FORMULATION AND EVALUATION OF CONTROLLED RELEASE TABLETS OF METOPROLOL SUCCINATE BY - OSMOTIC DRUG DELIVERY

{ DOWNLOAD AS PDF }

ABOUT AUTHORS:
Deepthi.P*, Samatha. M, N. Srinivas
Department of Pharmaceutics,
Mallareddy Institute of Pharmaceutical Sciences, Secunderabad
deepthisairi@gmail.com

ABSTRACT
Osmotically controlled drug delivery systems utilize the principle of osmotic pressure for the controlled delivery of active agents. The release rate of the drug from these systems is independent of the physiological factors of the gastrointestinal tract to a large extent. Metaprolol succinate β-receptor blocking agent was selected as a model drug to be formulated into osmotic drug delivery system. Elementary osmotic pump core tablets for Metaprolol succinate non- aqueous wet granulation were prepared by using osmogens like KCl. The coated tablets were drilled to different orifice sizes by using mechanical microdrill by mechanical means using softclix - modified sharp needle. The drilled orifice sizes on coated tablets were evaluated by using scanning ocular micrometer. It was observed that with an increase in osmogen content and pore size, rate of drug release was found to be increasing. The rate of drug release was found to be decreased with an increase in the membrane thickness. Based on different experimental trials, the optimized formulation was selected with respective to osmogen concentration, membrane thickness and orifice size that are following zero-order controlled release from the elementary osmotic pump tablets. The final selected elementary osmotic pump tablets have shown comparable dissolution profile with respective to marketed formulation.

INTRODUCTION
Controlled release¹ technology has rapidly emerged over the past few decades as a new field offering approaches to the delivery of drugs into systemic circulation at predetermined rate. Controlled release formulations² can achieve optional therapeutic responses, prolonged efficacy as well as decrease toxicity duo to achieving predictable and reproducibility release rate of drugs for extended period of time.

CR delivery systems provide desired concentration of drug at the absorption site permitting maintenance of plasma concentration within the therapeutic range and reducing dosing frequency. CR products provide significant benefits over immediate release formulations including greater effectiveness in the treatment of chronic conditions, reduced side effects, and greater patient convenience due to a simplified dosing schedule.

Osmosis³ can be defined as the passage of solvent molecules into a solution (containing both solute and solvent molecules) thought SPM or passage of solvent molecules usually water takes place from the SPM from a region of lower concentration to higher concentration.

Osmosis pressure⁴ can be defined as the pressure exerted as a result of osmosis or the pressure with which the solvent molecules cross from the semipermeable membrane or the required to stop the flow of solvent molecules from crossing the SPM is known as osmosis pressure.

The phenomenon of confining a solution to a membrane, permeable only to the solvent molecules, is known as osmosis and the membrane that allows only the solvent molecules to pass throught it is known as semipermeable membrane ⁵(SPM). Therefore osmosis can be defined as the passage of solvent molecules into a solution (containing both solute and solvent molecules) thought SPM or passage of solvent molecules usually water takes place from the SPM from a region of lower concentration to higher concentration.

[adsense:468x15:2204050025]

Elementary osmotic pump^6,7
In 1975, the major leap in osmotic delivery occurred as the elementary osmotic pump for oral delivery of drugs was introduced. The pump consists of an osmotic core containing the drug, surrounded by a semipermeable membrane with a delivery orifice. When this pump is exposed to water, the core imbibes water osmotically at a controlled rate, determined by the membrane permeability to water and by the osmotic pressure of the core formulation. As the membrane is non-expandable, the increase in volume caused by the imbibition of water leads to the development of hydrostatic pressure inside the tablet. This pressure is relieved by the flow of saturated solution out of the device through the delivery orifice. This process continues at a constant rate until the entire solid agent inside the tablet has been dissolved and only a solution filled coating membrane is left. This residual dissolved agent continues to be delivered at a declining rate until the osmotic pressure inside and outside the tablet are equal. Normally, the Elementary osmotic pump delivers 60-80% of its contents at a constant rate, and there is a short lag time of 30-60 min as the system hydrates before zero order delivery from the Elementary osmotic pump is obtained.

Fig 1: Schematic diagram of Elementary osmotic pump

DELIVERY ORIFICE⁸
To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system. The typical orifice size in osmotic pumps ranges from 600µ to 1 mm.

Metoprolol succinate⁸ is a cardioselective β1-adrenergic blocking agent used for acute myocardial infarction (MI), heart failure, angina pectoris and mild to moderate hypertension. It may also be used for supraventricular and tachyarrhythmias and prophylaxis for migraine headaches.

Mechanism of action:
Metoprolol competes with adrenergic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart. Beta(1)-receptor blockade results in a decrease in heart rate, cardiac output, and blood pressure.
Absorption is rapid and complete, 50%.
Biological half life is 3 - 7 hours and its therapeutic use in chronic respiratory diseases necessitates its formulation in to controlled release dosage forms.

MATERIALS AND METHODS
Materials:
Metoprolol succinate was recieved as a gift sample from Dr.Reddy's laboratories ltd, kcl, Microcrystalline cellulose 101 grade, Magnesium stearate, cellulose acetate,polyvinylpyrrrolidone K30, triethyl citrate was recieved from Drugs India Ltd.

Equipment:
Tablet compression machine 8 stn(Rimek), tablet compression machine 10 stn(pacific),gans coater machine(Gansons), fluid bed dryer(Ritsch), rapid mixer granulator (Kevin), Friabilator tester(Electrolab), Hardness tester(Dr.schleuingerphermotron), Tablet disintegration tester(Eletrolab), Halogen moisture Analysis (mettlertoledo), Tap density tester (Electrolab), Octagonal blender (Gansons)

Methodology:
Steps involved in manufacturing of tablets:

• Dispense the active pharmaceutical ingredients and excipients as per batch requirement.

• Metoprololsuccinate, Microcrystalline Cellulose were sifted through # 30 sieves.

• Potassium Chloride was passed through # 100 sieve.

• Metoprolol succinate, Microcrystalline Cellulose,Potassium Chloride was mixed in Rapid mixture granulator for10 mins.

• Prepared 4% PVP-k-30 with isopropyl alcohol, used as binding agent.

• Binder solution was added at a flow rate of 6ml/min to the premixed contents of step IV in the RMG to get a coherent wet mass.

• This wet mass was kneaded for 2-3 min to get wet granules.

• The wet Granules were passed through # 18 sieve and then dried in a fluid bed dryer at 30°c for 20mins at an airflow of 20 cfm (cubic foot per mint)

• The moisture content of the granules was determined by the moisture balance analyzer (LOD).

• The granules were loaded into the blend and mixed for 10min at 20 rpm

• Added the required quantity of magnesium stearate (sifted through # 50 sieve) and blend for another 5 min at 20 rpm.

• Compressed tablets equivalent to make 525mg metoprolol succinate using 10.5 mm round standard concave punch.

• The formulation was prepared for 600 tablets batch size.

Table 1:Formulation of metoprolol succinate core tablets 525 mg

Core composition
INGREDIENTS	Drug compartment composition, mg/core tablet (variable)
Batch no:	Fo 1	Fo 2	Fo 3	Fo 4	Fo 5	Fo 6	Fo 7
Ratio(M S :osmotic )	1:00	1:0.25	1:05	1:0.75	1:0.875	1:01	1:1.25
Metoprolol succinate	200	200	200	200	200	200	200
Potassium Chloride #100	0	50	100	150	175	200	250
Microcrystalline Cellulose-112	302.5	252.5	202.5	152.5	127.5	102.5	52.5
Polyvinylpyrrolidone-k-30	20	20	20	20	20	20	20
Magnesium stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Average weight	525	525	525	525	525	525	525

Evaluation of developed core formulation:
Granules were evaluated for various tests like Bulk density, Tap density, Carr’s compressibility index, Hausner Ratio, loss on drying. Tap density, Bulk density, Carr’s compressibility index, Hausner Ratio was determined by tap density tester and loss on drying was determined by Halogen moisture Analysis

Table 2: EVALUATION OF THE PHARMACEUTICAL POWDERS AND TABLETS

physical parameter	Fo 1	Fo 2	Fo 3	Fo 4	Fo 5	Fo 6	Fo 7
Ratio(M S :osmotic )	1:00	1;0.25	1:05	1:0.75	1:0.875	1:01	1:1.25
Average weight(mg)	525	524.6	525.2	525.4	524.5	525	524.7
LOD%	1.05	1.04	1.02	1.12	1.98	1.6	1.15
Bulk density(gm/ml)	0.429	0.464	0.472	0.498	0.478	0.548	0.566
Tap density(gm/ml)	0.574	0.821	0.896	0.638	0.548	0.998	0.653
Carr's compressibility index %	15.316	13.478	17.297	12.5	12.9	15.07	13.33
Hausner Ratio	1.331	1.069	1.0876	1.29	1.004	1.12	1.154
Friability %	1.029	0.014	0.014	0.073	0.2	0.043	0.13
Disintegration time(min)	18-20	8-9	2-3	1-1.5	1-1.5	1-2	1-2
Hardness(kp)	20-21	16.5-17.5	16-17	10-11	7.5-8	7.5-8	7.5-8
Thickness (mn)	5.63	5.63	5.5	5.5	5.5	5.5	5.5

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

Table 3:  Cumulative percentage of drug release of core tablets

Cumulative percentage of drug  release
Ratio(M S :osmotic )	Fo 1	Fo 2	Fo 3	Fo 4	Fo 5	Fo 6	Fo 7
Time(Hrs)	1:00	1:0.25	1:0.5	1:0.75	1:0.875	1:1	1:1.25
0.25	17.6	42.7	75.5	82.7	86	87.9	88.1
0.5	24.8	65.7	80.7	88.8	91.5	92.5	93.5
0.75	31.8	81.8	85.1	91.9	96	98.6	100.6
1	35	89.7	92.9	95.3	99.5	101.3	102.7

Figure 2: Cumulative percentage of drug release of core tablets

Coating with semi-permeable polymer:
Core tablets were coated by using a Ganscons coating machine with a perforated pan. A solution of cellulose acetate in acetone at a concentration of (4%w/v), containing TEC at concentration of 10% of w/w of cellulose acetate, level of plasticizer (TEC) was used as the coating solution. To the acetone, slowly cellulose acetate added with proper mixing. In between, plasticizer was added drop wise and through mixing was done to dissolve the cellulose acetate. Addition of plasticizer in the coating solution improves film properties like film flexibility. The final coating solution was filtered through # 80 sieve. The composition solution used was mentioned in the below tabular form.

Table 4: Coating solution composition

INGREDIENTS	Weight	CONCENTRATION (%)
Cellulose acetate	40gms	4%
Triethyl citrate	4 gms	0.4
Acetone	1000ml	Quantity sufficient

Core tablets of metoprolol succinate were place in coating pan and tablets were coated using the following parameters:
Pan rpm: 10-11
Coating solution spray rate: 4-5ml/min
In let temperature: 38°C
Outlet temperature: 28°C
Atomizer pressure: 1.0 kg/cm²
Fan pressure: 1-0.75 kg/cm²
Inlet air blower: 900 cpm
Outlet air blower:  1600 cpm

The coating solution was sprayed over the tablet bed  by a spray gun till a desired weight gain was obtained on the active core tablets .Later the osmotic pump tablets were dried at 50°C for 1 Hr to remove the residual organic solvent

Evaluation of coated formulation:
The coated tablets were evaluated by visual inspection of the film smoothness, Uniformity of coating. The parameter like weight variation, thickness, diameter of the tablets recorded before and after coating, was measured by Verniercaliper.  The measured parameters are :

Table 5: evaluation of coated formulation

Evaluation of coated formulation
physical parameter	Fo 1	Fo 2	Fo 3	Fo 4	Fo 5	Fo 6	Fo 7
Ratio(M S :osmotic )	1:00	1;0.25	1:05	1:0.75	1:0.875	1:01	1:1.25
Average weight(mg)	546	545.5	545.8	546.1	545.7	545.8	545.2
Thickness(mn)	5.81	5.79	5.68	5.64	5.69	5.68	5.69

Characterization of the tablets

Fourier transform infrared spectroscopy
FT-IR analysis was carried out for pure drug and for formulations using KBr pellet method on Fourier transform infrared spectroscopy (FTIR) spectrophotometer type Shimadzu model 8033, USA, in order to ascertain compatibility between drug and polymers used.

Figure 3: FT-IR spectrum of metoprolol succinate

Functional group	Literature value	Observed value
-OH	3400-3200	3353.45
-NH-	2700-2250	2633.91
C-O-CH3	2860-2810	2844.47

REFERENCE ID: PHARMATUTOR-ART-2192

PharmaTutor (ISSN: 2347 - 7881) Volume 2, Issue 6 Received On: 11/04/2014; Accepted On: 27/04/2014; Published On: 01/06/2014 How to cite this article: PDeepthi, M Samatha, N Srinivas; Formulation and Evaluation of Controlled Release Tablets of Metoprolol Succinate by - Osmotic Drug Delivery; PharmaTutor; 2014; 2(6); 190-200