disorder:
asthma. International Journal of Drug Delivery. 2011; 3: 348-356.
17. Dharmamoorthy G, Nandhakumar. Chronotherapeutics: a range of newer
drug delivery approaches for better patient compliance, International Journal
of Applied Biology and Pharmaceutical Technology. 2011; 2(4): 110-120.
18. Vishnu PP, Sharma JVC, Avinash A et al. Formulation and evaluation of
Terbutaline sulphate by pulsatile drug delivery system. International Journal
of Biopharmaceutics. 2016; 7(1): 7-12.
19. Kumar A, Sonam R. Pulsatile drug delivery system: method and technology
review, International Journal of Drug Development and Research. 2012;
4(4): 95-107.
20. Hamed Md.M, Rafiq M, Ali N, Sayeed A et al. Pulsatile drug delivery
systems: recent technology. International Journal of Pharmaceutical
Sciences and Research. 2013; 4(3): 960-969.
21. Mahajan AN, Pancholi SS. Formulation and evaluation of timed delayed
capsule device for chronotherapeutic delivery of terbutaline sulphate. ARS
Pharmaceutica. 2010; 50(4): 215-223.
22. Rao NGR, Panchal H, Hadi MA. Formulation and evaluation of biphasic
drug delivery system of Terbutaline sulphate for chronotherapy.
International Journal of Pharma and Bio Sciences. 2012; 3(3): 626-637.
23. Singh HN, Saxena S, Singh S, Yadav AK. Pulsatile drug delivery system:
Drugs used in the pulsatile formulations. Research Journal of
Pharmaceutical Dosage Forms and Technology. 2013; 5(3): 115-121.
24. Emami J, Boushehri MAS, Varshosaz J, Eisaei A. Preparation and
characterization of a sustained release buccoadhesive system for delivery of
Terbutaline sulphate. Research in Pharmaceutical Sciences. 2013; 8(4): 219-
231.
25. Ramani Nd, Kumar Pb, Kola R et al. Formulation and in-vitro evaluation of
Terbutaline sulphate sustained release tablets. Indian Journal of Research in
Pharmacy and Biotechnology. 2013; 1(5): 621-624.
26. Kumar TMP, Kumar HGS. Novel core in cup buccoadhesive systems and
films of Terbutaline sulphate development and in-vitro evaluation. Asian
Journal of Pharmaceutical Sciences. (2006) 1(3-4):175-187.
27. Gobade NG, Koland M, Harish KH. Asymmetric membrane osmotic
capsules for Terbutaline sulphate. Indian Journal of Pharmaceutical
Sciences. 2012; 74(1): 69-72.
28. Gupta VRM, Patil SS et al. Development and in-vitro evaluation of
chronomodulated delivery systems of Terbutaline sulphate. International
Journal of Research and Development in Pharmacy and Life Sciences. 2016;
5(4): 2280-2290.
29. Hadi MA, Saleem MD, Rao AS, Rao VU. Surface response methodology
for development and optimization of Aceclofenac pulsatile release drug
delivery system. Asian Journal of Pharmacy and Technology. 2014; 4(2):
74-82.
30. Patil V, Nagesh C, Praveen K, Rekha S, Chandrasekhara S et al. Pulsatile
drug delivery system of Terbutaline sulphate; using ph sensitive polymer.
American Journal of Advanced Drug Delivery. 2013; 1(4): 635-650.
31. Patil SS, Patil SV, Lade PD, Janugade BU et al. Formulation and evaluation
of press-coated Montelukast sodium tablets for pulsatile drug delivery
system. International. Journal of chem tech research. 2009; 1(3): 690-691.
32. Patel J, Patel D, Vachhani S, Prajapati ST, and Patel CN. Current status of
technologies and devices for chronotherapeutic drug delivery systems.
Research Journal of Pharmacy and Technology. 2010; 3(2): 344-352.
33. Nawaj SS, Khan M, Khan Dr. GJ, Sohel A. Design, development and
evaluation of press coated floating pulsatile tablet of antihypertensive agent.
Research Journal of Pharmacy and Technology. 2018; 11(3): 921-929.
34. Archana A, Manikanta AK, Shetty KSM. Formulation development and
evaluation of Sumatriptan pulsatile drug delivery using pulsincap
technology. Research Journal of Pharmacy and Technology. 2013; 6(12):
1375-1379.
35. Kalyani V, Basanthi K, and Murthy TEGK. Formulation and evaluation of
modified pulsincap drug delivery system for chronotherapeutic delivery of
Montelukast sodium. Research Journal of Pharmaceutical Dosage Forms
and Technology. 2014; 6(4): 225-229.
36. Rao NGR, Hadi MA, Panchal H. Formulation and evaluation of biphasic
drug delivery system of Montelukast sodium for chronotherapy.
International Journal of Pharmaceutical and Chemical Sciences. 2012; 1(3):
1256-1265.
37. Patel VD, Yegnoor AK. Development and evaluation of Celecoxib core in
cup tablets for pulsatile drug delivery. Research Journal of Pharmacy and
Technology. 2017; 10(3): 755-764.
38. Chowdary KPR, Shobarani RH, Narasu L, Bhat A et al. Formulation and
evaluation of chronopharmaceutical drug delivery of Theophylline for
nocturnal asthma. International Journal of Pharmacy and Pharmaceutical
Sciences. 2011; 3(2): 204-208.
39. Costa P, Lobo J.M.S. Modeling and comparison of dissolution profiles.
European Journal of Pharmaceutical Sciences. 2001; 13: 123-133.
40. Dighe PA, Kharat AR, Patil SV, Ramteke KH et al. Mathematical models of
drug dissolution: a review. Scholars Academic Journal of Pharmacy. 2014;
3(5): 388-396.
41. Rama B, Sandhiya V, Rathnam G, Ubaidulla U, Roy PS, Swetha M et al.
Chronopharmacotherapeutic release of HMG-COA reductase inhibitor:
using novel coating technique. World Journal of Pharmaceutical Research.
2016; 5(5): 784-797.
42. Harshitha R, Potturi PK, Ramesh R, Rajkumar N, Nagaraja G and Murthy
PNVN et al. Development of time programmed pulsincap system for
chronotherapeutic delivery of Diclofenac sodium. Research Journal of
Pharmacy and Technology. 2010; 3(1): 234-238.
43. Peppas NA, Ritger PL. A simple equation for description of solute release ii.
Fickian and anomalous release from swellable devices. Journal of
Controlled Release, 1987; 5: 37-42.
44. Siepmann J, Siepmann F. Mathematical modeling of drug delivery.
International Journal of Pharmaceutics. 2008; 364: 328-343.
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