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Journal Home Page www.bbbulletin.org BRITISH BIOMEDICAL BULLETIN Original Formulation and In vitro Evaluation of Metoprolol Succinate Extended Release Pellets Ch.Kalyani 1* , K. Veer Reddy 1, E.Anka Rao 2 and M Prashanta Kumari 3 1 VJ’s College of Pharmacy, Affiliated to Andhra University, Rajahmundry, Andhra Pradesh, India. 2 Scientist, Hetero Drugs, Hyderabad, Andhra Pradesh, India. 3 KJR College of Pharmacy, Affiliated to Andhra University, Rajahmundry, Andhra Pradesh, India. A R T I C L E I N F O Received 26 Sept 2013 Received in revised form 04 Oct 2013 Accepted 06 Oct 2013 Keywords: Metoprolol succinate, Pellets, HPMC, Di ethyl phthalate, Plasticizer. Corresponding author: VJ’S college of Pharmacy, Rajahmundry, Andhra Pradesh, India. E-mail address: [email protected] A B S T R A C T The objective of the present study was for improving bioavailability and reducing the dosage frequency of Metoprolol succinate in the form of extended release pellets by pan coating technology. Initially drug solution coated on different cores i.e. water soluble, insoluble and swellable cores and layered by different combinations of extended release polymers as EC(ethyl cellulose) 10 cps + HPMC (Hydroxy propyl methyl cellulose), EC 10 cps + Di ethyl phthalate and EC 10 cps + HPMC+ Diethyl phthalate. Formulated pellets were evaluated for flow properties, surface morphology, size analysis and in vitro dissolution studies. Studies were done on the effect of core nature and coating composition and effect of plasticizer. In vitro dissolution studies revealed that higher release observed from water-soluble core compared to insoluble and swellable cores. Controlled drug release observed from coating composition containing combination of EC + diethyl phthalate. Moderate drug release observed from combination of HPMC + EC+ diethyl phthalate. The mechanism of drug release follows Higuchi diffusion model. In conclusion the resulting formulations F6 (Water soluble core and coat was EC 10 cps + HPMC+ Di ethyl phthalate) can reduce the dosing frequency of the Metoprolol succinate to once daily. © 2013 British Biomedical Bulletin. All rights reserved
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Page 1: Journal Home Page BRITISH BIOMEDICAL … · 2016-08-10 · Journal Home Page BRITISH BIOMEDICAL BULLETIN Original Formulation and In vitro Evaluation of Metoprolol Succinate Extended

Journal Home Page www.bbbulletin.org

BRITISH BIOMEDICAL BULLETIN

Original

Formulation and In vitro Evaluation of Metoprolol Succinate Extended Release Pellets

Ch.Kalyani1*, K. Veer Reddy1, E.Anka Rao2 and M Prashanta Kumari3 1VJ’s College of Pharmacy, Affiliated to Andhra University, Rajahmundry, Andhra Pradesh, India. 2Scientist, Hetero Drugs, Hyderabad, Andhra Pradesh, India. 3KJR College of Pharmacy, Affiliated to Andhra University, Rajahmundry, Andhra Pradesh, India.

A R T I C L E I N F O Received 26 Sept 2013 Received in revised form 04 Oct 2013 Accepted 06 Oct 2013 Keywords: Metoprolol succinate, Pellets, HPMC, Di ethyl phthalate, Plasticizer. Corresponding author: VJ’S college of Pharmacy, Rajahmundry, Andhra Pradesh, India. E-mail address: [email protected]

A B S T R A C T

The objective of the present study was for improving

bioavailability and reducing the dosage frequency of Metoprolol

succinate in the form of extended release pellets by pan coating

technology. Initially drug solution coated on different cores i.e.

water soluble, insoluble and swellable cores and layered by

different combinations of extended release polymers as EC(ethyl

cellulose) 10 cps + HPMC (Hydroxy propyl methyl cellulose), EC

10 cps + Di ethyl phthalate and EC 10 cps + HPMC+ Diethyl

phthalate. Formulated pellets were evaluated for flow properties,

surface morphology, size analysis and in vitro dissolution studies.

Studies were done on the effect of core nature and coating

composition and effect of plasticizer. In vitro dissolution studies

revealed that higher release observed from water-soluble core

compared to insoluble and swellable cores. Controlled drug

release observed from coating composition containing

combination of EC + diethyl phthalate. Moderate drug release

observed from combination of HPMC + EC+ diethyl phthalate.

The mechanism of drug release follows Higuchi diffusion model.

In conclusion the resulting formulations F6 (Water soluble core

and coat was EC 10 cps + HPMC+ Di ethyl phthalate) can reduce

the dosing frequency of the Metoprolol succinate to once daily.

© 2013 British Biomedical Bulletin. All rights reserved

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Introduction

Several approaches existed for administration of drugs to the patients. In all those approaches oral administration has been received more attention due to more flexibility in designing of dosage forms. From the years onwards tremendous work had done for designing of controlled delivery systems to reduce the fluctuations in plasma concentrations which is observed in conventional delivery. The main aim in designing of controlled delivery is to reduce fluctuations in plasma concentrations and increasing the patient compliance. Now a days in pharmaceutical market per oral multi unit controlled release dosage forms (pellets, granules, nano particles, micro particles, mini tablets) are more important than single unit dosage forms (tablets and capsules) due to low risk of dose dumping, increasing the bioavailability of drugs, flexibility to produce different release patterns and targeted drug delivery1-4.

Pelletization technology is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small free flowing spherical units, (0.5 to 1.5 mm) known as pellets. Pellets not only have technological advancements but also show better flow properties, uniform and reproducible fill weights of capsules and tablets, disperse freely in GI tract leads to maximum drug absorption and pack easily without significant difficulties. Coating of multi-particulates is used for modifying the drug release such as targeted or extended release5, 6.

Metoprolol succinate is cardio selective β1 blocker used for the treatment of angina pectoris, hypertension and heart failure. According to the Biopharmaceutical classification system (BCS) Metoprolol succinate comes under class I drug means that highly soluble and highly permeable. It is rapidly and completely absorbed but due to extensive first pass effect, it is bioavaiable

only 50% after oral administration. Due to its short half life (3-7 hrs) drug should be administer 4 times daily. Whenever dose is missing leads to nocturnal attack. Therapeutic level of β1 (beta 1) blockage occurs when plasma concentration is 80-300 nM. Immediate release dosage forms increase the plasma concentration above 300nM leads to more β2 (beta 2) blockage and little β1 blockade. For maintaining the therapeutic concentration and eliminating the fluctuation in plasma concentration Metoprolol succinate is suitable agent for controlled drug delivery7, 8.

It is a challenge to pharmaceutical technologist to design a sustained release dosage form for class I drugs having extensive hepatic metabolism like Metoprolol succinate. Poor formulation leads to high rate of drug release and produce toxic concentrations in the body. Polymeric film coatings used for achieving sustained release because coated dosage forms enable précised drug release with good reproducibility. Main objective of the present study is to prepare extended release pellets of Metoprolol succinate by using three different inert cores i.e water soluble, water insoluble and water swellable and to study the effect of coating composition and the effect of water insoluble plasticizer in drug release. In the present study Hydroxy propyl methyl cellulose (HPMC) confers more hydrophilic nature to the film and alters its structure by virtue of pores and channels through which the substance can diffuse more easily to control the release pattern. Ethyl cellulose (EC) 10 cps is used as water insoluble polymer and di ethyl phthalate is used as water in soluble plasticizer 9, 10.

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Materials and Methods

Materials Metoprolol Succinate was a gift

sample by Dr. Reddy’s Laboratories, Hyderabad, India. Hydroxy propyl methyl cellulose (HPMC), ethyl cellulose 10 cps (PVP) were obtained from Dow chemical company, USA. Water swellable core, insoluble core and soluble cores are procured from Asahikasei Chemicals Corporation, Japan, Rhodi, UK and Nexus Drugs, Hyderabad, India respectively. Remaining all chemicals used were analytical grade.

Formulation of Extended release pellets A) Coating of the core pellets with drug

solution Inert cores (water soluble, water in

soluble and swellable) were sieved through 80# and drug loaded pellets were prepared by layering the aqueous solution of Metoprolol succinate on inert cores using fluid bed processor (Wurster technique).

Drug solution was prepared by heating the purified water up to 60°C and Metoprolol succinate was slowly added while heating with continuous stirring by pneumatic stirrer (Remi Motors Ltd. Mumbai) to get clear solution. Composition of drug loaded pellets and coating parameters for drug layering are shown in table 1 & 2 respectively.

Sprayed the drug solution on the pre-warmed the inert core beads by using Wurster technique. Continued the drug-loading till desired weight gain occurs to yield the unit dose as per the formula. After coating pellets were dried with an inlet air temperature maintained at 40 ± 3°C for 1 hour. B) Extended release coating of drug pellets

Ethyl cellulose was dissolved in required quantity of isopropyl alcohol with continuous stirring to prevent formation of

lumps and foam. To this 5% methylene chloride solution was added to get clear solution. To this mixture varying proportions of HPMC and di ethyl phthalate were added according to the composition shown in table 3.This is to evaluate the effect of plasticizer and polymer on dissolution behavior. Characterization of Pellets

Prepared Metoprolol succinate extended release pellets were evaluated for particle size, size distribution surface morphology, density, porosity, flow properties, friability drug content and in vitro dissolution studies. Surface Morphology

Surface morphology of extended release coated pellets was observed before and after dissolution by Trinocular Microscope (with Dewinter pharmapro 4.0 software) which was attached with a camera (Nikon). Particle Size distribution

Mechanical sieve shaker was used to evaluate the particle size distribution of pellets of each core. The particle size distribution for different batches is shown in the Table 5.

Drug content

Pellets of weight equivalent to unit dosage form were transferred in to 100ml volumetric flask. To this 10ml of methanol and 10 ml of 6.8 pH phosphate buffer was added and sonicated for 20 min for complete solubilization. Then make up the volume with phosphate buffer and dilutions were made to get the absorbance in linearity range and measured at 274 nm by using UV-Visible double beam spectrophotometer. In vitro Dissolution study & Kinetics

Dissolution study of formulations F1- F9 was performed using USP 23 Dissolution

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procedure over a 24-hour period (11), using an automated Electro lab paddle dissolution system tester coupled to an automated sample collector. Capsule containing pellets equivalent to 50 mg were taken and release study performed in 900ml of pH 6.8 phosphate buffer with USP Type-II apparatus at 100 rpm with temperature of 37 ± 0.5°C. At the predetermined sampling points (1, 2, 4, 8, 12 and 24 hours) 5 ml of aliquot sample was withdrawn and replaced with fresh dissolution medium. Pellets release of corresponding core was determined by UV-Visible Spectrophotometer at 274 nm.

In vitro drug release data was fitted into various mathematical models, zero-order, first –order, Higuchi for determination of rate and drug release mechanism 12-13. Comparative dissolution profile of optimized formulation and marketed formulation

In vitro dissolution profile of optimized formulation was compared with the similarity factor using marketed drug release profile (PROLOMET- XL) as a reference. Similarity factor 14, 15 (f2) is a logarithmic reciprocal square root transformation to the sum of squared errors. If f2 value in between 50-100 two dissolution profiles considered to be similar. Stability studies

Stability studies were performed according to ICH guidelines for the optimized formulation. Optimized formulation was kept at humidity chamber maintained at 40oC and 75% relative humidity (RH) for 3 months. The sample was analyzed for the physical changes and percent drug content at interval of 7, 15, 30, 60 and 90 days.

Results Surface Morphology

Surface morphology of pellets was observed by Trinocular Microscope and the

photographs of pellets before and after 24 hrs of dissolution presented were presented below Fig .1-4. Particle Size distribution and Drug content of the formulations

The particle size distribution and drug content of the Metoprolol succinate pellets were given in the Table 4.

In Vitro dissolution studies & kinetics

Fig.5-7 showed the dissolution profiles of Metoprolol succinate pellets in 6.8 pH phosphate buffer.

The dissolution data of batches were fitted to zero-order, first-order and Higuchi. The linearization parameters are shown in table 5. The average r2 of all batches was used to select best fit model. Comparative dissolution profile of optimized formulation and marketed formulation

From the in vitro release data obtained by dissolution studies formulation F6 was selected optimized formulation. The dissolution profile of the optimized formulation of extended release pellets was compared with marketed MS formulation (PROLOMET-XL) and similarity factor (f2) was found to be 60.34. Stability studies

The stability studies of optimized formulation showed no significant changes in the physical parameters when stored at temperature and humidity conditions of 40±20C/75±5% RH. Discussion

Metoprolol succinate is a ß1-selective adreno receptor blocking agent used for the treatment of hypertension and angina pectoris. Multi unit particulate systems are advantageous over single unit dosage forms to

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reduce dose fluctuations and increase bioavailability of drugs.

The present work was aimed to formulate Metoprolol succinate pellets on different cores i.e. water soluble, insoluble and swellable. After they are coated with different extended release coatings and release rate was observed.

Effect of core nature on pellets In this study, the drug release was

found to be higher from all the three ER coating formulations of water soluble core (F4, F5 & F6 releases 99%, 81% and 93.2% respectively) when compare to other two core formulations. The controlled release of drug from the water soluble core was seen only up to 8 h. After 8 hours, burst release of was observed (Fig 5b). However, other two formulations with water-insoluble core and water swellable yielded controlled release for approximately 24 hours (Fig 5a & 5c). Further, the drug release from water insoluble core and water swellable core has more or less similar rate.

The higher release from water-soluble core is due to disrupted integrity of the film after contact with dissolution medium. As dissolution media penetrates in to the film and chance of rupturing, leading to higher release.

Effect of type of extended release coating composition

Among all ER coating compositions, higher drug release was observed in F1, F4 & F7 (63%, 99% & 67% respectively) containing EC 10 cps + HPMC. This is due to higher hydrophilic nature of film and rapid hydration rate of film during dissolution leads to increased dissolution rate. On the other hand, the drug release was found to be less in F3, F6 & F9 (52% 93.2% & 55% respectively) containing ER coating of EC 10 cps + Di ethyl phthalate and moderate release was observed in F2, F5 & F8 (59%, 81% & 63% respectively) containing HPMC+EC10 cps +Di ethyl phthalate. The morphological

observation of these pellets before and after dissolution was seen in the Fig 1-4. Effect of water insoluble plasticizer on pellets

Three ER coating formulations were prepared with each core and from these coatings, effect of hydrophilic agent (HPMC) and diethyl phthalate (plasticizer) has been studied. HPMC has a property to form channels in the film along with EC 10 cps, which enhances the permeability of the film for dissolution. Hydrophobic di ethyl phthalate gives the flexibility to the film and extends the drug release.

The drug release in film with HPMC+EC 10 cps (F1, F4 & F7) was higher in the all three pellet formulations. This is due to absent of plasticizer in the formulation and leads to brittle in nature and rupture of the film during the dissolution. Additionally, HPMC channeling property further enhances the release. This release was found higher in the water-soluble core than water in-soluble core and water-swellable core. More controlled release effect was seen in the film with EC 10cps and Di ethyl phthalate (F3, F6 & F9) Moderate release was seen with the film having EC10 cps +HPMC+ Di ethyl phthalate (F2, F5 &F8). Drug Release Kinetics

Based on the in vitro dissolution studies F6 was considered as the optimized formulation for extended delivery of drug as it controls the release up to 24 hrs. All of the formulations follow first order release kinetics. Higuchi plots were found to be linear in all the cases except in case of formulation F9. Linearity indicates that the drug release from coated beads might be of diffusion type as proposed by Higuchi (1961) from insoluble matrices. Accordingly, drug release from these coated beads involves penetration of dissolution fluid, dissolution of drug in the medium and leaching out of the drug through interstitial channels or pores.

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Stability studies Samples were withdrawn and retested

for drug content after intervals of 7, 15, 30, 60 and 90 indicating that no significant reduction in the content of active drug was observed over a period of 3 months; the percent drug contained is found within a specified limit of USP. Therefore, there was no evidence of degradation of drug quantity. Comparative dissolution profile of optimized formulation and marketed formulation

Similarity factor of optimized formulation (F6) and marketed formulation was 60.32.f2 is greater than 50. Then two formulations are identical. Acknowledgements

The authors are thankful to Dr. Reddy’s Laboratories Hyderabad, Andhra Pradesh, for the generous gift sample of Metoprolol Succinate.

Authors’ Statements (Competing Interests)

The authors declare no conflict of interest. References 1. Ali Asghar L, Chandra S. Multi particulate

formulation approach to colon specific drug delivery: current perspectives. Journal of Pharmacy and Pharmaceutical Sciences. 2002; 9(3):327–338.

2. Chopra R, Podczeck F, Newton JM. The influence of pellet shape and film coating on the filling of pellets into hard shell capsules. European Journal of Pharmaceutics and Biopharmaceutics. 2002; 53(3): 327–333.

3. Lian-Dong H, Yang L, Xing T, Qian Z. Preparation and in vitro / in vivo evaluation of sustained release metformin hydrochloride pellets. Eur J Pharm Biopharm.2006; 64: 185-92.

4. Sousa J.J, Sousa A, Moura MJ, Newton JM. The influence of core materials and film

coating on the drug release from coated pellets. Int J Pharm.2002; 233: 111-122.

5. Suryakusuma H, Jun HW. Encapsulated hydrophilic polymer beads containing indomethacin as controlled release drug delivery systems. J Pharm Pharmacol. 1984; 36:497-501

6. Pong paibul Y, Price JC, Withworth CW. Preparation and evaluation of controlled release Indomethacin microspheres. Drug Dev Ind Pharm. 1984; 10:1597-1609.

7. Derle DV, Kasliwal NH, Development & comparative evaluation of xanthan gum & guar gum based sustained release matrix tablets of tizanidine HCL. Int Journal of Excipients.2006; 116- 119.

8. Rahman N, Yuen KH, Khan NA, Wong JW. Drug polymer mixed coating: a new approach for controlling drug release rates in pellets. Pharm Dev Technol. 2006; 11:71-77.

9. John w, Anderson B, Kendall MJ. Pharmacokinetic consideration of formulation of extended release Metoprolol succinate in the treatment of heart failure. Journal of cardiovascular Pharmacology. 2003; 41:151-157.

10. Aulton ME, Abdul-Razzak MH, Hogan JE. The mechanical properties of hydroxy propyl methylcellulose film derived from aqueous systems. Part 1: the influence of plasticizers. Drug Dev Ind Pharm. 1981, 7, 649-668.

11. The United States Pharmacopeal, 30th ed. Convention Inc., Washington Rockville, MD; 2007.

12. Costa P, Lobo JMS. Modeling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13:123-133.

13. Chavda HV, Patel CN. Chitosan superporous hydrogel composite-based floating drug-delivery system: A newer formulation approach. J Pharm Bioall Sci. 2010; 2:124-131.

14. Gohel MC, Panchal MK. Novel use of similarity factors f 2 and S d for the development of diltiazem HCl modified-release tablets using a 32 factorial design. Drug Dev Ind Pharm.2002; 28:77-87.

15. Banakar UV. Pharmaceutical dissolution testing. New York: Marcel Dekker; 1992.

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Table 1. Composition of Drug loaded Pellets

Ingredients Per Unit (mg)

Core (Water Soluble or in Soluble core or Water

swellable) 25

Metoprolol succinate 95

Purified water Q.s.

Theoretical average unit 120

Table 2. Parameters used for the drug loading & ER coating

Parameters For Drug loading For Extended release coating

Blower speed (rpm) 800-1300 800-1300

Inlet air temperature (°C) 35-50 35-55

Exhaust temperature (°C) 35-50 26-38

Product temperature (°C) 37-50 30-35

Atomization air pressure (bar)

1.6-2.5 2.0-2.5

Solution spray rate (rpm) 2-8 2-6

Table 3. Coating composition for extended release coating of Metoprolol succinate pellets

S.No Ingredients (gm) Water insoluble core Water soluble core Water swellable core

F1 F2 F3 F4 F5 F6 F7 F8 F9

1. Drug Loaded Pellets 250 250 250 250 250 250 250 250 250

2 Ethyl cellulose 10cps 67.5 60.4 67.5 67.5 60.4 67.5 67.5 60.4 67.5

3 HPMC 7.5 7.1 — 7.5 7.1 — 7.5 7.1 —

4 Diethyl phthalate — 7.5 7.5 — 7.5 7.5 — 7.5 7.5

5 Iso Propyl Alcohol 900 900 900 900 900 900 900 900 900

7 Purified water Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S

Table 4. Particle size Distribution and Drug content of Metoprolol Succinate Pellets

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F. Code Particle size Drug content

(%) Mesh size % w/w

F1 #30/#50 92.36 102.2±0.98

F2 #30/#50 85.69 107.8+0.41

F3 #30/#50 79.53 103.4+0.65

F4 #30/#50 80.17 105.5+0.48

F5 #30/#50 92.47 104±0.55

F6 #30/#50 88.16 101.3+0.55

F7 #30/#50 90.15 103.6+0.78

F8 #30/#50 91.23 103.5+0.78

F9 #30/#50 88.09 102.8+0.65

Table 5. Comparison of correlation coefficient the release rate constant for various

mathematical models

Formulations Zero order First order Higuchi Model

Pellets r2 Ko r2 K, r2 KhO F1 0.96 2.44 0.98 0.03 0.95 12.6 F2 0.97 2.28 0.97 0.03 0.95 11.6F3 0.98 2.91 0.99 0.02 0.95 10.7F4 0.94 4.05 0.98 0.11 0.94 21.0F5 0.97 3.44 0.99 0.06 0.94 17.5F6 0.98 3.12 0.99 0.05 0.95 15.9F7 0.99 2.66 0.99 0.03 0.95 13.4

F8 0.94 2.49 0.99 0.06 0.98 13.1F9 0.98 2.16 0.95 0.03 0.86 10.5

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Figure.1. Effect of Core nature on coated pellets before dissolution (Magnification with 100X)

Figure.2. Effect of Core nature on coated pellets after 24 hrs dissolution (Magnification with 100X)

Figure.3. Effect of plasticizer (Di ethyl phthalate) on coated pellets before dissolution (Magnification

with 100X)

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Figure. 5. Showed In vitro dissolution profiles from water in soluble core (5a), in soluble core (5b) & water swellable

cores (5c)

Figure.3. Effect of plasticizer (Di ethyl phthalate) on coated pellets after 24 hrs of dissolution

(Magnification with 100X)


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