Int J App Pharm, Vol 6, Issue 3, 1-3Review Article
FORMULATION AND EVALUATION OF FLOATING EFFERVESCENT TABLETS OF METOPROLOL SUCCINATE
P. PREETHA*, A. SREENIVASA RAO, G. SADHANA
Department of Pharmaceutics, Bhaskar Pharmacy College, Hyderabad.
Email: pallab_haldar@rediffmail.com
Received: 12 Feb 2014, Revised and Accepted: 16 April 2014
ABSTRACT
Objectives: Gastric retention systems releases drugs at the preferred absorption site optimizes delivery of the drug, maximizing its therapeutic benefits and reduces side effects by permitting a large portion of the drug to be absorbed before passing through the lower G. I tract. One promising approach for this is gastric floating drug delivery systems (GFDDS) developed has provided several advantages as shown by the encouraging results reported earlier.
Methods: In the present investigation, the drug Metoprolol succinate was selected for the design of GFDDS. The drug has its absorption window in the stomach and upper small intestine. It is aimed to design and evaluate GFDDS of Metoprolol succinate effervescent floating matrix tablets with three different swell able polymers, where Hydroxy Propyl Methyl Cellulose (HPMC K100 M) was used as a standard polymer. The prepared GFDDS were evaluated for their floating lag time and total floating time. The in vitro dissolution studies of the GFDDS was done in simulated gastric environment.
Results: The results conclusively demonstrated that floating tablets of Metoprolol succinate were effectively prepared with desired properties. Floating tablets of Metoprolol succinate were prepared by direct compression method. The directly compressed formulations exhibited better in-vitro drug release profiles.
Conclusion: Floating Metoprolol succinate tablets containing different grades of HPMC as polymer and sodium bi carbonate as effervescent agent showed an in vitro drug release up to 24hours whereas marketed conventional formulation showed its action up to 8 hours.
Keywords: Floating, Effervescent, Metoprolol succinate, HPMC K100M.
INTRODUCTION
Oral delivery of drugs is by far the most preferable route of drug delivery due to the ease of administration, patient compliance and flexibility in formulation, etc. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in GIT is to control gastric residence time. Dosage forms with a prolonged gastric residence time are known as gastro retentive dosage forms and they will bioavailability, therapeutic efficacy and possible reduction of the dose size [1].
Floating systems have bulk density lower than that of the gastric fluid, and thus remain buoyant in Stomach for a prolonged period. They float due to their low density than stomach contents or due to gaseous phase formed inside the stomach when they come in contact with gastric environment. Floating systems form a cohesive gel barrier and should release slowly to serve as reservoir. Different grades of HPMC polymer are used as polymers in this formulation. Higher molecular weight and slower rates of polymer hydration are associated with better floating properties.
This consists of carbon di oxide generating expanding system containing drug surrounded by hydrophilic membrane. This results in an increase in the GRT and a better control of fluctuations in the plasma drug concentrations. Floating drug delivery offers several applications for drugs having poor bioavailability because of the narrow absorption window in the upper part of the gastrointestinal tract. It retains the dosage forms at the site of absorption and thus enhances the bioavailability [2, 3].
MATERIALS AND METHODS
Materials
Metoprolol (Gift sample of Pharmatech labs.), HPMC K100M, HPMC K15M and MCC (Gift sample of Colorcon pvt. ltd, Mumbai), Sodium CMC (SD Fine Chemicals Ltd. Mumbai), PVP and sodium bi carbonate (Lobachemie pvt. ltd, Mumbai), Magnesium stearate and aerosol (SD Fine Chemicals Ltd. Mumbai).
Methods
Formulation
All the ingredients sufficient for a batch of 20 tablets according to formula was passed through sieve in order to enhance the flow and compaction properties and drug was triturated with polymer in a glass mortar and pestle to achieve a homogenous blend and geometrically mixing was done with effervescent agent, filler and other excipients sufficient for a batch of 20 tablets according to the formulae were passed through the mesh and thoroughly the blend was mixed with lubricated magnesium stearate to ensure complete mixing (table 1). Then mixed with Aerosil as glidant. Tablets containing metoprolol equivalent to 250mg were compressed by using 10.0 mm diameter, spherical tablet punches on a 16 station rotary compression machine at the hardness of 5 to 6 kg/cm2.
Pre-formulation
FTIR study
FTIR graphs of the pure drug and optimized formula were compared to show the compatibility between drug and the polymers.
Evaluation of pre-compression parameters
The bulked density, tapped density, angle of repose and compressibility index for powder blends was done.
Post compression parameters
The prepared tablets were evaluated for various quality control tests like measurement of Tablet thickness and diameter by using Vernier callipers, hardness measurement with Monsanto hardness tester, friability by Roche friabilator and content uniformity test.
Content uniformity test is performed to maintain the uniformity of weight of each tablet which should be in the prescribed range according to the Indian Pharmacopoeia. The content uniformity test is mandatory for tablets whose average weight is below 50mg. This test is performed by taking twenty tablets were selected randomly, weighed and powdered. A quantity of powdered tablet equal to 200 mg of metoprolol was dissolved in 0.1 N HCL in 100 ml volumetric flask. The so formed sample was diluted and the absorbance was measured at 223 nm using 0.1 N HCL as blank and the % drug content was estimated.
Buoyancy studies
The in vitro floating behavior of the tablets was studied by placing them in 1000 ml glass beaker filled with 900 ml of 0.1 N HCl (pH 1.2). The gas generating agents immediately evolves carbon dioxide in presence of HCl solution generating sufficient porosity which helped the dosage unit to float.
Floating lag time
The time taken by the tablet to emerge onto the surface of the liquid after adding to the dissolution medium simulated gastric fluid without pepsin, at pH 1.2, temperature 37+_0.5oC paddle rotations at 50rpm it is measured using the stopwatch.
Total floating time
The time taken by the tablet to float constantly on the surface of the gastric fluid without pepsin, at pH 1.2, temperature 37+_0.5oC., basket type rotation at 50rpm. It is measured using the stopwatch.
In vitro dissolution studies
Dissolution test was carried out using (DBK dissolution test apparatus) rotating basket method (apparatus 1). The stirring rate was 50rpm. 0.1 N hydrochloric acid was used as dissolution medium 900 ml and was maintained at 37+-2oC. Samples of 5 ml were withdrawn at predetermined time intervals, filtered and replaced with 5 ml of fresh dissolution medium. The collected samples were suitably diluted with dissolution fluid, wherever necessary and were analyzed for the metoprolol at 223 nm by using a double beam UV spectrophotometer (T60 UV-VISIBLE spectrophotometer) [4, 5].
Table 1: Formulae of Metoprolol GFDDS Prepared with HPMC K100M and HPMCK15M
Ingredients (mg) |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
Metoprolol |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
100 |
(mg) |
||||||||||||
HPMC K |
12.5 |
25 |
37.5 |
50 |
62.5 |
75 |
0 |
0 |
0 |
0 |
0 |
0 |
15 M |
||||||||||||
HPMC K 100M |
0 |
0 |
0 |
0 |
0 |
0 |
12.5 |
25 |
37.5 |
50 |
62.5 |
75 |
Sodium CMC |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
Sodium bicarbonate |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
20 |
PVP K 30 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
7 |
MCC |
98.1 |
85.6 |
73.1 |
60.6 |
48.1 |
35.6 |
98.1 |
85.6 |
73.1 |
60.6 |
48.1 |
35.6 |
Magnesium stearate |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
Aerosil |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
1.2 |
TOTAL(mg) |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
250 |
Accelerated stability studies
Controlled temperature and humidity condition
Optimized formulations were stripped packed for stability studies under controlled temperature and humidity condition. 30 tablets from each optimized formulations of Metoprolol were packed in strips of 0.04 mm thick aluminum foil laminated with PVC. The packed tablets were placed in a humidity chamber maintained at a relative humidity of 75 %. The humidity chambers were created by placing a beaker of saturated aqueous sodium chloride solution in a desiccator. The humidity chambers were kept in a hot air oven maintained at 40C. The packed tablet samples were withdrawn from the humidity chambers at time intervals of 0, 15days, 1 and 2 months. The tablets were evaluated for appearance, color and odour, moisture absorption, tablet crushing strength, friability, assay and in vitro dissolution study. Different humidity chambers and strip packs were used for the different sampling intervals such that the tablets were not in contact with external environment during the storage interval in the chambers
RESULTS AND DISCUSSION
Pre-formulation studies
IR studies were conducted for the pure drug and with the combination of HPMC K 100 and HPMC K 15 (fig. 1, 2 and 3). Hence after conducting the tests it was concluded that the drug and excipients are compatible with each other and showed good results
The pre formulation parameters like bulk density, tapped density, angle of repose, compressibility index and hausners ratio were evaluated (table 2). The post compression parameters like weight variation, hardness, friability and content uniformity was found to be in the limits.Floating lag time
The time taken by the tablet to emerge onto the surface of the liquid after adding to the dissolution medium simulated gastric fluid without pepsin, at pH 1.2, temperature 37+_0.5oC paddle rotation at 50rpm. It is measured using stopwatch (table 3)
Fig. 1:IR graph of metoprolol succinate
Fig. 2: IR graph of metoprolol and HPMC K 100
Fig. 3: IR graph of metoprolol and HPMC K 15
Table 2: Pre-Formulation Parameters
Formulation code/ Parameter |
Bulk density |
Tapped density |
Angle of repose |
Compres sibility index |
Hausner’ s ratio |
F1 |
0.462 |
0.591 |
26.06 |
21.8 |
1.25 |
F2 |
0.469 |
0.561 |
25.42 |
21.39 |
1.19 |
F3 |
0.59 |
0.68 |
29.19 |
13.04 |
1.15 |
F4 |
0.48 |
0.637 |
25.72 |
24.6 |
1.25 |
F5 |
0.475 |
0.565 |
26.45 |
16.03 |
1.19 |
F6 |
0.48 |
0.56 |
24.61 |
14.28 |
1.16 |
F7 |
0.451 |
0.565 |
23.34 |
20.17 |
1.25 |
F8 |
0.462 |
0.591 |
26.06 |
21.8 |
1.25 |
F9 |
0.52 |
0.62 |
29.24 |
16.12 |
1.19 |
F10 |
0.446 |
0.56 |
28.35 |
36.5 |
1.25 |
F11 |
0.48 |
0.56 |
24.28 |
31.1 |
1.16 |
F12 |
0.475 |
0.565 |
27.03 |
31.6 |
1.19 |
Table 3: Evaluation of Floating Time
Formulations |
Floating lag time |
Floating log time |
F1 |
8 min |
24 hrs |
F2 |
6 min |
24 hrs |
F3 |
10 min |
24 hrs |
F4 |
7 min |
24 hrs |
F5 |
5 min |
24 hrs |
F6 |
6 min |
24 hrs |
F7 |
8 min |
24 hrs |
F8 |
9 min |
24 hrs |
F9 |
10 min |
24 hrs |
F10 |
11 min |
24 hrs |
F11 |
6 min |
24 hrs |
F12 |
6 min |
24 hrs |
Table 4: In vitro Dissolution Results
Formulation code/Param eter |
F1( %) |
F2( %) |
F3( %) |
F4( %) |
F5( %) |
F6( %) |
F7( %) |
F8( %) |
F9( %) |
F10( %) |
F11( %) |
F12( %) |
1hr |
47 |
44 |
42 |
33 |
31 |
32 |
43 |
44 |
32 |
32 |
20 |
|
2hr |
58 |
58 |
56 |
43 |
43 |
38 |
55 |
55 |
44 |
41 |
38 |
28 |
4hr |
68 |
66 |
61 |
57 |
55 |
46 |
66 |
62 |
53 |
51 |
46 |
41 |
6hr |
77 |
72 |
68 |
65 |
68 |
58 |
73 |
68 |
65 |
63 |
52 |
51 |
8hr |
93 |
86 |
75 |
72 |
73 |
66 |
87 |
77 |
68 |
69 |
64 |
58 |
10hr |
98 |
95 |
86 |
83 |
84 |
72 |
93 |
85 |
83 |
82 |
76 |
66 |
12hr |
98 |
93 |
89 |
87 |
83 |
97 |
94 |
89 |
89 |
83 |
72 |
|
14hr |
98 |
96 |
94 |
92 |
88 |
98 |
93 |
93 |
88 |
77 |
||
16hr |
98 |
98 |
94 |
92 |
98 |
95 |
92 |
82 |
||||
18hr |
98 |
96 |
97 |
95 |
88 |
|||||||
20hr |
99 |
98 |
93 |
|||||||||
22hr |
97 |
|||||||||||
24hr |
99 |
method. The main aim was to optimize the formulation for 24 hrs invitro release and total floating time to more than 24 hrs. The results of invitro dissolution studies shows that the drug release rate decreases on increase in the viscosity of the polymer (Table 4 and fig. 4).
Fig. 4: Invitro dissolution Profile of F1 to F12 Formulations
Fig. 5: First order kinetics of optimized formulation F12
Fig. 6: Higuchi model of optimized formulation F12
The drug containing carbon dioxide generating expandable system surrounded by a hydrophilic polymer membrane can result in a sustained and controlled release of drug on contact with gastric fluids. On contact with acidic aqueous media, carbon dioxide is generated and entrapped within the gelling hydrocolloid causing the system to float. The results show that generated carbon dioxide remained entrapped for prolonged time periods that resulted in excellent floating abilities of all the formulations. All the formulations floated within 11 min and remained floating over a period of 24 hrs.It was observed that the release of metoprolol from all the formulations follows first order release kinetics and Higuchi model of diffusion (fig. 5 and 6). The invitro dissolution studies of the marketed conventional product and formulated optimized formulation were carried out. The optimized formulation F12 showed its pharmacological action approximately 24 hrs whereas marketed conventional formulation showed its action up to 8 hrs. The results show that it has significant gastro retention.
CONCLUSION
Metoprolol succinate is gastroprokinetic drug and the site of action is stomach and also the drug pH ranges from 3.5 to 5.5, the present work was aimed to formulate floating tablets of Metoprolol succinate using an effervescent approach for gastro retentive drug delivery system to improve its bioavailability. Metoprolol succinate is the drug of choice in the therapy of Hypertension. The tablets were formulated using polymers like HPMCK100M, HPMC K15M and along with effervescing agent sodium bicarbonate. Optimized formulation F12 containing 100 mg HPMC K100M was considered as the best product with respect to in vitro drug release for 24 hours release action, total floating time and improved bioavailability and site‐specific action.
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