International Journal of Applied Pharmaceutics

ISSN- 0975-7058 Vol 13, Issue 2, 2021

Original Article
DESIGN EXPERT SUPPORTED FORMULATION DEVELOPMENT, MATHEMATICAL
OPTIMIZATION AND PREDICTABILITY STUDY OF FLOATING TABLETS OF BISOPROLOL
FUMARATE

SHAIKH SHAOOR AHMAD2, SHAIKH SIRAJ N.1*, PATEL M. SIDDIK1, KHALIFA MAHMADASIF YUNUS1, MAKRANI
SHAHARUKH I.1, SIDDIQI HIFZURRAHMAN MD A.3, SHAIKH SALMAN ISMAIL4
1Ali-Allana College of Pharmacy Akkalkuwa Dist, Nandurbar, Maharashtra, India, 425415, 2Shree Swami Samarth Ayurvedic Pharmacy
(Allopathic Division) Ltd. Jalgaon 425001, Maharashtra, India, 3Department of Pharmaceutics, Jamia College of Pharmacy Akkalkuwa,
Nandurbar, 425415, Maharashtra, India, 4Pell Tech Health Care Pvt Ltd. Mumbai Maharashtra, India
Email: sirajsk1234@gmail.com
Received: 02 Dec 2020, Revised and Accepted: 05 Feb 2021
ABSTRACT
Objective: Focus of the study was to formulate Design expert Software assisted floating tablet of Bisoprolol Fumarate. Bisoprolol Fumarate is a Beta
adrenergic blocking agent, used to treat cardiac diseases favorable characters to be formulated as sustained release Gastro retentive floating tablets.
Methods: Floating Tablets of Bisoprolol Fumarate were prepared by using polymers such as Polyox N 12 K and Carbapol 940 P. Formulations were
prepared by using direct compression method and evaluated for various parameters like Hradness, thickness, weight variations, Floating lag time
Total floating time,% drug release and Stability Study etc.
Results: FTIR spectroscopic study indicates no drug-excipients interaction in the prepared formulations. Hardness or crushing strength of the
tablets of all the formulation was found between 5.8 and 6.5 kg/cm2. Floating lag time of all batches is in range of 1.18±2.0 to 2.43±1.6 (minutes). All
other parameters of all batches are within an acceptable range. The polymer Carbopol 940 P had the significant negative effect of on the floating lag
times. The In vitro dissolution profiles of optimized A3 Floating formulation of Bisoprolol Fumarate were found to sustain drug release 99.25 % up
to 12 h with floating lag time of 1.45 min; Designed formulation was stable after Stability study. Optimization study was carried out by using
32 factorial designs to fabricate formulations.
Conclusion: It can be conclude that reproducible results of various parameters in this developed formulation can easily scale up. Furthermore
designed formulation will be very effective for controlling blood pressure.
Keywords: Software Supported, Bisoprolol Fumarate, Carbapol 940 P, Floating, Direct compression, Floating lag time, Characterization
© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2021v13i2.40433. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION
Over the past few decades, gastric retention has received immense
popularity in segment of oral drug delivery [1]. Numerous
Gastroretentive drug delivery systems (GRDDS) have been designed
to retain drug in the gastric region for prolonged time2 and release
incorporated drug [2]. And thereby enable sustained and prolonged
input of the drug to the upper part of the GIT thus leading its optimal
bioavailability [3].
Reported techniques for fabrication of GRDDS are Floating [4-7].,
Sedimentation [8-11]., Mucoadhesion [12, 13]., Swelling and
expanding system [14]., modified shape [15]. etc. Techniques which
shown clinical evidence for prolonged gastric residence time is
floating, swelling and Mucoadhesion [16, 17].
Floating dosage drug delivery system (FDDS) have the sufficient
buoyancy to float over the gastric contents for a longer time and
hence it increases bioavailability of drugs which are primly
absorbed in stomach [18-23].
Mucoadhesive system is capable to adhere mucous membrane that
prevents their passage through the pylorus and the dosage forms
are retained in the stomach for a longer period of time [24-26].
Hypertension it is defined as abnormally high blood pressure (more
than 120/80 mm of Hg) in the arteries. It is generally symptoms less,
but increases the risk of various other CVS diseases like Stroke,
Heart Attack, and non-CVS diseases like renal damage, end-stage
renal failure [27].
Moreover Bisoprolol fumarate ((RS)-1-{4-[(2-isopropoxyethoxy)
methyl] phenoxy}-3-(Isopropylamino) propan-2-ol) is a beta
adrenergic blocking agent, used to treat cardiac disease [28]. For a
drug that have absorption window in the stomach, prolonging the
gastric residence time may significantly enhance the extent of its
absorption [28, 29].
So aim of present research work effervescent approach based
Floating tablets of Bisoprolol were fabricated by using various
polymers such as Polyox N 12 K and Carbapol 940 P with the help of
Design expert Software.
MATERIALS AND METHODS
Materials
Bisoprolol Fumarate was obtained as a gift sample from Mehta API
Pvt. Ltd. Tarapur Biosar, India. Polyethylene oxide (Polyox 12 K) was
gifts from Colorcon Asia Pvt. Ltd. Goa, India. Carbopol 940P, Sodium
Bicarbonate, Citric Acid,PVP K-30,Talc, Magnesium stearate,
Dicalcium Phosphate were purchased from Research Lab Fine Chem.
Ltd. Mumbai India.
Methods
Drug–excipient compatibility
The Infrared Spectra of pure Bisoprolol Fumarate, optimized
formulations were recorded between 600 and 4000 cm-1 by FT-IR
Spectrometer using KBr pellet technique to find out any possible
drug-excipient interaction.
Fabrication of floating tablets of bisoprolol fumarate
All the floating tablets were fabricated by using the direct
compression technique. Drug and Polyox N 12 K,Carbopol 940, PVP
K-30 and Dicalcium Phosphate were blended homogeneously with
the help of mortar. Blended mixture was passed through Sieve 60,
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Int J App Pharm, Vol 13, Issue 2, 2021, 242-248

finally Sodium bicarbonate and magnesium stearate,talc was added Characterization floating tablets of bisoprolol fumarate
and blended. The homogeneously blended mixture was compressed.
The final blend was then compressed into tablets on a 9-station Shape and appearance
rotary tablet machine (Rimek Mini Press–II, Karnavati, All formulations were prepared well and select randomly and picked
Ahemadabad,India) using 9-mm round plain punches. The detailed from each batch examined under the lens for shape and in the
composition of formulations is presented in table 3 [28, 29]. presence of light for color.
Optimization of the formulation parameters and the processing Tablet hardness
Concentrations of polyoxyethylene oxide polyox N 12 K (X1) and Hardness of the tablets was measured using a Monsanto hardness tester.
concentration Carbopol 940 P (X2) were selected as independent The hardness expressed in kg/cm2. For each batch three tablets were
variables, whereas gastro retentive parameters like floating lag tested. This tester applies force to the tablet diametrically [31].
time (Y1) and % Dug release at 10 h (Y2) were selected as
dependent variables as shown in table 1 and 2 [30]. Thickness
Five tablets of the formulation were picked randomly and thickness
was measured individually using a venire caliper.
Table 1: Layout of batches by 32 full factorial designs
Friability
Batch No. X1 X2
For each batch, 20 tablets were weighed and placed in the Roche
A1 -1 -1 friabilator and apparatus was rotated at 25 rpm for 4 min. After
A2 -1 0 revolutions, the tablets were de-dusted and weighed again. The
A3 -1 +1 percentage friability was measured using formula,
A4 0 -1
A5 0 0 …. (1)
A6 0 +1
A7 +1 -1 Where, % F = Friability in percentage W = Initial weight of tablets
A8 +1 0 Wt. = Weight of tablets after revolution.
A9 +1 +1 Friability below 1% was considered acceptable
Tablet weight variation
Table 2: Translation of coded value in an actual unit Weight variation was determined as per I. P. Results are expressed
as mean values±SD. 20 tablets were randomly selected from each
Coded value Polyox N12 K (X1) Carbopol 940 P(X2)
batch and individually weighed. The average weight and standard
-1 70 15 deviation of 20 tablets was calculated. The batch passes the test for
0 90 20 weight variation test if not more than two of the individual tablet
+1 110 25 weight deviates from the average weight [31].

Table 3: Composition of optimization batches

Ingredients (mg) Formulation batch code
A1 A2 A3 A4 A5 A6 A7 A8 A9
Bisoprolol Fumarate 20 20 20 20 20 20 20 20 20
Polyox N12 K 70 70 70 90 90 90 110 110 110
Carbopol 940 P 15 20 25 15 20 25 15 20 25
PVP K-30 10 10 10 10 10 10 10 10 10
Sodium Bicarbonate 45 45 45 45 45 45 45 45 45
Citric Acid 15 15 15 15 15 15 15 15 15
Talc 5 5 5 5 5 5 5 5 5
Magnesium Stearate 5 5 5 5 5 5 5 5 5
Dicalcium Phosphate QS QS QS QS QS QS QS QS QS
Total weight (mg) 260 260 260 260 260 260 260 260 260

*All the values are mean±SD of three determinations, QS =Quantity Sufficient

Drug content uniformity
5 Tablets are weighed and powdered, from it average weight
equivalent to dose of drug is weighed and added into 100 ml
volumetric flask; this powder is dissolved in 0.1 N HCl and sonicated
for 10 min. From the above solution, 1 ml is taken and diluted to 10
ml with 0.1 N HCl to get concentration of 50 μg/ml. Then this
solution is analyzed on UV Spectrophotometer using 222.0 nm
wavelengths. Each sample was analyzed in triplicate.
In vitro buoyancy study
The in vitro buoyancy was determined by floating lag time (FLT) and
total floating time (TFT). The time required for the tablet to rise to
the surface and float was determined as floating lag time. The tablets
were placed in a glass beaker, containing 100 ml of 0.1 N HCl as a
medium, maintained in a water bath at 37±0.5 °C. Floating lag time
and total floating duration were determined [32].
Water uptake studies
For each formulation batch, one tablet was weighed and placed in a
beaker containing 200 ml of 0.1 N HCl. After each interval the tablet
was removed from beaker and weighed again up to 12 h. The
swelling index study was performed in in triplicate and it calculated
by using following formula.
(Swelling index (S. I) = {(wt-wo)/wo} ×100 …. (2)
Where, S. I. = Swelling index
Wt. = Weight of tablet at time t
Wo = Weight of tablet before placing in the Beaker [32].
In vitro drug release studies
The release rate of Bisoprolol Fumarate from floating‐mucoadhesive
tablets was determined using USP dissolution testing apparatus II
(Paddle type). The dissolution test was performed by using 900 ml
of 0.1N HCl as a dissolution media having pH 1.2 as per USP
guidelines, at 37±0.5 °C and 75 rpm/min. A sample (1 ml) of the
solution was withdrawn from the dissolution apparatus hourly for
12 h, and the sample is replaced with fresh dissolution medium. The
samples were passed through what man filter paper and the
absorbance of these solutions was measured at 222 nm [33].

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Int J App Pharm, Vol 13, Issue 2, 2021, 242-248

Stability study
Stability studies were carried out at room temperature 40±20 °C and
75±5% RH for a specific time period up to 3 Mo for selected
formulations. For stability study, the tablets were sealed in
Aluminium packaging coated inside with polyethylene. These
sample containers were placed in Stability chamber and various
parameters were studied [34].
RESULTS AND DISCUSSION
FT-IR studies for drug–excipient compatibility
FTIR analysis was performed to authenticate the major functional
groups present in formulation blend. Compatibility studies of pure
drug Bisoprolol Fumarate with polymers were carried out prior to
the preparation of tablets. I. R spectra of pure drug Bisoprolol
Fumarate, and that of with polymers were obtained, which are
shown in fig. 1 to fig. 2. All the characteristic peaks of Bisoprolol
fumarate were present in spectra of formulation blend thus
indicating compatibility between drugs. It shows that there was no
significant change in the chemical integrity of the drug.
Physical properties of the compressed floating tablet systems
Floating tablets of Bisoprolol Fumarate were prepared by direct
compression method using various polymers such as Polyox N 12 K
and Carbapol 940 P. The results of the physical characteristics of
floating tablets are shown in table 4.

Fig. 1: FT-IR spectra of bisoprolol fumarate, the IR spectrum of pure drug was found to be similar to the reference standard IR Spectrum of
Bisoprolol fumarate given in Indian pharmacopoeia

Fig. 2: FT-IR spectra of formulation blend

Table 4: Physical properties of the compressed floating tablet systems

Formulations Hardness (kg/cm2) Thickness (mm) Friability (%) Weight variation (mg) Drug content (%)
A1 5.9 4.5±0.04 0.52±0.11 260±0.25 98.64±2.45
A2 5.8 4.5±0.02 0.42±0.01 260±1.25 98.85±1.80
A3 5.9 4.7±0.08 0.41±0.00 257±1.75 99.05±2.51
A4 6.0 4.3±0.07 0.50±0.09 261±1.25 98.75±3.66
A5 6.2 4.2±0.01 0.48±0.07 253±0.25 99.10±1.82
A6 6.5 4.8±0.09 0.43±0.02 255±2.25 97.95±2.17
A7 6.3 4.6±0.02 0.41±0.00 256±2.75 99.23±3.20
A8 6.4 4.4±0.02 0.45±0.04 263±1.75 98.86±2.12
A9 6.5 4.5±0.06 0.47±0.06 261±2.75 97.73±2.14

*All the values are mean±SD of three determinations

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All Formulations were prepared well and select randomly and Oxide (PEO)(X1) and Carbopol 940 P (X2) have a significant effect on
picked from each batch examined under lens for shape and in floating lag time. Moreover, the effect of the polymer Carbopol 940 P
presence of light for color. Tablets showed standard concave had significantnegative effect of on the floating lag times means
surfaces with circular shape. Tablets were white in color. increase Carbopol 940 amount (X2) will be accompanied by significant
Thickness of the tablets was measured using calibrated dial reduction in the floating lag times it might be due to the hydrophilic
calipers by picking three tablets randomly from all the batches. nature of Carbopol 940P produces faster medium penetration rate,
The physical evaluation of the tablets revealed uniform thickness. and thus, shorter time for gel layer formation these findings are
All the tablets passed the weight variation test, i.e., average similar to what has been reported by [36].
percentage weight variation was found within the pharmacopoeia
limits of±10%. Hardness or crushing strength of the tablets of all
the formulation was found between 5.8 and 6.5 kg/cm. Low Design-Expert® Software
Factor Coding: Actual FLT (MINUTES)
friability values (below0.41%) across all formulations indicated FLT (MINUTES)
Design Points
25
1.8
that the tablets possess good mechanical strength. The obtained 2.43

results were found to be well within the approved range (<1%) in 1.18
23
all the designed formulations. The drug content uniformity was X1 = A: PEO N 12 K

B: CARBOPOL 940 (MG)

X2 = B: CARBOPOL 940 2
examined as per I. P specification. All the batches of tablets were
found to comply with uniformity of content test. The drug content 21
1.8
uniformity studies revealed that drug content between 97.73±2.14 5
1.6
1.4

and 99.23±3.20 % is acceptable [35]. 2.2

19

Effect of independent variables on floating lag time (Y1)

Floating tablets is usually fabricated in such a way that its density 17

becomes low enabling it to float over gastric fluid. One of the crucial 2.4
factor in designing of floating drug delivery is floating lag time.
Sodium bicarbonate is responsible for the buoyancy of the tablets
15
70 80 90 100 110
due to the formation of CO2, when it came in contact with SGF pH
1.2. The observed results of floating lag times [35] and total floating A: PEO N 12 K (MG)
time of all formulations are displayed in table 5. Buoyancy study of
batches A1 to A9 shows good buoyancy characteristics. Total Fig. 4: A counter plot showing relationship between various
floating time of all the formulation was determined. levels of independent variables to gain fixed value of floating
lag time

Table 5: In vitro buoyancy study of optimized batches

Mathematical relationship in the form of polynomial equation for the
Formulation codes Floating lag time (min) Total FLT hours measured response floating lag time was obtained and given in
A1 2.30±1.24 >12 equation 3 below. Positive sign of X in the regression equation
A2 2.43±1.6 >12 indicated agonistic effect and negative sign of X in the regression
A3 1.45±1.8 >12 equation indicated antagonistic effect of independent variables on
A4 2.24±1.7 >12 response.
A5 2.1±1.4 >12
A6 2.14±2.0 >12 Final Equation in Terms of Coded Factors: FLT =+2.07-0.43 * A-0.16*
A7 1.20±1.5 >12 B+0.21 * A * B-0.41 * A2-0.038 * B2 (3)
A8 1.20±1.2 >12 Water uptake study
A9 1.18±2.0 >12
The swelling behaviour of of Bisoprolol fumarate floating
*All the values are mean±SD of three determinations throughout a period of 12 h is graphically illustrated in fig. 6.
Swelling of tablet excipients particles involves the absorption of a
Design-Expert® Software
liquid resulting in an increase in weight and volume. The swelling
Factor Coding: Actual
FLT (MINUTES) index of the tablets increases with an increase in the polymer
Design points above predicted value
Design points below predicted value concentration, specially and Carbopol 940 P, since the hydration of
such functional groups leads to solvent penetration inside the
2.43

1.18 2.6

X1 = A: PEO N 12 K
2.4 polymer matrix resulting in polymer network expansion and
X2 = B: CARBOPOL 940 2.2
arrangement of the polymer chains. When erosion of polymer
FLT (MINUTES)

2
1.8 dominates over water sorption hence the reduction in tablet weight
1.6
1.4
occurs because of constant due to constant erosion of matrix [37].
1.2
1 The Swelling Index of optimized batches is shown in fig. 5.

25

23

21
110
19 100
B: CARBOPOL 940 (MG)
90
17
80
15 70
A: PEO N 12 K (MG)

Fig. 3: A response surface plot showing effect of concentration

of independent variables on the floating lag time

To evaluate the effect of independent variables on floating lag time

design, expert software was used. A quadratic Model model was
suggested for floating lag time because of the significant p-
value(0.0045). From response surface plot and contour plot is cited in
fig. 4 and fig. 5. it can be observed that both polymers polyethylene Fig. 5: % Swelling index of optimized batches

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Int J App Pharm, Vol 13, Issue 2, 2021, 242-248

Polyox is a nonionic, highly swelling hydrophilic polymer absorbing decreased effect of Carbopol at higher amounts could be possibly
7 times its initial weight of water. The swelling ability of the tablets due the saturation of interstitial space between the swollen gel
could be attributed to the existence of hydrophilic moieties on both particles. Combination of the prolonged gastric residence time and
Polyox N 12K and Carbopol 940 P [38, 39]. sustained drug release is expected to improve therapeutic effect and
patient’s compliance [40].
Effect of independent variables on In vitro drug release (Y2)
Design-Expert was used to determine the degree of effect of each
polymer on the percent of drug release [40] is cited in fig. 6 and fig. 7 Design-Expert® Software
Factor Coding: Actual
% DR (percentage)
Design points above predicted value

The In vitro drug release studies of factorial batches were carried Design points below predicted value
100.22

out using USP Type II dissolution assembly. 91.65

% DR (percentage) = 91.65
Std # 9 Run # 9
X1 = A: PEO N 12 K = 110
X2 = B: CARBOPOL 940 = 25 102
100

% DR (percentage)
98
96
94
92
90 110

100
25
23
90
21
19 80
A: PEO N 12 K (MG)
17
B: CARBOPOL 940 (MG) 15 70

Fig. 8: A response surface plot showing effect of concentration

of independent variables on the % drug release
Fig. 6: % Drug release in graphical presentation: (A1 to A5)

Design-Expert® Software
Factor Coding: Actual % DR (percentage)
% DR (percentage) 25
Design Points
100.22

91.65
23
X1 = A: PEO N 12 K
94

B: CARBOPOL 940 (MG)

X2 = B: CARBOPOL 940

21

100 98 5 96

19

17

15
70 80 90 100 110

Fig. 7: % Drug release in graphical presentation: (A6 toA9)

A: PEO N 12 K (MG)

Mathematical relationship in the form of polynomial equation for the Fig. 9: A counterplot of showing the relationship between
measured response (%CDR at 10 h) was obtained and given in the various levels of independent variables to gain fixed value of %
equation below 4. drug release

% DR =+85.75-4.7* A-2.23* B+4.63* A* B …. (4)

The response surface and contour plots presenting the effects of the
independent variables on drug release are illustrated in fig. 9 and 10.
It is clear from these fig. that both polymers decrease the percent of
drug release. In addition, Eqs. (4) Show that Carbopol 940 P has a
more pronounced effect on the percent of drug released. This is
because of hydrophobic characteristics of the Carbopol 940 P. The
Optimization data analysis for the floating mucoadhesive tablets
Responses observed for nine formulations were fitted to Design
Expert Software. All values of R 2, degree of freedom and %
coefficient of variance etc were shown in table 6. Results of ANOVA
in table 6. for the dependent variables demonstrated that the model
was significant for all the three response variables [41].

Table 6: Result of ANOVA

Response model Sum of square Degree of freedom Mean square F value P value R square Ade. precision
Floating Lag time 2.05 5 0.41 9.89 0.0045 0.8759 9.263
% Drug release 250.96 3 83.65 3.87 0.0496 0.9636 7.281

From data given in table 6 it can be concluded that as predicted values agreed well with the experimental values, demonstrating the feasibility of the
model in the development of floating tablet dosage form.

Table 7: Stability studies of optimized A3 batch

Parameters Hardness (Kg/cm2) Friability (%) Drug content (%) Floating lag time (min)
Initial 5.9±2.1 0.41±0.00 99.05±2.51 1.45±1.8
After storage 5.7±1.8 0.54±0.41 98.65±1.04 2.43±1.2

*All the values are mean±SD of three determinations

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Stability study
Stability study is carried out on an optimized batch (A3) of
Bisoprolol fumarate floating tablets. As per table VII the tablet did
not show any physical changes during the study period, which is
show in table VII and the drug content was found to be
98.65±1.04%, On the basis of results of the stability study we
concluded that Designed formulation was stable after stability study.
CONCLUSION
In this study, an optimized novel floating tablets of Bisoprolol
Fumarate were was successfully prepared by using various
polymers such as Polyox N 12 K and Carbapol 940 P. Developed
floating tablet found to be good without chipping, capping
characteristics. Hardness or crushing strength of the tablets of all
the formulation was found between 5.8 and 6.5 kg/cm2. Floating lag
time of all batches are in range of 1.18±2.0 to 2.43±1.6 (minutes).
The polymer Carbopol 940 P had the significant negative effect of on
the floating lag times. The In vitro dissolution profiles of optimized
A3 floating formulation of Bisoprolol Fumarate were found to
sustain drug release 99.25 % up to 12 h with floating lag time of 1.45
min. 32full factorial design and optimization technique successfully
used in the fabrication of these formulations. Furthermore,
developed formulations were stable after stability study. The
promising outcomes from the current studies is selected Bisoprolol
Fumarate floating tablets could be regarded as a promising
gastroretentive drug delivery system that could improve the
bioavailability and hence Patient compliance.
ACKNOWLEDGEMENT
The authors are thankful to Hazrat Maulana G. M Vastanvi Sahab,
President, Jamia Islamia Ishaatul Uloom’s Ali Allana College of
Pharmacy Akkalkuwa, Dist-Nandurbar for providing the Research
work facilities.
FUNDING
Nil
AUTHORS CONTRIBUTIONS
All the authors have contributed equally.
CONFLICT OF INTERESTS
Declared none
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248
 MAKALAH

PREFORMULASI SEDIAAN FARMASI

Disusun untuk memenuhi salah satu tugas preformulasi

Disusun Oleh :

Kelompok 6 FA2

Selvia Putri Anugrah (221FF03049)

Dini Hikmah Rahayu (221FF03056)
Jesika Agustina (221FF03059)
Ilham Abdul Aziz Firdaus (221FF03062)
Nita Fatmawangi (221FF03064)
Karlina (221FF03066)
Sheila Putri As (221FF03074)

Dosen Pengampu :
Novaliana Devianti Sagita S.Farm,M.Farm.

PRODI S1 FARMASI FAKULTAS FARMASI

UNIVERSITAS BHAKTI KENCANA
TAHUN AJARAN 2023/2024

i
 KATA PENGANTAR

Puji syukur kami panjatkan atas kehadirat Tuhan Yang Maha Esa yang
telah memberikan kesehatan dan rahmat-Nya kepada kami sehingga kami dapat
menyelesaikan makalah yang berjudul “ Riview Jurnal” dengan baik dan tepat
waktu.

Demikian pula kami menyadari bahwa dalam penulisan makalah ini kami
masih banyak kekurangan dan kesalahan baik dalam segi substansi maupun tata
bahasa. Namun, kami tetap berharap agar makalah ini dapat memberikan
manfaat bagi pembaca. Oleh karena itu, kritik dan saran dari penulisan makalah
ini sangat kami harapkan dengan harapan sebagai masukan dalam perbaikan dan
penyempurnaan pada makalah kami berikutnya.

Akhir kata, atas perhatiannya untuk itu kami ucapkan terima kasih.

Bandung , 22 Februari 2024

Penulis

ii
 DAFTAR ISI

KATA PENGANTAR.................................................................................................................... i

DAFTAR ISI................................................................................................................................... ii

DAFTAR TABEL .......................................................................................................................... iii

BAB I PENDAHULUAN............................................................................................................... 1

1.1 Latar Belakang........................................................................................................... 1

1.2 Rumusan Masalah...................................................................................................... 2
1.3 Hipotesis...................................................................................................................... 2

BAB II METODOLOGI................................................................................................................ 3

2.1 Bahan dan Metodologi.............................................................................................. 3

BAB III PEMBAHASAN............................................................................................................... 6

3.1 Hasil Diskusi.............................................................................................................. 6

BAB IV PENUTUP.........................................................................................................................12

4.1 Kesimpulan................................................................................................................. 12

DAFTAR PUSTAKA..................................................................................................................... 13

iii
 BAB I

PENDAHULUAN

1.1 Latar Belakang

Selama beberapa dekade terakhir, retensi lambung telah mendapatkan

popularitas besar di segmen pemberian obat oral. banyak sekali Sistem
penghantaran obat gastroretentif (GRDDS) telah dirancang untuk menahan
obat di daerah lambung untuk waktu yang lama dan melepaskan obat yang
dimasukkan. dan dengan demikian memungkinkan memasukkan obat yang
berkelanjutan dan berkepanjangan ke bagian atas saluran pencernaan akan
menghasilkan bioavailabilitas yang optimal.
Teknik yang dilaporkan untuk pembuatan GRDDS adalah
mengambang, sedimentasi, dan mukoadhesi. sistem pembengkakan dan
perluasan merupakan bentuk yang dimodifikasi. teknik yang menunjukkan
bukti klinis untuk waktu tinggal lambung yang lama adalah mengambang,
bengkak dan mukoadhesi.
Sistem penghantaran obat dosis mengambang (FDDS) mempunyai
daya apung yang cukup untuk mengapung di atas isi lambung pada waktu
yang lebih lama dan oleh karena itu meningkatkan bioavailabilitas obat yang
terutama diserap di lambung.
Sistem mukoadhesif mampu melekatkan selaput lendir sehingga dapat
mencegah perjalanannya melalui pilorus dan bentuk sediaannya tertahan di
lambung untuk jangka waktu yang lebih lama.
Hipertensi didefinisikan sebagai tekanan darah tinggi yang tidak
normal (lebih dari 120/80 mm Hg) di arteri. Umumnya gejalanya lebih
ringan, namun dapat meningkatkan risiko berbagai penyakit CVS lainnya
seperti Stroke, Serangan Jantung, dan penyakit non-CVS seperti kerusakan
ginjal, gagal ginjal stadium akhir.
Oleh karena itu tujuan dari penelitian ini adalah dengan pendekatan
effervescent berbasis tablet Apung Bisoprolol yang dibuat dengan
menggunakan berbagai polimer seperti Polyox N 12 K dan Carbapol 940 P
dengan bantuan perangkat lunak ahli desain.

1
1.2 Rumusan Masalah :

 Apa saja teknik yang digunakan dalam pembuatan GRDDS?

 Sebutkan Karakterisasi tablet mengambang bisoprolol fumarat?
 Apakah Laju pelepasan Bisoprolol Fumarate dari tablet mukoadhesif terapung
ditentukan dengan menggunakan alat uji disolusi USP II (tipe Paddle)?
 Salah satu faktor krusial dalam perancangan pemberian obat terapung ialah?
 Mengapa digunakannya Design-Expert dalam pelepasan obat in vitro (Y2)?

1.3 Hipotesis :

Studi spektroskopi FTIR menunjukkan tidak ada interaksi obat-eksipien dalam

formulasi yang dibuat. Kekerasan atau kekuatan menghancurkan tablet dari semua
formulasi ditemukan antara 5,8 dan 6,5 kg/cm2. Waktu jeda mengambang untuk semua
batch berkisar antara 1,18±2,0 hingga 2,43±1,6 (menit). Semua parameter lain dari
semua batch berada dalam kisaran yang dapat diterima. Polimer Carbopol 940 P
mempunyai pengaruh negatif yang signifikan terhadap floating lag time. Profil disolusi
in vitro dari formulasi A3 Floating yang dioptimalkan dari Bisoprolol Fumarate
ditemukan dapat mempertahankan pelepasan obat 99,25 % hingga 12 jam dengan
waktu jeda mengambang 1,45 menit; Formulasi yang dirancang stabil setelah studi
Stabilitas. Studi optimasi dilakukan dengan menggunakan 32 desain faktorial untuk
membuat formulasi.
Adapun studi stabilitas dilakukan pada batch optimal (A3) ialah tablet
mengambang bisoprolol fumarat. Sesuai tabel VII, tablet tidak menunjukkan perubahan
fisik apa pun selama masa penelitian, seperti yang ditunjukkan pada tabel VI.I dan
kandungan obat ditemukan 98,65±1,04%, Berdasarkan hasil studi stabilitas kami
menyimpulkan bahwa formulasi yang dirancang stabil. dilakukannya fokus penelitian
ini ialah untuk merumuskan Desain tablet apung Bisoprolol Fumarate berbantuan
Software ahli. Bisoprolol Fumarate adalah agen penghambat adrenergik Beta, yang
digunakan untuk mengobati penyakit jantung dengan karakter yang menguntungkan
untuk diformulasikan sebagai tablet apung retentif Gastro pelepasan berkelanjutan.

2
 BAB II

METODOLOGI

2.1 Bahan dan Metodologi

 Bahan :

Bisoprolol Fumarate,Polietilen oksida (Polyox 12 K) Carbopol 940P, Sodium Talk,

Bicarbonate, talk, Citric Acid, PVP K-30, Magnesium stearate,dan Dicalcium Phosphate.

 Metode :

- Kompatibilitas obat-eksipien :
Spektrum Inframerah Bisoprolol Fumarate murni, formulasi yang dioptimalkan
dicatat antara 600 dan 4000 cm-1 dengan Spektrometer FT-IR menggunakan teknik
pelet KBr untuk mengetahui kemungkinan interaksi obat-eksipien.

- Pembuatan tablet mengambang bisoprolol fumarat:

Semua tablet terapung dibuat dengan menggunakan teknik kempa langsung.obat dan
Polyox N 12 K, Carbopol 940, PVP K-30 dan Dicalcium Phosphate dicampur secara
homogen dengan bantuan mortar. Campuran campuran dilewatkan melalui Saringan
60,Natrium bikarbonat dan magnesium stearat, bedak ditambahkan dan dicampur.
Campuran yang tercampur homogen dikompres.Campuran akhir kemudian dikompresi
menjadi tablet pada mesin tablet putar menggunakan pukulan polos bulat 9 mm.

- Optimalisasi parameter formulasi dan pengolahan :

Konsentrasi polioksietilen oksida polioks N 12 K (X1) dan konsentrasi Karbopol 940
P (X2) dipilih sebagai variabel independen, sedangkan parameter retensi gastro seperti
floating lag time (Y1) dan % pelepasan Dug pada 10 jam (Y2) dipilih sebagai variabel
dependen.
- Tablet Apung Bisoprolol Fumarate dibuat dengan menggunakan polimer seperti
Polyox N 12 K dan Carbapol 940 P.
Formulasi dibuat dengan menggunakan metode kempa langsung dan dievaluasi
dengan berbagai parameter seperti kekerasan, ketebalan, variasi berat, Floating lag time
Total floating time ,% pelepasan obat dan Studi Stabilitas dll.

- Karakterisasi tablet mengambang bisoprolol fumarat

- Bentuk dan penampilan
Semua formulasi disiapkan dengan baik dan dipilih secara acak dan dipilih dari setiap
batch yang diperiksa di bawah lensa untuk mengetahui bentuknya dan di hadapan
cahaya untuk mengetahui warnanya.

3
- Kekerasan tablet
Kekerasan tablet diukur menggunakan alat uji kekerasan Monsanto. Kekerasan
dinyatakan dalam kg/cm2. Untuk setiap batch, tiga tablet diuji. Penguji ini menerapkan
gaya pada tablet secara diametris.

- Ketebalan
Lima tablet formulasi dipilih secara acak dan ketebalan diukur secara individual
menggunakan jangka sorong.

- Kerapuhan
Untuk setiap batch, 20 tablet ditimbang dan ditempatkan dalam friabilator Roche dan
peralatan diputar pada 25 rpm selama 4 menit. Setelah revolusi, tablet-tablet tersebut
dibersihkan dari debunya dan ditimbang kembali. Dimana, %F = Kerapuhan dalam
persentase W = Berat awal tablet Wt. = Berat tablet setelah revolusi. Kerapuhan di
bawah 1% dianggap dapat diterima.

- Variasi berat tablet

Variasi bobot ditentukan sesuai IP. Hasil dinyatakan sebagai nilai rata-rata ± SD. 20
tablet dipilih secara acak dari setiap batch dan ditimbang satu per satu. Berat rata-rata
dan deviasi standar 20 tablet dihitung. Batch lolos uji uji variasi berat jika tidak lebih
dari dua berat tablet individu menyimpang dari berat rata-rata.

- Keseragaman kandungan obat

5 Tablet ditimbang dan dijadikan bubuk, ditimbang berat rata-rata setara dengan dosis
obat dan dimasukkan ke dalam labu takar 100 ml; bubuk ini dilarutkan dalam HCl 0,1
N dan disonikasi selama 10 menit. Dari larutan di atas diambil 1 ml dan diencerkan
hingga 10 ml dengan HCl 0,1 N hingga diperoleh konsentrasi 50 ÿg/ml. Kemudian
larutan ini dianalisis pada Spektrofotometer UV dengan menggunakan panjang
gelombang 222,0 nm. Setiap sampel dianalisis dalam rangkap tiga. Studi daya apung in
vitro Daya apung in vitro ditentukan oleh floating lag time (FLT) dan total waktu
mengambang (TFT). Waktu yang diperlukan tablet untuk naik ke permukaan dan
mengapung ditentukan sebagai floating lag time. Tablet ditempatkan dalam gelas kimia
yang berisi 100 ml HCl 0,1 N sebagai media, disimpan dalam penangas air pada suhu
37±0,5 °C. Waktu jeda mengambang dan total durasi mengambang ditentukan.

- Studi serapan air

Untuk setiap batch formulasi, satu tablet ditimbang dan ditempatkan dalam gelas kimia
yang berisi 200 ml HCl 0,1 N. Setelah setiap interval tablet dikeluarkan dari gelas
kimia dan ditimbang kembali hingga 12 jam. Studi indeks pembengkakan dilakukan
dalam rangkap tiga dan dihitung dengan menggunakan rumus berikut (Indeks
pembengkakan (S.I) = {(wt-wo)/wo} ×100 Dimana SI = Indeks Pembengkakan Berat.
= Berat tablet pada waktu

4
 Wo = Berat tablet sebelum dimasukkan ke dalam gelas kimia [32]. Studi pelepasan
obat in vitro Laju pelepasan Bisoprolol Fumarate dari tablet mukoadhesif terapung
ditentukan dengan menggunakan alat uji disolusi USP II (tipe Paddle). Uji disolusi
dilakukan dengan menggunakan 900 ml HCl 0,1N sebagai media disolusi yang
memiliki pH 1,2 sesuai pedoman USP, pada suhu 37±0,5 °C dan 75 rpm/menit. Sampel
(1 ml) larutan dikeluarkan dari alat disolusi setiap jam selama 12 jam, dan sampel
diganti dengan media disolusi baru. Sampel dilewatkan melalui kertas saring manusia
dan serapan larutan ini diukur pada 222 nm .

- Studi stabilitas
Studi stabilitas dilakukan pada suhu kamar 40±20 °C dan RH 75±5% untuk jangka
waktu tertentu hingga 3 Mo untuk formulasi terpilih. Untuk studi stabilitas, tablet
disegel dalam kemasan Aluminium yang bagian dalamnya dilapisi dengan polietilen.
Wadah sampel ini ditempatkan di ruang Stabilitas dan berbagai parameter dipelajari.

5
 BAB III

PEMBAHASAN

3.1 Hasil Diskusi

Studi FT-IR untuk kompatibilitas obat-eksipien

Analisis FTIR dilakukan untuk mengotentikasi gugus fungsi utama yang ada
dalam campuran formulasi. Studi kompatibilitas murni obat Bisoprolol Fumarate
dengan polimer dilakukan sebelum pembuatan tablet. Spektrum I R dari obat
murni Bisoprolol Fumarate, dan spektrum dengan polimer diperoleh, yang
ditunjukkan pada gambar 1 sampai gambar. 2. Semua puncak karakteristik
Bisoprolol fumarat terdapat dalam spektrum campuran formulasi sehingga
menunjukkan kompatibilitas antar obat. Hal ini menunjukkan bahwa tidak ada
perubahan signifikan pada integritas kimia obat.

Gambar 1 :
Spektrum FT-IR bisoprolol fumarat,spektrum IR obat murni ditemukan
serupa dengan standar referensi Spektrumm Bisoprolol fumarat yang
diberikan dalam farmakope.

Gambar 2 :
Spektrum FT-IR campuran formulasi

6
 Sifat fisik dari sistem tablet mengambang terkompresi
Tablet terapung Bisoprolol Fumarate dibuat dengan metode kempa langsung
menggunakan berbagai polimer seperti Polyox N 12 K dan Carbapol 940 P. Hasil
karakteristik fisik tablet terapung ditunjukkan pada tabel 4.

Semua Formulasi disiapkan dengan baik dan dipilih secara acak dan dipilih dari
setiap kelompok, diperiksa di bawah lensa untuk bentuknya dan di hadapan cahaya
untuk warna. Tablet menunjukkan permukaan cekung standar dengan bentuk
melingkar. Tablet berwarna putih.Ketebalan tablet diukur menggunakan kaliper dial
yang dikalibrasi dengan mengambil tiga tablet secara acak dari semua batch Evaluasi
fisik tablet menunjukkan ketebalan yang seragam.
Semua tablet lulus uji variasi berat, yaitu persentase rata-rata variasi berat
ditemukan dalam batas farmakope ±10%. Kekerasan atau kekuatan menghancurkan
tablet dari semua formulasi ditemukan antara 5,8 dan 6,5 kg/cm. Nilai kerapuhan yang
rendah (di bawah 0,41%) pada seluruh formulasi menunjukkan bahwa tablet memiliki
kekuatan mekanik yang baik. Hasil yang diperoleh ditemukan berada dalam kisaran
yang disetujui (<1%) di semua formulasi yang dirancang. Keseragaman kandungan
obat diperiksa sesuai spesifikasi I.P. Semua batch tablet ditemukan memenuhi uji
keseragaman konten. Studi keseragaman kandungan obat menunjukkan bahwa
kandungan obat antara 97,73±2,14 dan 99,23±3,20% dapat diterima
.
Pengaruh variabel independen terhadap floating lag time (Y1)
Tablet terapung biasanya dibuat sedemikian rupa sehingga kepadatannya menjadi
rendah sehingga dapat mengapung di atas cairan lambung. Salah satu faktor krusial
dalam perancangan pemberian obat terapung adalah floating lag time. Natrium
bikarbonat bertanggung jawab atas daya apung tablet karena pembentukan CO2, ketika
bersentuhan dengan SGF pH 1,2. Hasil pengamatan floating lag time [35] dan total
floating time seluruh formulasi ditampilkan pada tabel 5. Studi daya apung batch A1
hingga A9 menunjukkan karakteristik daya apung yang baik. Total waktu mengambang
seluruh formulasi ditentukan.

7
 Untuk mengevaluasi pengaruh variabel independen pada desain floating lag time,
digunakan perangkat lunak ahli. Model Model kuadrat disarankan untuk jeda waktu
mengambang karena nilai p yang signifikan (0,0045). Dari plot permukaan respons dan
plot kontur dikutip dalam gambar 4 dan gambar. 5. dapat diamati bahwa kedua polimer
tersebut adalah polietilen Oxide (PEO)(X1) dan Carbopol 940 P (X2) berpengaruh
signifikan terhadap floating lag time. Selain itu, pengaruh polimer Carbopol 940 P
mempunyai pengaruh negatif yang signifikan terhadap floating lag time yang berarti
peningkatan jumlah Carbopol 940 (X2) akan disertai dengan penurunan floating lag
time yang signifikan hal ini mungkin disebabkan oleh sifat hidrofilik dari Carbopol
940P yang dihasilkan. tingkat penetrasi media yang lebih cepat, dan dengan demikian,
waktu yang lebih singkat untuk pembentukan lapisan gel

8
Indeks Pembengkakan dari batch yang dioptimalkan ditunjukkan pada gambar. 5.

Studi serapan air

Perilaku pembengkakan Bisoprolol fumarat yang mengambang selama periode 12
jam diilustrasikan secara grafis pada gambar 6 .Pembengkakan partikel eksipien
tablet melibatkan penyerapan cairan yang mengakibatkan peningkatan berat dan
volume. Indeks pembengkakan tablet meningkat seiring dengan peningkatan
konsentrasi polimer, khususnya dan Carbopol 940 P, karena hidrasi gugus fungsi
tersebut menyebabkan penetrasi pelarut ke dalam matriks polimer yang
mengakibatkan perluasan jaringan polimer dan susunan rantai polimer. Ketika erosi
polimer mendominasi penyerapan air maka penurunan berat tablet terjadi karena
konstan akibat erosi matriks yang konstan Polyox adalah polimer hidrofilik nonionik
yang sangat mengembang dan menyerap 7 kali berat air awalnya. Kemampuan tablet
untuk mengembang dapat disebabkan oleh adanya gugus hidrofilik pada Polyox N
12K dan Carbopol 940 P.

Pengaruh variabel independen terhadap pelepasan obat in vitro (Y2)

Design-Expert digunakan untuk menentukan tingkat pengaruh masing-masing
polimer terhadap persen pelepasan obat [40] dikutip dalam gambar 6 dan gambar 7.
Studi pelepasan obat in vitro dari batch faktorial dilakukan dengan menggunakan
perakitan disolusi USP Tipe II.

9
 Permukaan respons dan plot kontur yang menyajikan pengaruh variabel
independen terhadap pelepasan obat diilustrasikan pada gambar 9 Jelas dari
gambar ini. bahwa kedua polimer menurunkan persen pelepasan obat. Selain itu,
Persamaan. (4) Tunjukkan bahwa Carbopol 940 P mempunyai pengaruh yang lebih
nyata terhadap persentase pelepasan obat. Hal ini karena karakteristik hidrofobik
dari Carbopol 940 P. penurunan efek Carbopol pada jumlah yang lebih tinggi
mungkin disebabkan oleh kejenuhan ruang interstisial antara partikel gel yang
membengkak. Kombinasi waktu tinggal lambung yang lama dan pelepasan obat
yang berkelanjutan diharapkan dapat meningkatkan efek terapeutik dan kepatuhan
pasien.

10
 Analisis data optimasi untuk tablet mukoadhesif mengambang. Respon yang
diamati untuk sembilan formulasi disesuaikan dengan Perangkat Lunak Pakar
Desain. Semua nilai R2, derajat kebebasan dan % koefisien varians dll
ditunjukkan pada tabel 6. Hasil ANOVA pada tabel 6. untuk variabel dependen
menunjukkan bahwa model tersebut signifikan untuk ketiga variabel respon.

Studi stabilitas

Studi stabilitas dilakukan pada batch optimal (A3) tablet mengambang

Bisoprolol fumarat. Sesuai tabel VII tablet tidak menunjukkan perubahan fisik
apa pun selama masa penelitian, seperti yang ditunjukkan pada tabel VII dan
kandungan obat ditemukan 98,65±1,04%, Berdasarkan hasil studi stabilitas kami
menyimpulkan bahwa formulasi yang dirancang stabil setelah studi stabilitas.

11
 BAB IV

PENUTUP

4.1 Kesimpulan :

Dalam penelitian ini, tablet terapung baru yang dioptimalkan dari Bisoprolol
Fumarate berhasil dibuat dengan menggunakan berbagai polimer seperti Polyox N
12 K dan Carbapol 940 P. Tablet terapung yang dikembangkan ternyata baik tanpa
terkelupas, tertutup. karakteristik. Kekerasan atau kekuatan menghancurkan tablet
dari semua formulasi ditemukan antara 5,8 dan 6,5 kg/cm2. Waktu jeda
mengambang untuk semua batch berada dalam kisaran 1,18±2,0 hingga 2,43±1,6
(menit).
Polimer Carbopol 940 P mempunyai pengaruh negatif yang signifikan terhadap
floating lag time. Profil disolusi in vitro dari formulasi mengambang A3 yang
dioptimalkan dari Bisoprolol Fumarate ditemukan dapat mempertahankan
pelepasan obat 99,25 % hingga 12 jam dengan waktu jeda mengambang 1,45 menit.
32desain faktorial lengkap dan teknik optimasi berhasil digunakan dalam
pembuatan formulasi ini. Selain itu, formulasi yang dikembangkan stabil setelah
dilakukan studi stabilitas. Hasil yang menjanjikan dari penelitian saat ini adalah
tablet mengambang Bisoprolol Fumarate yang dipilih dapat dianggap sebagai
sistem penghantaran obat gastroretentif yang menjanjikan yang dapat
meningkatkan bioavailabilitas dan kepatuhan pasien.

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minocycline hidroklorida: formulasi, evaluasi dan optimasi in vitro .
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