Formulation Design, Optimization and Evaluation of Carvedilol Phosphate Gastro Retentive Floating Tablets

Current Research in Pharmaceutical Sciences 2015; 05 (04): 124-135
124
ISSN 2250 – 2688
Received: 03/12/2015
Revised: 18/12/2015
Accepted: 26/12/2015
Raghavendra Kumar Gunda, J N
Suresh Kumar, V Satyanarayana, G
Swarupa Rani, G Venkateswarlu
Narasaraopeta Institute of
Pharmaceutical Sciences, Narasaraopet,
Guntur (Dt), Andhra Pradesh, India-
522601
Correspondence
Raghavendra Kumar Gunda
Department of Pharmaceutics
Narasaraopeta Institute of
Pharmaceutical Sciences, Narasaraopet,
Guntur (Dt), Andhra Pradesh, India-
522601
E-mail: raghav.gunda@gmail.com
Formulation Design, Optimization and Evaluation of Carvedilol
Phosphate Gastro Retentive Floating Tablets
Raghavendra Kumar Gunda, J N Suresh Kumar, V Satyanarayana, G
Swarupa Rani, G Venkateswarlu
e
ABSTRACT
The main objective of present research work is to formulate the floating tablets of Carvedilol
Phosphate using 32
factorial design. Carvedilol Phosphate, non-selective α1-β1-blocking agent
belongs to BCS Class-II and Indicated for treatment of Hypertension/moderate Heart Failure.
The Floating tablets of Carvedilol Phosphate were prepared employing different
concentrations of HPMCK100M and Sodium bicarbonate in different combinations by Direct
Compression technique using 32
factorial design. The concentration of HPMCK100M and
Sodium bicarbonate required to achieve desired drug release was selected as independent
variables, X1 and X2 respectively whereas, time required for 10% of drug dissolution (t10%),
50% (t50%), 75% (t75%) and 90% (t90%) were selected as dependent variables. Totally nine
formulations were designed and are evaluated for hardness, friability, thickness, % drug
content, Floating Lag time, In-vitro drug release. From the Results concluded that all the
formulation were found to be with in the Pharmacopoeial limits and the In-vitro dissolution
profiles of all formulations were fitted in to different Kinetic models, the statistical
parameters like intercept (a), slope (b) & regression coefficient (r) were calculated.
Polynomial equations were developed for t10%, t50%, t75%, t90%. Validity of developed
polynomial equations were verified by designing 2 check point formulations (C1, C2).
According to SUPAC guidelines the formulation (F8) containing combination of 25%
HPMCK100M and 3.75% Sodium bicarbonate, is the most similar formulation (similarity
factor f2=88.801, dissimilarity factor f1= 2.250 & No significant difference, t= 0.095) to
marketed product (CARDIVAS). The selected formulation (F8) follows Higuchi’s kinetics,
and the mechanism of drug release was found to be Non-Fickian Diffusion (n= 1.035, Super
Case-II transport).
Keywords: Carvedilol Phosphate, 32
Factorial Design, Gastro retentive Floating Tablet,
HPMCK100M, Floating Lag Time, SUPAC.
1. INTRODUCTION
Oral administration is the most convenient, widely used route for both conventional and
novel drug delivery systems, and preferred route of drug delivery for systemic action. Tablets are
the most popular oral solid formulations available in the market and are preferred by patients and
physicians alike. There are many reasons for this, not the least of which would include acceptance
by the patient and ease of administration. patient compliance and flexibility in formulation etc.
From immediate release to site specific delivery, oral dosage forms have really progressed.

125
In long-term therapy for the treatment of chronic disease
conditions, conventional formulations are required to be
administered in multiple doses and therefore have several
disadvantages1
. However, when administered orally, many
therapeutic agents are subjected to extensive presystemic
elimination by gastrointestinal degradation and/or first pass hepatic
metabolism as a result of which low systemic bioavailability and
shorter duration of therapeutic activity and formation of inactive or
toxic metabolites2
.
Rapid gastrointestinal transit can result in incomplete drug
release from a device above the absorption zone, leading to
diminished efficacy of the administered dose. Therefore, different
approaches have been proposed to retain the dosage form in the
stomach. These include bioadhesive systems, swelling and
expanding systems and floating systems. Large single-unit dosage
forms undergo significant swelling after oral administration, and
the swollen matrix inhibits gastric emptying even when the pyloric
sphincter is in an uncontracted state3
. Gastric floating drug
delivery system (GFDDS) can overcome at least some of these
problems and is particularly useful for drugs that are primarily
absorbed in the duodenum and upper jejunum segments. The
GFDDS is able to prolong the retention time of a dosage form in
the stomach, thereby improving the oral bioavailability of the drug.
Gastroretentive dosage forms significantly extend the period of
time, over which drug may be released and thus prolong dosing
intervals and increase patient compliance.4,5
Such retention systems
are important for certain kind of drugs, which are degraded in the
intestine like antacids or certain antibiotics, enzymes that act
locally in the stomach6-8
. This systems can be retained in the
stomach and assist in improving the oral sustained delivery of
drugs that have an absorption window in a particular region of the
gastrointestinal tract, thus ensuring optimal bioavailability.
Over the past 30 years, as the expense and complications
involved in marketing new drug entities have increased, with
concomitant recognition of the therapeutic advantages of
controlled drug delivery, the goal in the designing sustained /
controlled drug delivery system is to reduce the dosing frequency
or to increase effectiveness of the drug by localization at the site of
action, reducing the dose required, or providing uniform drug
delivery3
.
Since the early 1950s, the application of polymeric
materials for medical purposes is growing very fast. Polymers have
been used in the medical field for a large extent 4
. Natural polymers
remain attractive primarily because they are inexpensive, readily
available, be capable of chemical modifications, non-
carcinogenicity, mucoadhesivity, biodegradable, biocompatible,
high drug holding capacity and high thermal stability and easy of
compression5
. This led to its application as excipient in hydrophilic
drug delivery system. The various natural gums and mucilages
have been examined as polymers for sustained drug release in the
last few decades for example; Sodium bicarbonate, tragacanth
gum, xanthan gum, pectin, alginates etc. In the development of a
Gastro retentive Floating tablet dosage form. Availability of wide
variety of polymer and frequent dosing interval helps the scientist
to develop sustained release product. cellulose derivatives such as
carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose,
hydroxyproyl cellulose (HPC), and hydroxypropyl methyl
cellulose (HPMC) have been extensively studied as polymer in the
Floating tablet formulations along with gas generating agent like
NaHCO3
9
. These polymers are most preferred because of its cost
effectiveness, broad regulatory acceptance, non-toxic and easy of
compression. These dosage forms are available in extended release,
targeted release, delayed release, prolonged action dosage form.
Some factors like molecular size, diffusivity, pKa-ionization
constant, release rate, dose and stability, duration of action,
absorption window, therapeutic index, protein binding, and
metabolism affect the design of sustained release formulation. The
future of sustained release products is promising in some area like
chronopharmacokinetic system, targeted drug delivery system,
mucoadhesive system, particulate system that provide high promise
and acceptability.
Developing Floating formulations BCS Class-II drugs has
become a challenge to the pharmaceutical technologists. Fast
release drug generally causes toxicity if not formulated as extended
release dosage form. Among various formulation approaches, in
controlling the release of water-soluble drugs, the development of
sustained release coated granules has a unique advantage of
lessening the chance of dose dumping which is a major problem
when highly water-soluble drug is formulated as matrix tablets.
Oral sustained release dosage form by direct compression
technique is a simple approach of drug delivery systems that
proved to be rational in the pharmaceutical arena for its ease,
compliance, faster production, avoid hydrolytic or oxidative
reactions occurred during processing of dosage forms10
. The
selection of the drug candidates for Floating drug delivery system
needs consideration of several biopharmaceutical, pharmacokinetic
and pharmacodynamic properties of drug molecule11
.
In the present study, a Gastro retentive floating dosage
form of Carvedilol Phosphate has been developed that makes less
frequent administering of drug also to improve Bioavailability.
Carvedilol Phosphate is a a non-cardioselective alpha1-
beta adrenergic blocking agent with no intrinsic sympathomimetic
activity and weak membrane-stabilising activity. The alpha 1-
adrenergic blocking activity of CV causes vasodilation and reduces
peripheral vascular resistance. At higher doses calcium channel

126
blocking activity also observed. It is most effective in management
of hypertension, angina pectoris, moderate heart failure of ischemic
or cardiomyopathic origin, and left ventricular dysfunction with
myocardial infarction. Chemical name of Carvedilol Phosphate is
(2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2 methoxy phenoxy)
ethyl]amino]propan-2-ol phosphate salt (1:1) hemihydrate. has a
terminal half-life of 7-10 hr, but most of the drug is eliminated
with a half-life of about 2 hr, and the recommended oral dose for
adult is two times a day.
Carvedilol Phosphate has advantage over traditional β-
blockers with respect to hemodynamic and metabolic effects. Such
results indicate its safe and effective therapeutic application
particularly in patients with complicated Cardiovascular Diseases
(CVDs), even in paediatric and geriatric patients12
. It has narrow
absorption window i.e. upper part of gastrointestinal tract
(GIT).Therefore a good candidate for gastroretentive dosage
form13,14
. The recommended adult oral dosage of Carvedilol
Phosphate is 12.5 mg twice daily for the effective treatment of
hypertension. However, fluctuations of drug concentration in
plasma may occur, resulting in side effects or a reduction in drug
concentration at receptor side. As the drug is effective when the
plasma fluctuations are minimized, therefore sustained release
dosage form of Carvedilol Phosphate is desirable. The short
biological half life of drug (7 h) also favors development of
sustained release formulations.
The gastroretentive drug delivery systems can be retained
in the stomach and assist in improving the oral sustained delivery
of drugs that have an absorption window in a particular region of
the gastrointestinal tract. These systems help in continuously
releasing the drug before it reaches the absorption window, thus
ensuring optimal bioavailability. Thus, there is a need to maintain
Carvedilol Phosphate at its steady state plasma concentration.
Hence, the study was carried out to formulate and evaluate
Floating dosage form of Carvedilol Phosphate as a model drug and
had a aim that final batch formulation parameters should shows
prolong drug release. Development of dosage form depends on
chemical nature of the drug/polymers, matrix structure, swelling,
diffusion, erosion, release mechanism and the in vivo environment.
It is an important issue is to design an optimized
formulation with an appropriate dissolution rate in a short time
period and minimum trials. Many statistical experimental designs
have been recognized as useful techniques to optimize the process
variables. For this purpose, response surface methodology (RSM)
utilizing a polynomial equation has been widely used. Different
types of RSM designs include 3-level factorial design, central
composite design (CCD), Box-Behnken design and D-optimal
design. Response surface methodology (RSM) is used when only a
few significant factors are involved in experimental optimization.
The technique requires less experimentation and time, thus proving
to be far more effective and cost-effective than the conventional
methods of formulating sustained release dosage forms 15-18
.
Hence an attempt is made in this research work to
formulate Floating Tablets of Carvedilol Phosphate using
HPMCK100M and Sodium bicarbonate . Instead of normal and
trial method, a standard statistical tool design of experiments is
employed to study the effect of formulation variables on the release
properties. Large scale production needs more simplicity in the
formulation with economic and cheapest dosage form. The
Floating tablets formulation by direct compression method is most
acceptable in large scale production.
A 32
full factorial design was employed to systematically
study the drug release profile . A 32
full factorial design was
employed to investigate the effect of two independent variables
(factors), i.e the amounts of HPMCK100M and Sodium
bicarbonate on the dependent variables, i.e. t10%, t50%, t75%, t90%, (
Time taken to release 10%,50%75%,90% respectively).
2. MATERIALS AND METHODS
2.1 Materials
Materials used in this study were obtained from the
different sources. Carvedilol Phosphate was a gift sample from
Cipla Ltd, Mumbai, India. HPMCK100M from colorcon, Sodium
bicarbonate, Micro crystalline cellulose were procured from Loba
Chemie Pvt.Ltd, Mumbai. Other excipients such as Stearic acid,
citric acid, Aerosil and talc were procured from S.D. Fine Chem.
Ltd., Mumbai.
2.2 Formulation Development of Carvedilol Phosphate
Sustained Release Tablets
The factorial design is a technique that allows
identification of factors involved in a process and assesses their
relative importance. In addition, any interaction between factors
chosen can be identified. Construction of a factorial design
involves the selection of parameters and the choice of responses19
.
A selected three level, two factor experimental design (32
factorial design) describe the proportion in which the independent
variables HPMCK100M and Sodium bicarbonate were used in
formulation of Carvedilol Phosphate Floating Tablets. The time
required for 10% (t10%), 50% (t50%), 75% (t75%) and 90% (t90%) drug
dissolution were selected as dependent variables. Significance
terms were chosen at 95% confidence interval (p<0.05) for Final

127
Equations. Polynomial equations were developed for t10%, t50%,
t75%, t90%, (step-wise backward Linear Regression Analysis).
The three levels of factor X1 (HPMCK100M) at a
concentration of 25%, 31.25%, 37.25%. three levels of factor X2
(Sodium bicarbonate) at a concentration of 3.75%, 7.5%, 11.25%
(% with respect to total Tablet weight ) was taken as the rationale
for the design of the Carvedilol Phosphate floating tablet
formulation. Totally nine Carvedilol Phosphate floating tablet
formulations were prepared employing selected combinations of
the two factors i.e X1, X2 as per 32
Factorial and evaluated to find
out the significance of combined effects of X1, X2 to select the
best combination and the concentration required to achieve the
desired prolonged release of drug (by providing gastro retentivity)
from the dosage form.
2.3 Preparation of Carvedilol Phosphate Floating Tablets
All the ingredients were accurately weighed and passed
through mesh # 60. In order to mix the ingredients thoroughly drug
and polymer were blended geometrically in a mortar and pestle for
15 minutes then sodium bicarbonate, talc and aerosil were mixed
one by one. After thoroughly mixing these ingredients, the powder
blend was passed through # 44 mesh. Powder blend was
compressed by using rotary tablet punching machine (RIMEK),
Ahmedabad). Compressed tablets were examined as per official
standards and unofficial tests. Tablets were packaged in well
closed light resistance and moisture proof containers.
2.4 Experimental Design
Experimental design utilized in present investigation for
the optimization of Excipients concentration such as,
concentration of HPMCK100M was taken as X1 and concentration
of Sodium bicarbonate was taken as X2. Experimental design was
given in the Table 1. Three levels for the Concentration of
HPMCK100M were selected and coded as -1= 25%, 0=31.25%,
+1=37.5%. Three levels for the Concentration of Sodium
bicarbonate were selected and coded as -1= 3.75%, 0=7.5%,
+1=11.25%. Formulae for all the experimental batches were given
in Table 2 20
.
2.5 Evaluation of carvedilol phosphatesustained release tablets
2.5.1 Hardness 21
The hardness of the tablets was tested by diametric
compression using a Monsanto Hardness Tester. A tablet hardness
of about 2-4 kg/cm2
is considered adequate for mechanical
stability.
2.5.2 Friability 21
The friability of the tablets was measured in a Roche
friabilator (Camp-bell Electronics, Mumbai). 20 Tablets were
taken, Weighed and Initial weight was noted (W0) are dedusted in a
drum for a fixed time (100 revolutions, in a Roche Friabilator) and
weighed (W) again. Percentage friability was calculated from the
loss in weight as given in equation as below. The weight loss
should not be more than 1 %
Friability (%) = [(Initial weight- Final weight)/(Initial weight)] x
100
2.5.3 Content Uniformity 21
In this test, 20 tablets were randomly selected and the
percent drug content was determined, the tablets contained not less
than 85% or not more than 115% (100±15%)of the labelled drug
content can be considered as the test was passed.
2.5.4 Assay 22
The drug content in each formulation was determined by
triturating 20 tablets and powder equivalent to 100 mg was
dissolved in 100ml of 0.1N Hydrochloric acid by sonication for 30
min. The solution was filtered through a 0.45μ membrane filter,
diluted suitably and the absorbance of resultant solution was
measured spectrophotometrically at 240 nm using 0.1 N
Hydrochloric acid as blank.
2.5.5 Thickness 21
Thickness of the all tablet formulations were measured
using vernier calipers by placing tablet between two arms of the
vernier calipers.
2.5.6 In Vitro Buoyancy Studies 23,24
The tablets were placed in a 100-mL beaker containing
0.1N HCl. The time required for the tablet to rise to the surface and
float was determined as floating lag time.
2.5.7 In vitro Dissolution Study 22
The In vitro dissolution study for the Carvedilol
Phosphate Floating tablets were carried out in USP XXIII type-II
dissolution test apparatus (Paddle type) using 900 ml of 0.1 N HCl
as dissolution medium at 50 rpm and temperature 37±0.5°C. At
predetermined time intervals, 5 ml of the samples were withdrawn
by means of a syringe fitted with a pre-filter, the volume
withdrawn at each interval was replaced with same quantity of
fresh dissolution medium. The resultant samples were analyzed for
the presence of the drug release by measuring the absorbance at
240 nm using UV Visible spectrophotometer after suitable
dilutions. The determinations were performed in triplicate (n=3).

128
2.5.8 Kinetic modeling of drug release 25-28
The dissolution profile of all the formulations was fitted
in to zero-order, first-order, Higuchi and Korsmeyer-peppas
models to ascertain the kinetic modeling of drug release.
3. RESULTS AND DISCUSSION
Gastro Retentive Floating tablets of Carvedilol Phosphate
were prepared and optimized by 32
factorial design in order to
select the best combination of different release rate modifiers,
HPMCK100M, Sodium bicarbonate and also to achieve the desired
prolonged release of drug from the dosage form(by retaining drug
at gastric environment). The two factorial parameters involved in
the development of formulations are, quantity of HPMCK100M &
Sodium bicarbonate polymers as independent variables (X1, X2),
and In vitro dissolution parameters such as t10%, t50% , t75% & t90%
as dependent variables. Totally nine formulations were prepared
using 3 levels of 2 factors and all the formulations containing 25
mg of Carvedilol Phosphate were prepared as a floating tablet
dosage form by Direct Compression technique as per the formulae
given in Table 2.
All the prepared tablets were evaluated for different post
compression parameters, drug content, mean hardness, friability,
mean thickness, mean diameter, Floating lag time as per official
methods and results are given in Table 3. The hardness of tablets
was in the range of 4.49-4.69 Kg/cm2
. Weight loss in the friability
test was less than 0.68%. Drug content of prepared tablets was
within acceptance range only. Results for all Post-compression
parameters were tabulated or shown in Table 3. In-vitro
Dissolution studies were performed for prepared tablets using 0.1
N HCl as a dissolution media at 50 rpm and temperature 37±0.5°C.
The In-vitro dissolution profiles of tablets are shown in Fig.1 and
the dissolution parameters are given in Table 4. Cumulative %
Drug release of Factorial Design Formulations F1-F9 at 10 Hr were
found to be in the range of 72.93-100.78 %. From the dissolution
parameters of Formulations reveals that , As the amount of
polymer in the tablet formulation increases, the drug release rate
decreases and as the concentration of gas generating agent
(NaHCO3) increases the drug release increases and at the same
time floating lag time decreases. Therefore, required release of
drug can be obtained by manipulating the composition of
HPMCK100M and Sodium bicarbonate.
Much variation was observed in the t10% , t50%, t75% and t90%
due to formulation variables. Formulation F8 containing 100 mg of
HPMCK100M, 30 mg of Sodium bicarbonate showed promising
dissolution parameter (t10%= 0.415 h, t50% = 2.750 h, t75% = 5.501 h,
t90% = 9.130 h) which meets the objective of work by providing
more gastric retentivity and maximum drug release. The difference
in burst effect of the initial time is a result of the difference in the
viscosity of the polymeric mixtures. Dortunc and Gunal have
reported that increased viscosity resulted in a corresponding
decrease in the drug release, which might be due to the result of
thicker gel layer formulation29
.
The In vitro dissolution data of Carvedilol Phosphate
Floating formulations was subjected to goodness of fit test by
linear regression analysis according to zero order and first order
kinetic equations, Higuchi’s and Korsmeyer-Peppas models to
assess the mechanism of drug release. The results of linear
regression analysis including regression coefficients are
summarized in Table 4 and plots shown in fig.1,2,3,4. It was
observed from the above that dissolution of all the tablets followed
first order kinetics with co-efficient of determination (R2
) values in
the range of 0.872-0.998. The values of r of factorial formulations
for Higuchi’s equation was found to be in the range of 0.931-0.997,
which shows that the data fitted well to Higuchi’s square root of
time equation confirming the release followed diffusion
mechanism. Kinetic data also treated for Peppas equation, the slope
(n) values ranges from 0.809- 1.056 that shows Non-Fickian
diffusion mechanism (Super Case-II Transport). Polynomial
equations were derived for t10%, t50%, t75% and t90% values by
backward stepwise linear regression analysis. The dissolution data
(Kinetic parameters) of factorial formulations F1 to F9 are shown in
Table 5.
Polynomial equation for 3² full factorial designs is given in
Equation
Y= b0+b1 X1+b2 X2+b12 X1X2+b11 X1²+b22 X2²…
Where, Y is dependent variable, b0 arithmetic mean
response of nine batches, and b1 estimated co-efficient for factor
X1. The main effects (X1 and X2) represent the average result of
changing one factor at a time from its low to high value. The
interaction term (X1X2) shows how the response changes when two
factors are simultaneously changed. The polynomial terms (X1² and
X2²) are included to investigate non-linearity. Validity of derived
equations was verified by preparing Two Check point
Formulations of Intermediate concentration (C1, C2).
The equations for t10%, t50% t75% and t90% developed as follows,
Y1= 0.581+0.170X1-0.082X2+0.003X1X2-0.0910 X1
2
-0.055X2
2
(for t10%)
Y2= 3.820+1.110X1-0.550X2+0.015X1X2-0.600 X1
2
-0.340X2
2
(for t50%)
Y3= 7.630+2.225X1-1.10X2+0.025X1X2-1.200 X1
2
-0.682X2
2
(for t75%)
Y4 = 12.680+3.700X1-1.820X2+0.04X1X2-1.980 X1
2
-1.130X2
2
(for t90%)

129
The positive sign for co-efficient of X1 in Y1, Y2, Y3 and
Y4 equations indicates that, as the concentration of HPMCK100M
increases, t10%, t50%, t75% and t90% value increases. In other words the
data demonstrate that both X1 (amount of HPMCK100M) and X2
(amount of Sodium bicarbonate) affect the time required for drug
release (t10%, t50%, t75% and t90%). From the results it can be
concluded that, As the amount of polymer in the tablet formulation
increases, the drug release rate decreases and as the concentration
of gas generating agent (NaHCO3) increases the drug release
increases , drug release pattern may be changed by appropriate
selection of the X1 and X2 levels. The Dissolution parameters for
predicted from the polynomial equations derived and those actual
observed from experimental results are summarised in Table 6.
The closeness of Predicted and Observed values for t10%, t50%, t75%
and t90% indicates validity of derived equations for dependent
variables. The Contour Plots were presented to show the effects of
X1 and X2 on t10%, t50%, t75% and t90%. The final best (Optimised)
formulation (F8) is compared with marketed product
(CARDIVAS) shows similarity factor (f2) 88.801, difference
factor (f1) 2.25 (There is no significant difference in drug release
because tcal is<0.05).
Table 1: experimental design layout
Formulation
Code
X1 X2
F1
1 1
F2
1 0
F3
1 -1
F4
0 1
F5
0 0
F6
0 -1
F7
-1 1
F8
-1 0
F9
-1 -1
4. CONCLUSION
The present research work envisages the applicability of
rate retarding agent and Gas generating agent such as
HPMCK100M and Sodium bicarbonate respectively in the design
and development of Gastro Retentive Floating tablet formulations
of Carvedilol Phosphate utilizing the 32
factorial design. From the
results it was clearly understand that As the amount of polymer in
the tablet formulation increases, the drug release rate decreases and
as the concentration of gas generating agent (NaHCO3) increases
the drug release increases and both of these polymers can be used
in combination since do not interact with the drug which may be
more helpful in achieving the desired floating delivery of the drug
for longer periods. The optimized formulation followed Higuchi’s
kinetics while the drug release mechanism was found to be Non-
Fickian Diffusion (Super Case-II Transport), First order release
type, controlled by diffusion through the swollen matrix. On the
basis of evaluation parameters, the optimized formulation F8 may
be used once a day administration in the management of
Hypertension , Angina Pectoris and moderate Heart Failure..
5. ACKNOWLEDGEMENTS
The author would like to thank Management, Principal,
Teaching, Non-teaching Staff of Narasaraopeta Institute of
Pharmaceutical Sciences, Narasaraopet, Guntur (D.t), A.P., India
for providing support for successful completion of research work.
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131
Table 2: Formulae for the preparation of carvedilol phosphate floating tablets as per experimental design
Name of Ingredients
Quantity of Ingredients per each Tablet (mg)
F1 F2 F3 F4 F5 F6 F7 F8 F9
Carvedilol Phosphate
25 25 25 25 25 25 25 25 25
HPMCK100M
150 150 150 125 125 125 100 100 100
Sodium bicarbonate 45 30 15 45 30 15 45 30 15
Micro crystalline cellulose
122 137 152 137 162 177 172 187 202
Stearic acid
40 40 40 40 40 40 40 40 40
Citric acid
10 10 10 10 10 10 10 10 10
Aerosil
4 4 4 4 4 4 4 4 4
Talc
4 4 4 4 4 4 4 4 4
Total Weight
400 400 400 400 400 400 400 400 400
Table 3: Post-compression parameters for the formulations
S.No Formulation
Code
Hardness
(kg/cm2
)
Floating
lag time
(min)
Diameter
(mm)
Thickness
(mm)
Friability
(%)
Weight
Variation
Drug
Content (%)
1 F1 4.65 1.2 9.94 4.66 0.64 400.07 95.56
2 F2 4.66 3.6 9.96 4.67 0.62 400.32 95.76
3 F3 4.68 4.2 9.97 4.68 0.57 400.05 95.75
4 F4 4.55 0.9 9.95 4.51 0.69 400.60 93.50
5 F5 4.55 3.3 9.98 4.59 0.65 400.45 95.75
6 F6 4.60 4.2 10.05 4.62 0.53 400.90 97.25
7 F7 4.43 0.5 10.00 4.42 0.68 400.23 94.59
8 F8 4.48 2.8 10.02 4.49 0.61 400.66 97.20
9 F9 4.55 3.5 10.01 4.54 0.55 400.03 96.83

132
Table 4: Regression analysis data of 32
factorial design formulations of carvedilol phosphate
F1 to F9 are factorial formulations, r-correlation coefficient, a-Intercept, b-Slope and MP-Marketed Product.
Table 5: Dissolution parameters of carvedilol phosphate floating tablets 3² full factorial design batches
S.NO
Formulation
Code
KINETIC PARAMETERS
ZERO ORDER FIRST ORDER HIGUCHI KORSMEYER-PEPPAS
a b r a b r a b r a b r
1 F1 12.34 7.72 0.970 1.993 0.072 0.998 5.285 27.410 0.991 0.960 1.055 0.938
2 F2 10.578 7.330 0.975 1.991 0.063 0.998 5.716 25.920 0.992 0.934 1.050 0.941
3 F3 9.403 7.168 0.978 1.991 0.058 0.998 6.300 25.234 0.991 0.909 1.059 0.949
4 F4 14.531 8.269 0.961 2.004 0.090 0.994 4.639 29.625 0.991 0.998 1.062 0.919
5 F5 12.925 7.403 0.959 1.978 0.066 0.994 4.295 26.553 0.990 0.965 1.043 0.914
6 F6 10.515 7.484 0.965 1.989 0.064 0.994 6.388 26.596 0.986 0.901 1.104 0.924
7 F7 42.205 6.711 0.808 1.926 0.159 0.872 20.915 26.853 0.931 1.300 0.809 0.822
8 F8 18.632 8.402 0.952 2.018 0.110 0.984 1.682 30.512 0.995 1.056 1.035 0.890
9 F9 16.335 8.466 0.964 2.026 0.105 0.986 3.459 30.413 0.997 1.031 1.044 0.910
10 MP 19.612 8.484 0.951 2.028 0.118 0.982 1.058 30.889 0.996 1.070 1.023 0.888
S. NO
FORMULATION
CODE
KINETIC PARAMETERS
t10% (h) t50% (h) t75% (h)) t90% (h)
1 F1
0.639 4.216 8.430 14.005
2 F2
0.740 4.815 9.621 15.985
3 F3
0.790 5.158 10.314 17.137
4 F4
0.511 3.362 6.721 11.167
5 F5
0.698 4.565 9.133 15.175
6 F6
0.720 4.708 9.417 15.649
7 F7
0.285 1.889 3.778 6.273
8 F8 0.420 2.746 5.495 9.128
9 F9 0.438 2.878 5.755 9.555
10 MP
0.387 2.545 5.092 8.462

133
Table 6: Dissolution parameters for predicted and observed values for check point formulations
FORMULATION CODE PREDICTED VALUE ACTUAL OBSERVED VALUE
t10% (h) t50% (h) t75% (h) t90% (h) t10% (h) t50% (h) t75% (h) t90% (h)
C1 0.500 3.3075 6.603 10.973 0.502 3.302 6.602 10.971
C2 0.588 3.868 7.728 12.852 0.587 3.870 7.730 12.849
Fig.1: Comparative Zero Order Plots for F1-F9
COMPARITIVE HIGUCHI PLOTS FOR
FORMULATIONS F1-F9
0
20
40
60
80
100
120
0 1 2 3 4
√T
%CDR
F1
F2
F3
F4
F5
F6
F7
F8
F9
Fig.3: Comparative Higuchi Plots for F1-F9
Fig.2: Comparative First Order Plots for F1-F9
COMPARITIVE KORSMEYER-PEPPAS PLOTS
FOR FORMULATIONS F1-F9
0
0.5
1
1.5
2
2.5
0 0.2 0.4 0.6 0.8 1 1.2
Log Time
Log%CDR
F1
F2
F3
F4
F5
F6
F7
F8
F9
Fig.4: Comparative Korsmeyer-Peppas Plots for F1-F9
COMPARITIVE ZERO ORDER PLOTS FOR FORMULATIONS F1-F9
0
20
40
60
80
100
120
0 2 4 6 8 10 12
Time(h)
%CDR
F1
F2
F3
F4
F5
F6
F7
F8
F9
COMP ARITIVE FIRST ORDER P LOTS FOR
FORMULATIONS F 1 -F 9
-0.5
0
0.5
1
1.5
2
2.5
0 5 10 15
Time(h)
Log%UR
F1
F2
F3
F4
F5
F6
F7
F8
F9

134
Fig.5:Response Surface plot for t10%
Fig.7: Response Surface plot for t50%
Fig.9: Response Surface plot for t75%
Fig.6: Contour plot for t10%

135
Fig.11: Response Surface plot for t90% Fig.12: Contour plot for t90%

Formulation Design, Optimization and Evaluation of Carvedilol Phosphate Gastro Retentive Floating Tablets

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