Design, development and evaluation of metoprolol succinate extended

Vol-2/Issue-5/Sept-Oct 2013
PhTechMed
ISSN: 2278-1099
Design, Development and Evaluation of Metoprolol Succinate Extended
Release Tablet
*Nikhate Ram D and Dr. Singh S
Department of pharmaceutics, HSBPVT’s, GOIs, College of Pharmacy, Kashti, MS, India Abstract
Metoprolol Succinate is an antihypertensive drug used in the management of hypertension, angina pectoris and heart failure in doses
ranging from 25 mg to 200 mg. The present study was aimed to design an extended-release solid oral matrix tablets. Matrix tablet of
Metoprolol Succinate was formulated through application/incorporation of swellable and/or soluble cum erodible hydrophilic
polymers, using in different ratio of drug: polymer MCC-PH-101, Hypromellose (K-4M, K-15M, K-100LV). The interference study
was done using DSC. DSC Studies revealed that there was no interaction between the drug and the polymers used. In order to obtain
the best optimized product different formulation were developed and evaluated for pre-compression, post-compression and release
kinetics. In vitro dissolution studies were carried out in phosphate buffer mixed (pH 6.8). From the in vitro dissolution studies, the
optimized formulation showed that drug release at 1, 4, 8, 20, 24 hrs was obtained as 12.2, 28.9, 52.4, 93.7% respectively as per
specification. The drug release kinetics follows Hixson-Crowell cube root law model which shows continuous and uniform drug
release for extended period of time. Storage stability as assessed by stability studies for the optimized matrix tablets at different
stability storage conditions as per ICH. The result showed no difference in physical as well as dissolution profile. Form this studies it
was concluded, that a stable extended-release swellable matrix tablet formulation of Metoprolol Succinate was successfully developed
for once day.
Key Words: Metoprolol Succinate, HPMC K4M, HPMC K 15M, HPMC K100LV, Hixson-Crowell
Introduction
Metoprolol Succinate is an antihypertensive (cardioselective Pre-compressional Evaluation
β-blocker) used in the management of hypertension, angina Per formulation study such as angle of repose, density pectoris and heart failure in doses ranging from 25 mg to 200 analysis, compressibility index, Hausner ratio, solubility mg. It is a water soluble drug with bioavailability of 40-60 % analysis and particle size analysis were performed on API and and plasma half-life 3 - 7 hrs. Hence, conventional tablet is on granulation ready for compression. (United State insufficient to achieve the therapeutic plasma concentration for Pharmacopoeia, 2007; Lachman L et al, 1987) long duration of time and a dosage regime of twice or thrice Formulation of Uncoated
daily is required (United State Pharmacopoeia, 2007; British The drug and the excipient except aerosil were shifted from the sieve and then granules per were prepared using non- Recent advances in novel drug delivery systems aim to aqueous wet granulation method using povidone k-30 as a enhance safety and efficacy of drug molecules by formulating granulating agent. Lubricated powder blend was compressed a convenient dosage form for administration and to achieve in to tablets on the 16 station rotary tablet compression better patient compliance. Once daily dosing of drugs having machine using 10.0 mm round standard convex punches. short elimination half life, through design of extended-release Further the tablets were coated by IC-MS-218 (hypromellose, oral formulation is the most preferred approach in improving diethyl phthalate, purified talc, ethylcellulose, titanium patient convenience, drug therapy and safety (Chein YW et al, dioxide). The composition of formulation batches is presented 1992; Augsburger L et al, 2002; Vyas SP et al 2002; Hoffman in table no 1. (Siepmann J, 2001 ; Ford JL et al 1991; Colombo P1993; Doelkar E,1986; Peppas NA et al 1986; The present study was aimed at design extended-release solid oral matrix tablets of Metoprolol Succinate through Post compression evaluation parameters for coated tablets
incorporation of swellable and erodible hydrophilic polymers, Post compression parameters were evaluated for Description, using in different ratio of drug: polymer. Thickness, Hardness, Friability Weight variation, Uniformity Materials and Methods
of drug content, In vitro dissolution studies using HPLC, Materials
Mathematical modeling of in vitro dissolution and Short term Metoprolol Succinate and excipient such as Microcrystalline stability studies as per ICH guidelines (for 60 days).( United Cellulose (PH-101), Hypromellose (K-15M, K-100LV), State Pharmacopoeia, 2007; Costa P et al 2001; Varma Ethylcellulose (100 mPas), Povidone (K-30), Isopropyl alcohol, Sodium Starch Glycollate, Sodium Stearyl Fumarate, Result and discussion
Colloidal Anhydrous Silica and Purified Talc was procured Interference study
from Alkem Labs. Ltd Mumbai. All other ingredient and DSC thermograms of pure drug Metoprolol Succinate and prepared tablet is presented in figure no.1 and 2. DSC Address for Correspondence
thermogram of Metoprolol Succinate shows sharp endothermic peak at 138.8°C, indicating the melting point of stable crystalline drug. However, the DSC thermograms of tablet of optimized formulation showed sharp endothermic peak at 135.35°C. These thermograms indicate that was no significant changes in melting point, peak shape, area and peak location www.pharmtechmedica.com
Vol-2/Issue-5/Sept-Oct 2013
Nikhate et al.,
Table 1: Composition of all formulation
Batch No.
Ingredients
(mg/tab)
(mg/tab)
(mg/tab)
(mg/tab) (mg/tab)
(mg/tab)
(mg/tab)
(mg/tab)
(mg/tab)
(mg/tab)
(mg/tab)
(mg/tab)
Table 2: Pre-compression parameters of all formulations
Angle of repose
Bulk density
Tapped density
Compressibility
Batch No.
index (%)
character
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Table 3: Post Compression Parameters of all Formulations
Batch No.
Thickness (mm)
4.27 ± 0.2 4.14 ± 0.2 3.95 ± 0.2 3.95 ± 0.2 3.87 ± 0.2 3.74 ± 0.2 3.94 ± 0.2 4.10 ± 0.2 3.76 ± 0.2 3.85 ± 0.2 3.90 ± 0.2 4.22 ± 0.2 3.93 ± 0.2 Hardness (N)
Friability (%)
Weight variation (mg)
Uniformity of drug content (%)
Figure 1: DSC thermogram of Metoprolol Succinate
Figure 2: DSC thermogram of formulation no 13
Vol-2/Issue-5/Sept-Oct 2013
Nikhate et al.,
were found. Therefore, this study revealed that there was no release matrix tablet formulation containing antihypertensive interaction between the drug, polymers and other excipients. drug Metoprolol Succinate. A stable extended-release Pre-compressional evaluated
swellable matrix tablet formulation of Metoprolol Succinate The micromeritics studies on pure drug were carried out and was successfully developed that has in vitro drug release as per the results indicated that the drug possesses very, poor flow properties. Hence, to overcome this problem by converting References
them to granules this was done by non-aqueous wet granulation technique using povidone K-30 as a binder to Formulary -25, Vol.3, Asian edition, United State improve the flow as well as compressibility characteristics. Evaluation of the blend which was ready for compression was 2. British Pharmacopoeia (2007): Vol.-2, The Stationary carried out at the various stages to know the effect on flow property of the blend. The result of pre compression is tabulated in table no 2. Post-compressional evaluated
Sustained release preparations, Adv. Drug Del. Rev.;33, The result of post compression is tabulated in table no 3 .The thickness of tablets was obtained in the range of 3.74 to 4.27 4. Chein YW, (1992): Novel Drug Delivery System, 2nd mm. Hardness was obtained in Newton’s in the range 69 to edition, Marcel Dekker Inc; New York, p.2. 127. Weight variation in the range 250 to 300mg and content 5. Augsburger L, Bonck JA, Brzeezko AW, (2002): uniformity of drug release in rang 101.3 to 103.32%. The optimized formulation shows thickness 3.76 to 4.27 (mm), Extended Release Formulation of water soluble drugs, hardness in was obtained as 119 to 73 (N), friability was obtained in rang of 0.003 to 0.009 (%), Weight variation was 6. Hoffman A, (1998): Pharmacodynamsic aspects of Sustained release preparations, Adv. Drug Del. Rev. 33, In vitro drug release study
The formulation where prepared using different concentration 7. Lachman L, Liberman HA, Kanig JI, (1987): The Theory of polymers such as Microcrystalline Cellulose (PH-101) and Practice of Industrial Pharmacy, 3rd edition, Varghese (100.5-18.5mg), Hypromellose (K-4M) (45-85mg), (K-15M) (75-50mg), (K100LV) (25-40mg), Sodium Starch Glycollate (6mg). The optimized formulation (F13) which contain above 8. Siepmann J, Peppas NA, (2001): Modeling of Drug polymer has retarded the release of drug for 24hrs. Further the release was retarded may be due to swelling phenomena of hydroxypropyl methylcellulose, Advanced drug delivery Hypromellose. The result of in vitro release is presented in figure no 3. Upon the application of different drug release 9. Ford JL, Mitchell K, Rows P, Armstrong DJ, (1991): model kinetics, it was found that formulation no 11 follows the Higuchi model, B.No.A-012 follows Hixson-Crowell cube root law, while the optimized formulation B.No.A-013 follows hydroxypropyl methylcellulose matrices: effect of the Hixson-Crowell cube root law model which shows continuous drug release for extended period of time. The result 10. Colombo P, (1993): Swelling-Controlled Release in of mathematical model is presented in the table no 4. There Hydrogel matrices for oral route, Adv.Drug Deliv.Rev. was no change obtained in the physical as will In vitro release of optimized formulation which conform the stability of 11. Doelkar E, (1986): Water-swollen cellulose derivatives in pharmacy, in: Peppas NA (Ed), Hydrogels in Medicine and Pharmacy, vol.2, CRC Press, Boca Raton, p.115-160. 12. Peppas NA, Lustig SR, (1986): Solute diffusion in hydrophilic network structures, in: .A. Peppas (Ed.), Hydrogels in Medicine and Pharmacy, Vol.1, CRC Press, 13. Polishchuk AY, Zaikov GE,(1997): Multicomponent Transport in Polymer Systems for Controlled Release, Overseas Publishers Association, Amsterdam, 14. Costa P, Sousa JM, (2001): Eur. J. Pharm. Sci., Time (hours)
15. Varma VS, (2004): Factors affecting mechanism and Figure 3: Comparative in vitro dissolution profile
kinetics of drug release from matrix-based oral controlled Conclusion
drug delivery system, Am J.Drug Deliv. 2(1): 43-57. Recent advances in novel drug delivery systems aim to enhance safety and efficacy of drug molecules by formulating 16. Natalie McClure, (1997): Stability Studies in Overview of a convenient dosage form for administration and to achieve ICH Guidelines for Drug Products. Matrix Pharmaceutical better patient compliance. Once daily dosing of drugs having short elimination half life, through design of extended-release oral formulation is the most preferred approach in improving patient convenience, drug therapy and safety. In the present investigation, an attempt was made to formulate an extended-

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