 Abstract | | |
An extended release tablet provides prolonged periods of drug in plasma levels thereby reduce dosing frequency, improve patient compliance and reduce the dose-related side effects. Ranolazine is indicated for the chronic treatment of angina in patients who have not achieved an adequate response with other anti-anginal agents. The present investigation was undertaken to design extended release tablets of Ranolazine employing hypromellose phthalate grade HP-55, ethocel standard 7FP premium ethyl cellulose, Surelease E-7-19040, Klucel HF pharm and Natrosol Type 250 HHX as matrix forming agents using wet granulation method. Formulated tablets were evaluated for uniformity of weight, assay, water content, in vitro drug release studies and stability studies. The drug release followed first order kinetics with both erosion and diffusion as the release mechanism. It is concluded that the desired drug release pattern can be obtained by using natrosol type 250 HHX compared to other polymers. The similarity factor (f2) was calculated to select best formulation by comparing in vitro dissolution data of the commercial formulation Ranexa® . The formulated tablets fulfilled the compendia requirements. The formulated Ranolazine Extended release tablets were found to be stable. Keywords: Ehocel, extended release tablets, hypromellose phthalate, klucel HF pharm and natrosol, ranolazine, surelease
How to cite this article:
Murthy T, Mukkala BP, Babu VS. Formulation and evaluation of ranolazine extended release tablets: Influence of polymers. Asian J Pharm 2011;5:162-6 |
| Introduction | |  |
Extended release drug delivery technology can provide smooth plasma levels of drug over longer periods of time, reduce dosing frequency and improve the patient compliance. [1] Ranolazine is indicated for the treatment of chronic angina. Unlike other anti-anginal medications such as nitrates and beta blockers, ranolazine does not significantly alter either the heart rate or blood pressure. Hence, it is of particular use in individuals with angina that is nonresponsive to maximal tolerated doses of other anti-anginal medications. [2] Cellulose ethers (hydroxypropylcellulose HPC and hydroxyethylcellulose HEC) are commonly employed as the hydrophilic, swellable and must erodible matrix polymers for orally administered types of controlled release systems. [3],[4] Ethyl cellulose and Surelease were used as release retardant binder for the manufacturing of inert matrices for controlled release formulations. [5],[6],[7] In this study, attempts were made to study the influence of polymers on release profiles of extended release tablets of Ranolazine.
| Materials and Methods | | |
Ranolazine was procured from the Natco Pharma Ltd, Hyderabad. Microcrystalline cellulose (FMC biopolymer, New York), Hypromellose phthalate grade HP-55 (Shin-Etsu chemical.co.ltd, Japan), Klucel HF pharm Hydroxy Propyl cellulose and Natrosol type 250 HHX Hydroxy Ethyl cellulose (Hercules incorporated, Wilmington, U.S.A.), Ethocel standard 7FP premium ethyl cellulose and Surelease E-7-19040 aqueous ethyl cellulose dispersion (Colorcon Asia Private limited, Goa), Magnesium Stearate (Signet Chemical Corporation, Mumbai) were used in this investigation.
Preparation of ranolazine extended release tablets
The ranolazine extended release tablets were prepared by wet granulation technique. Drug and other excipients were accurately weighed, mixed and sifted through ASTM (American society of Testing and Materials) 40 mesh. Isopropyl alcohol and water were used as the granulation fluid [Table 1]. The wet mass was passed through ASTM 12 mesh and granules were dried at 50°C. Dried granules were further passed through ASTM 18 mesh. The granules were lubricated and compressed into oblong shaped (16.5 X 8.0 mm) tablets using 12-station rotary compression machine (Rimek minipress -II MT). Composition of the ranolazine extended release tablets was showed in [Table 1].
Evaluation of tablets
Uniformity of weight
All prepared tablets were evaluated for its uniformity of weight according to the United States pharmacopoeia. [8]
Water content (By KF method)
Approximately 35 to 40 ml of a mixture of methanol was transferred to the titration vessel and titrated with Karl Fischer reagent to the electrometric end point. Five tablets of ranolazine extended release were ground to a fine powder in an atmosphere of temperature and relative humidity known not to influence the results. Total of 300 mg of the powder was accurately weighed and transferred into the titration vessel, mixed and titrated with the Karl Fischer reagent to the electrometric endpoint. [9] Calculated the water content of the specimen in mg taken using the following formula
Where,
S is the volume (ml) of reagent consumed in the second titration
F is the water equivalence factor of the Karl Fischer reagent,
W is the weight of sample taken in grams.
In vitro drug release studies
In vitro drug release studies were conducted in 900 ml of 0.1 N HCL using USP apparatus type II (paddle) at a stirrer speed of 50 rpm and temperature was maintained at 37±0.5°C. Five milliliter of the sample was withdrawn at regular intervals of time (30 min, 1st , 2 nd , 4th , 6th , 8th , 12th , 20th , and 24th hour) and filtered through 0.45 μ m membrane filter. The same volume was replenished with fresh dissolution medium to maintain the sink conditions. [10] The samples were analyzed at a λmax of 272 nm using UV-Visible spectrophotometer.
Assay
Drug content was determined with the HPLC technique. Twenty tablets was accurately weighed and powdered to fine powder. Equivalent to 500 mg of ranolazine was accurately weighed and transferred in to 100 ml of volumetric flask. About 50 mL of mobile phase (phosphate buffer (pH 7.0): methanol (35: 65)) was added, and sonicated for 30 minutes with occasional shaking. Cooled to room temperature and made the volume up to the mark with mobile phase. It was mixed well and filtered though a 0.45-μ m membrane filter. The resulting solution was suitably diluted and injected into the Supelcosil C18, (250 x 4.6 mm), 5 μ m column maintained at ambient temperature. The flow rate of mobile phase was maintained at 1.0 ml/min for 15 min runtime. The sample was detected at a λmax of 220 nm.
Related substances
Related substances were determined using by HPLC method. 20 tablets was accurately weighed and powdered to fine powder. Equivalent to 500 mg of ranolazine was accurately weighed and transferred in to 100ml of volumetric flask. 50 ml of mobile phase (phosphate buffer (pH 7.0): methanol (35: 65)) was added, and sonicated for 20 minutes with occasional shaking. Cooled to room temperature and made the volume up to the mark with mobile phase. Mixed well and filtered though a 0.45 μ m membrane filter. The resulting solution was suitably diluted and injected into the supelcosil C18, (250 × 4.6 mm), 5 μ m column maintained at ambient temperature. The flow rate of mobile phase was maintained at 1.0 ml/min for 60 min runtime. The sample was detected at 220 nm. Related substances were calculated by area normalization method.
Stability studies
The Ranolazine extended release tablets were packed in unit-of-use high density polyethylene bottle (60 tablets per 150 cc bottle) with child resistant closure and stored at temperature of 40±2°C/75±5.0% RH (accelerated). Samples were analyzed for description, identification, water content, dissolution, assay, and related substances at regular intervals of time as per ICH guidelines. [11]
| Results and Discussion | | |
The tablets formulated with Hypromellose phthalate grade HP-55, exhibited the burst release at the end of half an hour and hence this was undesirable. The tablets formulated with Ethocel Standard 7 FP premium, with combination of Ethocel Standard 7 FP premium and Hypromellose phthalate grade HP-55 and with Surelease E-7-19040 as the rate controlling polymers, the drug was found to be completely released at the end of 12 hours, whereas the formulation is intended to be a once-a- day formulation with an anticipated 90% release at the end of 20 hour. The rate of drug release was controlled with the inclusion of Natrosol Type 250 HHX and Klucel HF pharm as the release controlling polymer with the active core. As the amount of Natrosol Type 250 HHX and Klucel HF pharm increased then the % drug release was decreased. The tablets were formulated with combination of Natrosol Type 250 HHX and Klucel HF pharm as rate controlling polymer exhibited release profile similar to that of tablets containing Natrosol type 250 HHX and Klucel HF pharm.
Based on the results obtained from the preliminary investigations, Natrosol type 250 HHX was concluded as good rate controlling polymer compared to klucel HF pharm, ethocel Standard 7 FP premium, surelease E-7-19040 and hypromellose phthalate grade HP-55 [Table 2] and [Figure 1]. | Figure 1: Comparative in vitro dissolution profiles of ranolazine tablets formulated with various polymers and marketed formulation
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 | Table 2: In vitro drug release data of Ranolazine extended release tablets 500 mg
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The in vitro drug release profiles of formulations were compared with the reference product (Ranexa® Ranolazine ER tablet 500 mg) as per Office of Generic Drugs (OGD) recommendations. The similarity factor (f2) was calculated and ranolazine tablets formulated with Natrosol type 250 HHX as matrix forming agent was exhibited good similarity (69.92) compared to others.
To study the release kinetics, data obtained from in vitro drug release studies were plotted in various kinetic models:
Zero order: C=K0 t
K0 - zero order release rate constant
t- Time in hours
First order: Log C = log C0 - Kt/2.303
C0 -initial concentration of drug
k- First order release rate constant
To evaluate the mechanism of drug release from Ranolazine extended release tablets, data of drug release were plotted in Korsmeyer et al's equation:
Mt/ M8=ktn
Where
Mt/ M8- the fractional solute release,
t - Release time in hrs,
k- Kinetic constant characteristics of the drug/polymer system, and
n- An exponent that characterizes the mechanism of release of tracers.
For cylindrical matrix tablets, if the exponent n=0.45, then the drug release mechanism is Fickian diffusion, and if 0.45 < n <0.89, then it is non-Fickian or anomalous diffusion. An exponent's value of 0.89 is indicative of case-II Transport or typical Zero-order release. [12]
The drug release kinetics followed first order [Table 3] and mechanism of drug release was found to be combination of diffusion and erosion as the n value found to be 1.3095. | Table 3: In vitro drug release kinetics of Ranolazine extended release tablets 500 mg
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Results from stability studies [Table 4] indicated that there was no appreciable change observed in physical properties, assay, and dissolution during the testing period. | Table 4: Stability studies of optimized formulation of Ranolazine extended release tablets 500 mg
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| Conclusion | | |
In the present investigation, an attempt was made to formulate ranolazine extended release tablets to provide effective drug release for 24 hours. Natrosol type 250 HHX was found to be more effective as rate controlling polymer compared to other polymers. Tablets containing Natrosol type 250 HHX (120 mg) as matrix forming agent was considered to be the optimized formulation with the desired drug release profile. The formulated Ranolazine extended release tablets were found to be stable as per ICH guidelines.
| Acknowledgements | | |
The authors are grateful for the Natco Pharma Ltd, Hyderabad and Management of Bapatla College of Pharmacy, Bapatla for providing appropriate facilities.
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Correspondence Address:
TEGK Murthy
Department of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur, Andhra Pradesh - 522 101
India
DOI: 10.4103/0973-8398.91992
[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4] |
