Indian J.Pharm. Educ. Res.
44(1), Jan-Mar, 2010
Once-Daily Sustained-Release Matrix Tablets of Metoprolol
Tartrate : Formulation and In-vitro Evaluation
Hiremath S.N.*1, Patil S.D2., Swamy P.V3. and Md.Younus Ali4
1
Pravara RES College of Pharmacy, Chincholi, Nashik-422101, Maharastra (India).
2
Research Associate, Glenmark Pharmaceuticals Ltd, Sinnar,
Nashik-422113, Maharastra (India).
3,4
Department of Pharmaceutics, H.K.E. Society's College of Pharmacy, Sedam Road,
Gulbarga-585 105. Karnataka (India).
*
For Correspondence: snhiremath@rediffmail.com
Abstract
The purpose of the present work was to design and evaluate the once daily sustained release matrix tablets of
metoprolol tartrate based on hydrophilic matrices of hydroxypropyl methyl cellulose (HPMC) of different viscosity
grades (Methocel K4M, K15M and K100M) and Carbopol-940. The compressed matrix tablets were evaluated for
various parameters like hardness, friability, weight variation, drug content uniformity, drug-polymer interaction and
in-vitro drug release studies. In-vitro drug release studies were performed in pH 6.8 phosphate buffer using USP
apparatus-II (paddle) at 50 rpm. The drug release rate from higher viscosity grade matrices was slower when
compared to lower viscosity grades. Increase in drug-polymer ratio from 1:1 to 1:3 resulted in decreased release of
metoprolol tartrate. Inclusion of Carbopol-940 in tablets along with HPMC resulted in a further reduction in the drug
release rate. Formulation containing drug-polymer ratio (1:3) with the combination of HPMC and Carbopol as
matrix material showed promising results and release approximately 90% of metoprolol tartrate in 20 hours. The
drug release mechanism was predominantly found to be non-Fickian (anomalous) diffusion controlled. Release
profile also showed a tendency to follow near zero-order kinetics. The results of this study provided the framework for
further work involving both in-vivo studies and scale-up .
Key word: Metoprolol Tartrate; HPMC; Matrix; Sustained release
INTRODUCTION simple formulations of Metoprolol tartrate up to 4 times
The purpose of this study was to design and evaluate daily. Based on these properties and the well-defined
once daily sustained release matrix tablets of metoprolol relationship between the beta blocking effect and plasma
tartrate using various grades of HPMC as matrix material. drug concentration, Metoprolol tartrate lends itself to
Metoprolol tartrate is selective 1-adrenoreceptor an sustained-release (SR) formulation. Metoprolol
blocking agent used in the treatment of various tartrate SR formulations smooth out peaks and valleys in
cardiovascular disorders and prophylaxis of migraine1-2. theplasma levels and enable less frequent dosing. Dosing
It has been classified as a class I substance according to intervals are typically reduced to once or twice a day3.
the Biopharmaceutics Classification Scheme (BCS), In the present work hydrophilic polymers such as
meaning that it is highly soluble and highly permeable. carbomers (carbopol-940) and cellulose derivatives such
The drug is readily and completely absorbed throughout as HPMC of various grades have been used as release
the whole intestinal tract but is subject to extensive first retarding agents. Cellulose derivatives have been widely
pass metabolism resulting in incomplete bioavailability used in the formulation of hydrogel matrices for
(about 50%). After a single oral dose, peak plasma controlled drug delivery. Among them, HPMC is the
concentrations occur after about 1-2 hours. The drug is most extensively utilized because of its ease of use,
eliminated within 3 to 4 hours, which, depending on availability and very low toxicity. Carbomers and HPMC
therapeutic intention, makes it necessary to administer are hydrophilic polymers with high gelling capacities.
Indian Journal of Pharmaceutical Education and Research When these polymers comes in contact with water it
Received on 15/10/2008; Modified on 17/02/2009
Accepted on 30/08/2009 c APTI All rights reserved
undergoes rapid hydration of the macromolecules in the
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Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010
solid-liquid interface followed by formation of a viscous throughout the experiment. One tablet was used in each
layer. The matrix system produced as a result of this test, 5 ml sample of dissolution medium was withdrawn
process can pass along the gastrointestinal tract without by means of a syringe fitted with a prefilter at specified
breaking up and releasing the active ingredient intervals of time and was immediately replaced with
progressively4. fresh medium. The sample was analyzed for drug release
MATERIALS AND METHODS by measuring the absorbance at 274.2 nm using UV-
Metoprolol tartrate and Cellactose were gift samples Visible spectrophotometer after suitable dilution.
from Astra-Zeneca Pharma India Limited., Bangalore Drug-Excipient Interaction study
and Anglo-French, Bangalore respectively. HPMC There is always possibility of drug-excipient interaction
(Methocel K4M, K15M and K100M) procured in any formulation due to there intimate contact. The
commercially from Colorcon India Private Limited, Goa. drug-excipient interaction studies were carried out by
Carbopol-940, magnesium stearate and talc are obtained employing IR spectrocopic technique, which is one of
from S.d Fine Chemicals Limited, Mumbai. the most powerful analytical techniques that offers
Preparation of Matrix Tablets possibility of chemical identification. The IR spectrum of
The sustained release matrix tablet formulation consisted metoprolol tartrate, cellactose, HPMC (K100 M),
of a drug, polymer and diluent. The ratios of the drug and carbopol 940 and formulation F10 were obtained by KBr
polymer were maintained at 1:1, 1:2 and 1:3 levels, while pellet method .
diluent content was varied. The composition of various RESULTS AND DISCUSSION
tablet formulations are given in Table-1. The drug, The prepared matrix tablets were evaluated for
polymer and diluents were passed through a 100-mesh parameters such as hardness, weight variation, friability,
sieve and thoroughly mixed in a glass mortar for 15 drug content uniformity and were found to be in the range
minutes. The lubricant and glidants were added to the of 5.60±0.59 to 5.90±0.37, 199±0.87 to 254±1.46,0.59 to
previous mixture and again mixed for 5 minutes. Then the 0.67, 96.32±1.41 to 99.72±.052 respectively (Table-2).
tablets were directly compressed using a Cadmach Single IR spectroscopy was used as a means of studying drug-
Punch Tablet Machine. The compressed tablets were excipient interaction. The IR spectrum of metoprolol
evaluated for physical parameters such as weight tartrate exhibits peak at 1162.7 cm-1 is due to ether
uniformity, hardness, friability, drug content uniformity linkage, peak at 3693.9 cm-1 is due to (-OH-) linkage and
and in vitro release pattern. peak at 2981.1 cm-1 is due to secondary amine (-NH-)
Drug Content Uniformity confirm the structure of the drug. The IR spectrum of F10
Five tablets were powdered in a mortar, from this powder formulation exhibited peak at 1167.7 cm-1 is due to ether
equivalent to 50 mg of drug was taken in a 100 ml round linkage, peak at 3694.8 cm-1 is due to (-OH-) linkage and
bottom flask. It was extracted by shaking with two peak at 2926.5 cm-1 is due to secondary amine (-NH-).
successive 10 ml portions of methanol for 15 min each, The presence of all the above peaks in the formulation
filtered in a 25 ml volumetric flask and the filtrate was confirms undisturbed structure of metoprolol tartrate and
made up to the mark with methanol. Further appropriate there was no drug-excipient interaction.
dilutions were made and the absorbance was measured at From the in vitro dissolution studies, it was observed that
2 7 6 n m u s i n g a S h i m a d z u 1 7 0 0 U V / Vi s among the three different drug-polymer ratios used,
spectrophotometer against methanol blank. formulations with drug-polymer ratio 1:1 showed higher
In-vitro Drug Release Studies 5, 6 drug release rates, when compared to 1:2 and 1:3. As the
In vitro dissolution studies of metoprolol tartrate tablets polymer concentration is increased, the drug release rates
were carried out in USP XXIII tablet dissolution test were found to be decreasing. Higher drug release rates
apparatus-II (Electrolab) employing a paddle stirrer were observed for formulations with lower polymer ratio.
rotating at 50 rpm, 900 ml of pH 6.8 phosphate buffer was An increase in polymer concentration causes increase in
used as a dissolution medium. The temperature of the the viscosity of the gel as well as the formation of the gel
dissolution medium was maintained at 37±0.5 ºC layer with longer diffusional path. This could cause a
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Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010
decrease in effective diffusion coefficient of drug and constant incorporating structural and geometrical
therefore a reduction in drug release rate. Among the characteristics of the device, and n is the diffusional
three grades of polymers used, the tablets prepared with exponent and characterizes the type of release
lower viscosity grade polymer i.e., HPMC K4M have mechanism during the dissolution process. For
shown greater drug release rates when compared to drug non–Fickian release, the n value falls between 0.45 and
release rates of higher viscosity grade polymers HPMC 0.89, while in case of Fickian diffusion, n=0.45; for zero
K15M and K100M. order release (case II transport), n=1, and for super case II
In all the formulations studied from F1 to F10 (Fig. 1), transport, n>17.
formulations containing HPMC K15M (F7) and K100M The values of n were estimated by linear regression of log
(F8) with drug-polymer ratio 1:3 containing cellactose as (Mt/M) versus log (t) for different formulations and was
a diluent have shown sustained release of metoprolol found to be in between 0.45 to 0.89 indicating that
tartrate up to 15 h. Further to prolong the drug release up diffusion is the predominant mechanism limiting the drug
to 20 h, an attempt was made by incorporating Carbopol- release. The formulations prepared were found to release
940 (release-modifying agent) in the formulations. the drug by non-Fickian transport (anomalous) since the
Formulations F9 and F10 containing drug-polymer ratio slope values for Peppas plot were found to be in the range
(1:3) with polymers composition of HPMC of 0.45 to 0.89 and also follows a near zero order release
K15M:Carbopol-940 (2:1) in F9 and with polymers profile ('r' values for F9 and F10 formulations were found
composition of HPMC K100M: Carbopol-940 (2:1) in to be 0.984 and 0.994 respectively). From the above
F10 were prepared. The dissolution profiles of discussion, it may be concluded that HPMC along with
formulations shows that F9 and F10 have sustained the Carbopol-940 can be used as an aid to control the delivery
release of drug for more than 20 h. The dissolution of water soluble drug from matrix tablets. Among the
profiles of formulations containing HPMC and various formulations of metoprolol tartrate developed,
Carbopol-940 i.e., F9 and F10 have shown much slower the formulations F9 and F10 appear suitable for further
release rates when compared to formulations containing pharmacodynamic and pharmacokinetic evaluation in a
HPMC alone i.e., F1 to F8. suitable animal model.
The mechanism of drug release was studied using Peppas ACKNOWLEDGEMENT
equation, Mt/M =ktn, where, Mt/M is fractional release of We are grateful to Astra-Zeneca Pharma India Limited,
the drug, 't' denotes the release time, K represents a Bangalore for providing the gift sample of Metoprolol
Tartrate.
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Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010
Table 1. Composition of various tablet formulations
Ingredients (mg/tablet)
FC Methocel Drug
MT C-940 Cellactose Talc MS Polymer:
K4M K15M K100M
F1 50 50 -- -- -- 100 2 2 1:1
F2 50 100 -- -- -- 50 2 2 1:2
F3 50 -- 50 -- 100 2 2 1:1
F4 50 -- 100 -- -- 50 2 2 1:2
F5 50 -- -- 50 -- 100 2 2 1:1
F6 50 -- -- 100 -- 50 2 2 1:2
F7 50 -- 150 -- -- 50 2 2 1:3
F8 50 -- -- 150 -- 50 2 2 1:3
F9 50 -- 100 -- 50 50 2 2 1:2:1
F10 50 -- -- 100 50 50 2 2 1:2:1
FC: Formulation Code, MT: Metoprolol Tartrate, C-940: Carbopol-940,
MS: Magnesium Stearate.
Table 2. Physicochemical evaluation of matrix tablets of metoprolol tartrate
FC Hardnessa Friabilityb Weight Variationc Drug Contentd
(kg/cm²) (%) (mg) (%)
F1 5.80±0.76 0.64 202±0.42 99.72±0.52
F2 5.90±0.51 0.62 200±0.25 98.10±3.00
F3 5.60±0.59 0.63 199±0.87 97.10±1.53
F4 5.90±0.49 0.59 202±0.92 97.50±2.51
F5 5.80±0.34 0.62 200±0.32 96.78±2.08
F6 5.80±0.51 0.64 201±0.60 96.32±1.41
F7 5.60±0.42 0.66 243±2.55 98.62±0.60
F8 5.80±0.67 0.63 249±0.08 99.36±0.28
F9 5.90±0.37 0.61 254±1.46 99.60±0.20
F10 5.70±0.49 0.67 249±0.66 99.60±0.76
FC: Formulation code, a Mean ± S.D., n= 6 tablets, b n= 10 tablets, c Mean ± S.D.,
n = 20 tablets and d Mean ± S.D., n=5 tablets, SD: Standard Deviation.
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Indian J.Pharm. Educ. Res. 44(1), Jan-Mar, 2010
Fig. 1 : Drug release profiles of sustained release matrix
tablets of Metoprolol Tartrate (F 1 to F 10) formulations.
Fl & F2: Drug -polymer ratio 1:1 & 1:2 using HPMC F7 & F8: Drug -polymer ratio 1:3 using HPMC K15M &
K4M Polymer KI00M Polymer
F3 &F4: Drug -polymer ratio 1:1 & 1:2 using HPMC F9&FI0: Drug -polymer ratio 1:3 with polymers
K15M Polymer composition of HPMC K15M : Carbopol-940 (2: 1) in F9
F5 & F6: Drug -polymer ratio 1:1 & 1:2 using HPMC and with polymers composition of HPMC KI00M:
KI00M Polymer Carbopol-940 (2:1) in F10
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