formulation and evaluation of bilayer tablet of metoprolol succinate and chlorthalidone

15 Pages·2016·1.08 MB·English

IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY

Research Article
Available online at www.ijrpc.com

FORMULATION AND EVALUATION OF BILAYER TABLET
OF METOPROLOL SUCCINATE AND CHLORTHALIDONE
Maheshwari C. Date1* and KB. Erande2
1Department of Quality Assurance Techniques, M.G.V‟S Pharmacy College,
Panchavati, Nasik-422003, Maharashtra, India.
2Department of Quality assurance techniques, M.G.V‟s Pharmacy College,
Panchavati, Nasik-422003, Maharashtra, India.

ABSTRACT
In present study, an attempt was made to prepare bilayer tablet of Metoprolol Succinate and
Chlorthalidone. Bilayer tablet concept has been investigated to develop combination of sustained

and immediate released tablet. Metoprolol Succinate is a ẞ -selective adreno-receptar blocking
1
agent with half life3-4 hrs. Chlorhtalidone is an oral antihypertensive/ diuretic, due to its limited
aqueous solubility bioavaibility is low. To improve bioavaibility and solubility, Inclusion complex of
Chlorthalidone was prepared with Hydroxy propyl ẞ- Cyclodextrin. Sustained release of metoprolol
tablet was formulated by using synthetic (HPMC E15) and natural (moringa oliefera gum) polymer
in different concentrations, nine formulations were prepared at three levels (+1, 0, -1) of polymer
concentration. Immediate release tablet of Chlorthalidone were formulated by using sodium starch
glycolate and crosspovidone, four batches were formulated at two level (+1, -1) of polymer

concentration. Batches of formulation were formulated by using Design expert10 software. The
formulations are made by employing the direct compression method. The tablets were subjected to
weight variation test, drug content, hardness, friability, and in-vitro release studies, release kinetics

of sustained release tablet. Among all formulation, F8 batch of metoprolol Succinate tablet
containing high concentration of polymers showed 12hrs release and F1 batch of Chlorthalidone
showed good released in 35min.

Keywords: Metoprolol succinate, Chlorthalidone, bilayer tablet.

INTRODUCTION Classification Scheme, meaning that it is
Tablet is a solid pharmaceutical dosage form. highly soluble and highly permeable. The drug
It comprises a mixture of active substances is readily and completely absorbed throughout
and excipients, usually in powder form, the whole intestinal tract but is subject to
pressed or compressed form a powder into a extensive first pass metabolism resulting in
solid dose. Over the past 30 years, as the incomplete bioavaibility (about 50%). After a
expense and complication involved in single oral dose, peak plasma concentration
marketing new drug entities have increased, occurs after about 1-2 hours. The drug is
with concomitant recognition of the therapeutic eliminated within 3 to 4 hours, which
advantages of controlled drug delivery, greater depending on therapeutic intension, makes it
attention has been focused on development of necessary to administer simple formulations of
sustained release or controlled release drug metoprolol up to 4 times daily. To avoid these
delivery systems.1 and for better patient compliance Metoprolol
Metoprolol Succinate is a cardio selective ẞ- Succinate sustained release tablet was
blocker that has been classified as a class I formulated. Dosing interval typically reduced to
substance according to the Biopharnaceutics once or twice a day.2
702
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

MATERIALS AND METHODS Evaluation of moringa oleifera gum11,12
Metoprolol succinate and Chlorthalidone was a (a) Loss on drying
gift sample from Ajanta Pharmaceutical, The method adopted was that specified in the
Aurangabad and IPCA laboratories B.P 2004 for acacia. One gram of the sample
respectively, Mumbai. HPMC–E-15, Avicel- was transferred into each of several Petri
102, Crosspovidone, Sodium starch glycolate, dishes and then dried in an oven at 105°C until
magnesium stearate, Talc was obtained from a constant weight was obtained. The moisture
Modern Science Pvt. Ltd, Nashik. content was then determined as the ratio of
weight of moisture loss to weight of sample
Method expressed as a percentage. The results are
Drug and Excipients Compatibility Studies mentioned in Table No.1.
UV spectroscopy
The both drugs were scanned in UV (b) pH determination
Spectrophotometer to detect the λmax and to pH was determined by shaking a 1%w/v
draw the calibration curve of the drug in water, solution of the sample in water for 5 min and
phosphate buffer (pH 6.8) and in methanol as the reading were noted by digital pH meter.
a solvent. The drugs were used in The results are mentioned in Table No.1.
concentration ranges of 20-45 and 5-25 ppm
of Chlorthalidone and Metoprolol Succinate (c) Tannin test
respectively. The spectra and calibration curve To the 10ml of 10%w/v solution of gum, then
of both the drugs are as shown in Figure 1, 2, 0.1ml of ferric chloride test solution was added
3, 4, 5 and 6 respectively. to it. Gelatinous precipitate formed but neither
a precipitate nor liquid shows dark blue color
FTIR spectral studies nor result was reported. The results are
The infrared spectra of Metoprolol Succinate mentioned in Table No.1.
and Chlorthalidone were recorded by
SHIMADZU 84005 FTIR spectrometer, (d) Starch test
equipped with an Inferometer detector. The 10 ml of 10%w/v solution was prepared.
Samples were prepared by KBr disc method (2 To it 0.1 ml of 0.005M Iodine was added. The
mg sample in 100 mg KBr) and examined in results are mentioned in Table No.1.
the transmission mode. Each spectrum was
measured over a frequency range of 4000– (e) Sucrose and fructose test
400 cm−1. To 1 ml of 10% w/v solution. To it the 4 ml of
The spectra shown in Figure 7, 8 distilled water was added then to it 0.1 gm of
respectively. resorcinol and 2 ml of hydrochloric acid was
added. The results are mentioned in Table
DSC studies No.1.
DSC analysis was performed using Shimadzu-
Thermal Analyzer DSC 60 on 2-5mg samples. (f) Swelling power test
Sample was heated in an open nitrogen pan at A 1 gm of transfered to 100 ml measuring
a rate of 10°C/min conducted over a cylinder containing 90ml of water, shake well
temperature range of 50 to 200°C for for 30 seconds and allow to stand for 24 hours,
Metoprolol Succinate and Chlorthalidone shaking gently on 3 occasions during this
under nitrogen flow of 2 bar pressure. The period .The sufficient water was added to
spectra shown in Figure 12, 13respectively. produce 100 ml, mixed gently for 30 seconds,
avoiding the entrapment of air, allow to stand
Collection and evaluation of moringa for 5 hours and measured the volume of
oliefera gum mucilage. The determination was repeated for
Collection11,12 three times. The results are mentioned in
The moringa oleifera tree located in Table No.1.
Shirasgaon, in yeola Dist. Nashik was
identified. The tree trunk was incised working Preparation of Metoprolol Succinate
from the base up towards the branches. The sustained release tablet
incisions were 10-15 mm long and 4-5 mm Different formulas (Table No.2, 3) were
deep. The gum then started to seeping out prepared to achieve good sustained release
from the incisions and coagulated in 10-20 action of Metoprolol succinate by using HPMC
days. When the gum was sufficiently dried it E-15 and Moringa oliefera gum in different
was collected and spread out to dry. The gum ratios.
was collected from trees (injured site). The granules were prepared by wet
granulation technique.
703
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

Wet granulation Friability14,15,16
All excipients were weighed separately. Friability is the measure of tablet strength. In
Accurately weighed quantity of Metoprolol this test, number of tablets subjected to
Succcinate & polymers (HPMC E15 & Moringa combined effect of shock abrasion by utilizing
oliefera) were mixed thoroughly in mortar & a plastic chamber which revolves at a speed of
granulated using 10% w/v starch solution as a 25rpm, dropping the tablets at a distance of 6
binder. The granules so obtained were placed inches in each revolution. A sample of pre-
in oven at 60ºC for 2 hr. These granules were weighed tablets was placed in Roche Friability
again passed through 22 mesh sieve after tester (Kumar Mfg. Ltd.) This was then
getting dry. The fine granules formed are then operated for 100 revolutions. The tablets then
lubricated with 0.5% w/w Magnesium stearate. deducted and reweighed. Permitted friability
The flow properties were determined. These limit is 1.0%. Tablets were then weighed and
granules were then compressed into tablet friability values were determined and are
(each 200mg) using mm concave punch of 10 reported in Table. No. 8.
station shiv pharma ETBC 1974 machine.
Friability = (W2 – W1 / W1) X 100
Formula design Where W1 is the initial weight and W2 is the
Formulas were design by 32 factorial design, final weight of the tablets.
nine batches were formulated. Three levels
(+1, 0, -1) and two polymers (HPMC E15 and Weight variation14,15,16
Moringa oliefera) were selected and master Twenty tablets were weighed individually.
formula were prepared. Final weight of Average weight was calculated from the total
sustained release tablets were adjusted to weight of all tablets. The individual weights
200mg. Master formulas with quantities is as were compared with the average weight. The
shown in Table No. 2, 3. percentage difference in the weight
variation should be within the acceptable
Evaluation parameters (Metoprolol limits (7.5%). The percent deviation was
Succinate sustained release tablet) calculated using the following formula and
Evaluation of pre compression parameters reported in Table No.8.
of the powder blends.
Pre-compression parameters of the prepared % Deviation = Individual weight – Average weight x 100
blend of all the formulations were studied by Average weight

determining the Bulk density, Tapped density, Drug Content Uniformity Study14,15,16
Compressibility index, Hausner‟s ratio and
Five tablets were weighed individually and
Angle of repose. The results are shown in
powdered. The powder equivalent to 10 mg of
Table No. 7.
Metoprolol succinate was weighed and

dissolved in small amount of phosphate buffer
Evaluation of post compression
(pH 6.8). The volume was made to 100 with
parameters of the powder tablets14,15,16
phosphate buffer (pH 6.8). From this stock
The compressed Metoprolol Succinate
solution, 25 µg/ml dilution was prepared. The
sustained release tablet were subjected to
drug contents of the resulting solution were
various physical tests which include hardness,
calculated from UV absorbance at 222 nm.
friability, weight variation, thickness and drugs
Results are mentioned in Table No. 8.
content uniformity. The results are shown in

Table No. 8.
Swelling index test11,13

The extent of swelling was measured in terms
Hardness test14,15,16
of percentage weight gain by the tablets. The
For each formulation, the hardness of three
swelling behaviour of all the formulation was
tablets was checked using the Monsanto
studied. One tablet from each formulation was
hardness tester (LAB- HOSP) average values
kept in petri plate containing phosphate buffer
are shown in Table No.8.
pH 6.8. at the end of 2,4, 6,8, 10 and 12hrs

tablets were withdrawn, soacked on tissue
Thickness 14,15,16
paper and weighed, and then percentage
The thickness of tablet is important for
weight gain by the tablet was calculated using
uniformity of tablet size. The thickness of the
formula.
tablets was determined using a Vernier

Calliper. Three tablets from each batch were
Mt–Mo
used, and average values are shown in Table
SI = X 100
No 8.
Mo

704
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

Where, SI = Swelling index
Mt = Weight of tablet at time„t‟ and Characterization of Inclusion Complex
Mo = Weight of tablet at time „0‟ Inclusion Complex of Chlorthalidone were
The results are mentioned in Table No.8. characterized using following analytical
techniques
In - vitro Drug Release Study6,13, a) Saturation solubility studies
The release rate of Metoprolol succinate b) Drug content estimation
sustained release matrix tablets was c) FT-IR spectral analysis
determined using United States d) Differential Scanning Calorimetry.
pharmacopoeia (USP) Dissolution testing
Apparatus 2 (paddle method). The dissolution (a) Saturation Solubility Study9,17
test was performed using 900ml of Phosphate Saturation solubility studies were carried out
buffer pH 6.8, at 37 ± 0.5ᵒC and 50 rpm. A for all inclusion complexes prepared. This
sample (5ml) of the solution was withdrawn study was the basic criteria to identify and
from the dissolution apparatus and the judge the inclusion complex of choice, which
samples were replaced with fresh dissolution would enhance the solubility and so, would
medium. The samples were filtered through show good results in in-vitro dissolution
filter paper. Absorbance of these solutions was studies. Solubility studies were carried out in
measured at 222 nm using a UV/ Visible glass vials. In each of these vials, 10 ml
Spectrophotometer. The drug release was distilled water was added. Excess quantities of
plotted against time to determine the release inclusion complex were added into each of
profile. The results are mentioned in Table vials. These vials were shaken continuously
No.9. for 24 hours on a lab shaker and the resulting
solutions were filtered, appropriate dilutions
Drug release kinetics,13,14.16 were made and UV absorbances were
All formulations were subjected to various recorded at 257 nm. Result is shown in Table
mathematical kinetic models like Zero-order, No. 12
First-order, Higuchi, Korsmeyer-Peppas to
understand the release patterns and establish (b) Drug Content9,17
the kind of mechanism followed by Metoprolol About 10 mg drug equivalent of solid
Succinate release from tablet. Results are dispersion were weighed accurately and
reported in Table No.10. and Figure transferred to 100 ml volumetric flask to which
No.16,17. 20 ml methanol was added and sonicated for
15 min. Final volume was made up with
Solubility enhancement of Chlorthalidone methanol. From this stock solution (100
Solubility Study of Chlorthalidone µg/ml), 1 ml was withdrawn and further diluted
To determine solubility of Chlorthalidone, it up to 10 ml with methanol. This solution was
was performed in water and Phosphate buffer used for the assay for drug content by UV
pH 6.8. Solubility studies were carried out in spectrophotometer at 276 nm. Concentration
glass vials. In each of these vials, 25 ml of of drug in stock solution was calculated by
each media were added. Excess quantity of using calibration curve and from which percent
drug (50 mg) was added into each of vials. drug content in solid dispersions was
These vials were shaken continuously for 24 calculated.
hours on a lab shaker and the resulting W
A
solutions were filtered, appropriate dilutions % Drug content = X 100
were made and UV absorbances were W
T
recorded at 275nm. Where, W = Actual drug content, and
A
W = Theoretical drug content.
T
Preparation of Inclusion complex of Results are shown in Table No. 13
Chlorthalidone by kneading method9,17
Drug and Hydroxypropyl-β-Cyclodextrin in the (c) FT-IR Spectroscopy9,17
proportion of appropriate molar ratio were Fourier transform infrared spectroscopy was
mixed in a mortar for one hour with small employed to characterize further the possible
quantities of methanol was added interactions between the drug and the carrier
intermittently to get slurry like consistency. The in the inclusion complex on a FT-IR
paste was dried in the oven at the temperature spectrophotometer by the conventional KBr
of 45˚C. Dried complex were pulverized into pellet method. The spectra were scanned over
fine powder and sifted with sieve # 80. a frequency range 4000-400 cm-1 with a
resolution of 4 cm-1.peaks are shown in Figure
No. 11.
705
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

(d) Differential Scanning Calorimetry (DSC) % Deviation = Individual weight – Average weight x 100
9,17 Average weight
Results are mentioned in Table No. 14.
The possibility of any interaction between the

drug and the carriers during preparation of Thickness 14,15,16
inclusion complex was assessed by carrying
The thickness of tablet is important for
out thermal analysis of drug alone as well as
uniformity of tablet size. The thickness of the
that of the optimized inclusion complex, using
tablets was determined using a Vernier
DSC. DSC analysis was performed using
Calliper. Three tablets from each batch were
Shimadzu- Thermal Analyzer DSC 60 on 2-5
used, and average values are shown in Table
mg samples. Samples were heated in an open
No. 14.
nitrogen pan at a rate of 10°C/min conducted

over a temperature range of 30 to 315°C Hardness 14,15,16
under a nitrogen flow of 10 ml/min.37,39
For each formulation, the hardness of three
Thermogram are as shown in Figure No. 15.
tablets was checked using the Monsanto
hardness tester (LAB- HOSP) average values
Formulation of immediate release
are shown in Table No. 14.
Chlorthalidone Tablet

Factorial design Drug Content Uniformity Study9,16
From the literature survey studies the
Five tablets were weighed individually and
concentration of Crosspovidone & Sodium
powdered. The powder equivalent to 10 mg of
starch glycolate were selected. Based on
Chlorthalidone was weighed and dissolved in
concentration 2 factors will be evaluated, each
small amount of phosphate buffer (pH 6.8).
at 2 levels, & experimental trials will be
The volume was made to 100 with phosphate
performed at 4 possible combinations. The
buffer (pH 6.8). From this stock solution, 25
amount of Crosspovidone & Sodium starch
µg/ml dilution was prepared. The drug
glycolate was selected as independent
contents of the resulting solution were
variables. Four batches were formulated and
calculated from UV absorbance at 222 nm.
evaluated for weight variation, disintegration,
Results are mentioned in Table No. 14.
dissolution etc. test. Master formula is given in

Table No. 6. Friability14,15,16

Friability is the measure of tablet strength. In
Evaluation of powder blends
this test number of tablets subjected to
Powder blend of IR tablet were evaluated for
combined effect of shock abrasion by utilizing
bulk density, tapped density, carr‟s Index,
a plastic chamber which revolves at a speed of
compressibility index, hausner‟s ratio and
25rpm, dropping the tablets at a distance of 6
angle of repose as per procedure. Results are
inches in each revolution. A sample of pre
shown in table
weighed tablets was placed in Roche Friability

tester (Kumar Mfg. Ltd.) This was then
Preparation of IR tablet
operated for 100 revolutions. The tablets then
In IR tablet SSG and crosspovidone were used
dedusted and reweighed. Permitted friability
as a disintegrating agent, where avicel used as
limit is 1.0%.Tablets was then weighed and
binder and diluent. Magnesium stearate used
friability values were determined and results
as lubricant. Weighed the quantity of drug and
are reported in Table No. 14.
polymer, all ingredients were mixed properly.

Magnesium stearate was added to lubricate
W -W
the mixture. Preformulation study was done 1 2
Friability = X 100
and IR tablets were formed by direct
W
compression. 1
Where,

W = weight of the tablets before test,
Evaluation of IR Chlorthalidone tablet 1
W = weight of the tablets after test
Weight Variation14,15,16 2

Twenty tablets were weighed individually. Disintegration test14,15,16
Average weight was calculated from the total The in-vitro disintegration studies were carried
weight of all tablets. The individual weights
out using Tablet Disintegration Test
were compared with the average weight. The
Apparatus. One tablet was placed in each of
percentage difference in the weight
the six tubes of the basket assembly and disk
variation should be within the acceptable
was added to each tube. This assembly was
limits (7.5%). The percent deviation was
then suspended in one-liter beaker containing
calculated using the following formula. water maintained at 37±20C. The basket was

then moved up and down through a distance
706
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

of 5 to 6 cm at a frequency of 28 to 32 cycles In-vitro dissolution study6,9
per minutes. The time required for complete In vitro release of the tablets (Table-3) was
disintegration of the tablet was recorded. The conducted using USP dissolution apparatus II
test was performed for tablets of all type of (UV-1700 Schimadzu Corporation, Japan) at
formulation (F1-F4). The results are shown in 75 rpm, using phosphate buffer pH 6.8 and
Table No. 14. 0.1N HCl as a dissolution media maintained at
37±0.5°. Samples were withdrawn at various
Drug content uniformity9,17 time intervals, diluted and assayed at 275 nm,
One tablet was crushed and 25ml of methanol using an UV/VIS spectrophotometer. All the
was mixed and shaken for 15 minutes. results were performed in triplicate. The results
Sufficient water was added to produce 100 ml. are shown in Table No. 15.
Solution was filtered and the absorbance
maxima of the resulting solution was recorded RESULT AND DISCUSSION
as 275 nm. The results are shown in Table The prepared tablets were evaluated for
No. 14. Weight variation, hardness, friability, thickness,
drug content and dissolution studies. Results
of all formulation of both Metoprolol Succinate
sustained release tablet and Chlorthalidone
Immediate release tablet were given in Tables.

Fig. 1: UV Spectrum of Metoprolol succinate in Water

Fig. 2: UV Spectrum of Chlorthalidone in Methanol:Water
707
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

1
0.9
0.8
0.7
e y = 0.0306x + 0.0139
c 0.6
n
a R² = 0.9992
b 0.5
r
o
s 0.4
b
A
0.3
0.2
0.1
0
0 5 10 15 20 25 30 35
Concentration (ppm)

Fig. 3: Calibration Curve of Metoprolol succinate in Distilled Water

0.8
0.7
0.6
e 0.5 y = 0.0296x - 0.0174
c
n R² = 0.9977
a
b 0.4
r
o
s
b
A 0.3

0.2
0.1
0
0 5 10 15 20 25 30
Concentration (ppm)

Fig. 4: Calibration Curve of Metoprolol succinate in Phosphate buffer pH 6.8

0.35
0.3
0.25
e
c
n 0.2
a
b
r
o 0.15
s
b y = 0.0068x - 0.0021
A 0.1
R² = 0.9992
0.05
0
0 10 20 30 40 50
Concentration (ppm)

Fig. 5: Calibration Curve of Chlorthalidone in Methanol:Water
708
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

0.25
0.2
e
c
n 0.15
a
b
r
o 0.1 y = 0.0057x + 0.0216
s
b
A R² = 0.9953
0.05
0
0 10 20 30 40
Concentration

Fig. 6: Calibration Curve of Metoprolol succinate in Phosphate buffer pH 6.8

Fig.
7: IR spectrum of Metoprolol succinate (pure drug)

Fig. 8: IR spectrum of Chlorthalidone (pure drug)
709
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

Fig. 9: IR spectra of Metoprolol succinate and Chlorthalidone along with all polymers

Fig. 10: IR spectra of Chlorthalidone along with hydroxyl propyl ẞ- cyclodextrin

Fig. 11: FT-IR. Spectrum of Chlorthalidone: HP-β-CD Inclusion Complex
710
IJRPC 2016, 6(4), 702-716 Maheshwari C. Date et al. ISSN: 22312781

Fig. 12: Thermogram of pure Metoprolol succinate

Fig. 13: Thermogram of pure Chlorthalidone

Fig. 14: Thermogram of bilayer tablet formulation
711