Sustained Release Wax Matrix Tablet of Metoprolol Succinate

 

Paresh R. Mahaparale¹* and Bhanudas S. Kuchekar²

¹Padm. Dr. D. Y. Patil College of Pharmacy, Akurdi, Pune- 411 044

²MAEER’S Maharashtra Institute of Pharmacy, Erandwane, Pune- 411 038

*Corresponding Author E-mail: prmahaparale@yahoo.com

 

ABSTRACT:

The objective of this study was to design wax matrix tablets for oral sustained release of Metoprolol succinate and to investigate the sustained release behavior of the fabricated tablets. Matrices were prepared by melt granulation technique using Hydrogenated vegetable oil, Compritol and Precirol as a release retardant material. The FT-IR study indicated the compatibility of drug with excipients. The effect of different wax materials, different ratio of wax materials and excipients on release profile of metoprolol succinate was also studied. Tablet matrices containing dicalcium phosphate has given more retardant effect on release of drug than other excipients. One of the best formulations further studied for sintering time and temperature effect using direct compression method. Matrix tablet showed no change in physical appearance, drug content after storage 40⁰C/ 75% RH for 3 months.

 

 

 

INTRODUCTION:

Conventional oral drug delivery systems are slowly fading away in the market owing to its disadvantages. These delivery systems produce fluctuation in drug plasma level that either exist at safe therapeutic level or quickly falls below the minimum effective level. This effect is usually totally dependent on the particular agents biological half life, frequency of administration and release rate. Extended oral drug delivery systems are highly recognized today for their benefits, improving the disadvantages of conventional drug delivery system.

 

To be successful as extended-release products the drug must be released from the dosage form at a predetermined rate in gastrointestinal fluids, maintain sufficient gastrointestinal residence time and be absorbed at a rate that will replace the amount of drug being metabolized and excreted. Extended drug delivery systems are used in the treatment of chronic rather than the acute condition and they process a good margin of safety^[4,7].

 

Metoprolol succinate is cardioselective agent used in the treatment of hypertension, angina pectoris and heart failure. Its half life is about 3-7 hours. Its bioavailability is 50% following oral administration. Usual oral dosage regimen is 25 mg to 100 mg. To meet the need for effective and well tolerated β1 blockage an extended release formulation of Metoprolol succinate is beneficial^[1,2].

 

Wax materials have major application in sustained release system, especially for highly water soluble drugs. Such wax material provides several advantages ranging from good stability at varying pH value and moisture levels to well established safe application in human. Matrix delivery system using wax materials usually employ a core of drug embedded in the hydrophobic material which is in the molten form. Melt granulation is a process in which the granulation is obtained through the addition of wax, which melts or softens at relatively low temperature. The various meltable binders used for the sustained drug delivery systems are Bees wax, Carnauba wax, Glyceryl Behenate (Compritol 888 ATO), Glyceryl palmitosterate (Precirol ATO 5) and Hydrogenated Vegetable Oil^[4,6,7].

 

In present work an attempt has been made to develop extended release tablets of Metoprolol Succinate by melt granulation technique by using different concentrations of wax matrix forming materials.

 

MATERIALS AND METHODS:

Materials

Metoprolol succinate and Hydrogenated vegetable oil was obtained as a gift sample from Lupin Research Park, Pune. Compritol ATO 888, Precirol ATO 5 was obtained from Colorcon Asia Pvt Ltd., Goa, Other excipients like lactose, DCP, Avicel PH 101 was obtained from Signet Chemical Corporation, Mumbai.

 

Preparation of sustained release wax matrix tablet of Metoprolol succinate by melt granulation technique

The waxy substances like Compritol 888 ATO, Precirol ATO 5 and HVO were respectively melted in porcelain dish on a water bath maintained at constant temperature as per their melting points. Metoprolol succinate was gradually added to the molten wax with continuous stirring. The molten mixture was allowed to cool and solidified at room temperature. The solidified mass was pulverized in mortar and passed through sieve no. 22. The obtained mass was compressed to prepare tablet. In order to study the effect of different wax substance, different ratio of wax (1:1, 1:2, 1:3), different excipients the various formulations are developed ^[3,5]. Also one of the best formulation was studied for sintering temperature and time using direct compression method^[11]. (Table 1).

 

Drug excipient compatibility study (IR Spectroscopy)

Drug excipient compatibility study was done by using IR Spectroscopy.

 

In vitro Dissolution Studies

In vitro drug release study for the prepared matrix tablets was conducted for period of 20 hours using a six-station USP XXIII type II (paddle) apparatus at 37°C ± 0.5°C and 50 rpm speed. The dissolution studies were carried out in 500 ml of 6.8 pH phosphate buffer, under sink condition. At predetermined time intervals, 10 ml aliquot samples were withdrawn from the dissolution medium and immediately replaced by the same volume of fresh medium. The volume was filtered through 0.45µm membrane filter (Millipore) and measured spectrophotometrically at 274 nm for the content of metoprolol succinate using an UV Spectrophotometer (shimadzu model 1700)^[2,3].

 

Stability Study

In the present work, stability study was carried out for one of best formulation (M7), at 40°C ± 20C, RH 75% ± 5% conditions for 90 days. Formulation M7 was selected for stability study because it was found to be good retardant and showed the release more similar to Marketed Product. The formulation was evaluated for Hardness, Friability, Assay (%) and In vitro drug release^[16].

 

 

RESULTS AND DISCUSSION:

Drug excipient compatibility study (IR Spectroscopy):

From FTIR study, it was found that there was no interaction between drug and wax substance. Characteristic peaks of drug was found in melt granulated mass also (Fig.1).

 

Table 1: Formulations of Metoprolol succinate by melt granulation method

*Metoprolol succinate 95 mg is equivalent to 100 mg of Metoprolol tartrate

 

Fig 1: Drug excipient compatibility study (FTIR)

Dissolution Study:

Table 2: Dissolution data of formulations

 

 

Table 3: Effect of sintering temperature and sintering time on optimized formulation

 

	Effect of sintering temperature (M7)			Effect of sintering time at temp 80°C (M7)
Time (Hrs)	60°C	70°C	80° C	1 Hours	2 Hours	3 Hours
1	48.62	24.14	29.84	29.84	28.22	27.67
2	77.61	40.23	40.76	40.76	38.45	36.62
4	98.73	65.48	51.82	51.82	49.71	48.93
8	-	78.46	68.09	68.09	67.35	66.12
12	-	89.34	80.92	80.92	78.14	77.47
16	-	98.52	90.52	90.52	88.67	87.12
20	-	-	99.92	99.92	98.12	97.32
f2	9.99	39.09	50.06	50.06	53.97	56.41
t25	< 1	1.1	< 1	< 1	< 1	< 1
t50	1.1	2.8	3.8	3.8	4	4.2
t70	1.8	5.3	8.6	8.6	8.9	9.2
t90	3.6	12.2	15.8	15.8	16.8	17.1
Best Fit Model	First order	Matrix	Matrix	Matrix	Matrix	Matrix

 

Effect of different Wax substances on release profile of drug:

The tablet prepared using hydrogenated vegetable oil was found to retard more release of drug as compared to Compritol and Precirol(Fig. 2). Release retardation effect was found to be in order of HVO > Compritol > Precirol.

This may be due to more hydrophobicity imparted by HVO^[5,10].

 

Fig. 2.Effect of different wax on release profile of drug

Effect of drug: wax ratio on release profile of drug:

The sustained release hydrophobic matrix tablet was prepared using ratio of 1:1, 1:2 and 1:3 for the Compritol ATO 888. It was found that as ratio increases release retardant effect also increases (Fig. 3).This may be due to dispersion of drug in more quantity of hydrophobic matrix which imparts more hydrophobicity to the system. ^[5,14].

 

Fig. 3.Effect of ratio of wax on release profile of drug

Effect of excipients on release profile of drug:

Excipients like microcrystalline cellulose, dicalcium phosphate, lactose was used as diluents for wax matrix tablet.

 

Sustained release wax matrix tablets prepared with lactose showed faster release, this may be due to formation of pores or channels due to dissolution of lactose (Fig. 4). Along with dissolution of lactose tablet also gets eroded and hence release was found to be faster. Wax matrix tablets containing MCC as an excipient showed faster release as compared to DCP as an excipient. This may be due to slight swelling property of MCC which causes more channel formation and entry of dissolution media.  DCP can retard release of drug due to its insoluble tendency. The release of drug from wax matrix tablet without excipient showed more sustained release than wax matrix tablet containing excipients. In wax matrix system, drug is uniformly and molecularly dispersed in wax system. When the granules are compressed drug remains in intimate contact with wax. Presence of excipients in wax matrix system disturbs the intactness and integrity of tablet^[9,12,13].

 

Fig. 4. Effect of different excipients on release profile of drug from Compritol matrix system

 

Effect of sintering temperature and time on release profile of drug

The method consisted of mixing drug and Compritol in powder form with dicalcium phosphate followed by direct compression. The compressed matrices were kept in hot air oven at 60°, 70°, and 80° C for an hour. After dissolution study it was found that sintered tablet kept at 80° C showed more retardant effect (Fig. 5). The 60° C temperature is not sufficient to melt the wax to form wax matrix system. But at 80° C the wax gets sufficiently melted and compact mass is formed. The drug gets entrapped in molten wax system. Hence retardation of drug release was observed by keeping tablet at 80°C. It indicates that sintering temperature markedly affect the drug release properties through wax matrix system.

The further study trials were performed at 80°C for an hour, 2 hour and 3hours. After dissolution study, there was no significant change observed on retardation of drug at 80⁰ though the time changed from an hour to 3 hours. This may be due to melting point of Compritol is 72° C, an hour may be sufficient to melt the wax^[11,15].

 

Fig. 5.Effect of sintering temperature on release profile of drug (Formulation M7)

 

Fig. 6. Effect of sintering time on release profile of drug (Formulation M7)

 

Dissolution Kinetics:

Most of the formulations showed Higuchi matrix as best fit model which indicates release of drug is by matrix diffusion mechanism.

 

 

Stability Study:

From stability study, it was found that there was no significant change in hardness, friability, assay and in vitro dissolution of drug (Table 4).  As wax is hydrophobic and is having melting point of 72° C, the stability condition not causes any change in formulation and hence not affects parameters.

 

Table 4: Stability study of optimized formulation

 

CONCLUSION:

From the dissolution study, it was found that release retardation effect was in the order of HVO > Compritol > Precirol. The release retardant effect increases with increase in ratio of drug: wax. Wax matrix tablet containing DCp as an excipient showed slower release than other two excipients, may be due to insoluble nature of DCP. Wax matrix system containing lactose showed faster release. This may be due to solubility of lactose and formation of channels in matrix system. The M7 formulation showed more similarity in dissolution with marketed formulation. In sintering study, 80°C temperature for an hour was sufficient to control the release of drug. The stability condition not causes any significant change in formulation.

 

REFERENCES:

1.       "Metoprolol". The American Society of Health System Pharmacists. http://www.drugs.com/monograph/metoprolol succinate.html. Retrieved 3 April 2011.

2.       Metoprolol succinate, United States of  Pharmacopoeia, The official compendia of standards, Asian edition, Vol-I. 1229.

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7.       Barthelemy P., Laforet J.P., Farah N., Joachim J., Compritol 888 ATO: An innovative hot melt coating agent for prolonged release drug formulations, European Journal of Pharmaceutics and Biopharmaceutics, 47(1999): 87-90.

8.       Hamdani J.,Moes A.J.,Amighi K., Physical and thermal characterization of Precirol and Compritol as liphophilic Glycerides used for the preparation of controlled release matrix pellets, Int J pharm. Jul 2003;260(1): 47-57

9.       Patel N.M., Soniwala M. M., Influence of release enhancer on release of Vanlafaxine hydrochloride from Glyceryl Behenate matrix tablet, Indian Drugs 2008; 45(2), 98-104

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12.     Jordhan T., Mandal T.K., Effect of lactose on drug release from plastic matrix system, Pharm Res. 1995;12, S 170

13.     Zhang Y. E., Schwartz J. B., Effect of diluents on tablet integrity and controlled drug release, Drug Dev Ind Pharm., 2000, 26(7): 761-765.

14.     Sutana W., Craig D.Q.M., Newton J.M., An evaluation of the mechanism of drug release from Glyceride bases, J.Pharm. Pharmacol., 1995 (47): 182-187.

15.     Uhumwangho M. U., Ramana Murthy K. V., Release Characteristics of Diltiazem Hydrochloride Wax-Matrix Granules–Thermal Sintering Effect, J. Appl. Sci. Environ. Manage. June 2011; Vol. 15 (2): 365 - 370

16.     Fung, H.L., Drug stability: Principles and Practice, Drug and Pharmaceutical Sciences, Vol. 43, Marcel Dekker Inc., New York: 235.

 

 

Received on 07.09.2012       Modified on 05.10.2012

Accepted on 11.11.2012      © RJPT All right reserved