www.wjpps.com Vol 8, Issue 8, 2019. 1669
FORMULATION DEVELOPMENT AND EVALUATION OF
IMMEDIATE RELEASE RIVAROXABAN TABLETS
Bidkar S.J., Sadakal S.U.*, Dr. Dama G.Y., Bidkar J.S, Dr. Umalkar D.G Department of Pharmaceutics, SGMSPM, Sharadchandra Pawar College of Pharmacy,
Dumberwadi (Otur) Pune- 412409, Maharashtra, India.
ABSTRACT
The present work is to formulate and evaluate immediate release tablets of Rivaroxaban tablets. Rivaroxaban is an anticoagulant medication (blood thinner), which is taken by orally. Tablets were prepared by direct compression method. Eight different formulations were made (F1-F8) using different super disintegrating agents. Using different Superdisintegrant and different concentrations of excipients. Concentration of SLS and PVPK-30 concentration were varied for all batches. Dissolution of rivaroxaban IR tablet was carried out in 900ml buffer at 75rpm by taking the concentrations of PVPK-30 and SLS. Dissolution of IR tablet of rivaroxaban containing different concentration of PVP K-30 changes the dissolution profile. When 5% and 8% PVP K-30 is used in the formulation the release of drug from IR tablet of rivaroxaban is decreased as compared to 2.5%. While using 6% and 8% of SLS in the formulation, it showed maximum release of drug from tablet as compared to 4% of SLS. From all the batches f7 batch shows best results as compare to other formulations. KEYWORDS: Immediate release, super disintegrating agents, Dissolution, Direct Compression.
INTRODUCTION
The research work is concerned with the formulation, development and evaluation of immediate release tablet of Rivaroxaban.
Many dosage forms are designed to release the drug immediately or at least as quickly as possible after administration. This is useful if a fast onset of action is required for therapeutic
SJIF Impact Factor 7.421 Volume 8, Issue 8, 1669-1683 Research Article ISSN 2278 – 4357
*Corresponding Author Sadakal S.U.
www.wjpps.com Vol 8, Issue 8, 2019. 1670 reasons. Immediate release allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug.
The term ―Immediate release‖ pharmaceutical formulation includes any formulation in which the rate of release of drug from the formulation and/or the absorption of drug, is neither appreciably, nor intentionally, retarded by galenic manipulations. Immediate release delivery systems give a fast onset of action and for a therapeutic action the drug should be in solution, therefore disintegration of the dosage form and dissolution of the drug may have to occur first depending on the dosage form. Immediate release systems usually release the drug in a single action following a first order kinetics profile. The time of action of the drug is limited to the time that the concentration of the drug is above the MEC.
Rivaroxaban is an anticoagulant medication (blood thinner), which is taken by orally. IUPAC name of rivaroxaban is (S)-5-chloro-n-{[2-oxo-3[3-oxomorpholin-4-yl) phenyl] oxazolidin-5-yl]methyl} thiophene-2-carboxamide. It is available in the market under the brand name Xarelto. Rivaroxaban is also used to treat and prevent deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism). Rivaroxaban is a direct factor Xa inhibitor. It works by blocking the formation of blood clots. It is initially developed by Bayer and marketed by Janssen pharmaceuticals in United States. Rivaroxaban was approved for medical use in 2011 and it was patented in U.S 2007. Rivaroxaban patent is expired in 2020. It is first available active direct factor Xa inhibitor which is taken by orally. Rivaroxaban exhibits dose-dependent bioavailability. For the 10 mg dose, bioavailability is approximately 80-100% and unaffected by food. Bioavailability of the 20 mg dose is 66% in a fasting state, though exposure is increased when taken with food (mean area under the curve [AUC] and Cmax increased by 39% and 76%, respectively). It is recommended that the 15 mg and 20 mg doses be taken with the evening meal. Absorption of rivaroxaban is dependent on the site of drug release in the GI tract.
www.wjpps.com Vol 8, Issue 8, 2019. 1671 In the present study an attempt has been made to prepare immediate release tablets of Rivaroxaban. Using different Superdisintegrant and different concentrations of excipients. Concentration of SLS and PVPK-30 concentration were varied for all batches. Best batches were optimized using dissolution of there tablets and % cumulative drug release was calculated from tablet. Depending on pre, post compression parameters and % cumulative release of drug batches were optimized. In eight batches of immediate release tablet SLS and PVPK-30 concentration was used in different concentrations.
MATERIALS
Rivaroxaban, Sodium starch Glycolate, Sodium lauryl sulphate, MCC-102, Magnesium stearate, Polyvinylpyrrolidone K-30, Talc.
METHODS
Evaluation of Powder Blend Angle of repose
Angle of repose was determined by using fixed funnel method. The fixed funnel method employ a funnel that was secured with its tip at a given height (2cm), above the graph paper that was placed on a flat horizontal surface. Granules or tablet blend were carefully poured through the funnel until the apex of the conical pile just touches the tip of the funnel. Thus, with r being the radius of the base of the conical pile. Angle of repose was calculated using the following equation.
= tan¹ Here, h = Height of pile r = Radius of pile θ = Angle of repose Bulk density
Bulk density was determined by pouring a weighed quantity of tablet blend into graduated cylinder and measuring the height. Bulk density is the ratio of mass of tablet blend to bulk volume.
Bulk density = Here;
www.wjpps.com Vol 8, Issue 8, 2019. 1672 v = Bulk Volume (cm.3)
Tapped Density
Tapped density is ratio of mass of tablet blend to tapped volume of tablet blend. Accurately weighed amount of tablet blend poured in graduated cylinder and height is measured. Then cylinder was allowed to 100tap under its own weight onto a hard surface. The tapping was continued until no further change in height was noted.
Tapped density = Here;
m = weight of powder or granules (gm.) v = Tapped Volume (cm³)
Hausner’s Ratio
Hausner’s ratio indicates the flow properties of powder and measured by the ratio of tapped density to bulk density. Hausner’s ratio was determined by the given formula.
Hausner’s Ratio =
Carr’s Index (Compressibility Index)
Compressibility is the ability of powder to decrease in volume under pressure, Using bulk density and tapped density the percentage compressibility of powder were determined, which is given as carr’s compressibility index. It is indirectly related to the relative flow rate. Carr’s compressibility index was determined by the given formula.
Table 1: Formula for IR tablet.
Sr. No Ingredients Category
01 Rivaroxaban Oral Anticoagulant 02 Sodium starch Glycolate Superdisintegrant 03 Sodium lauryl sulfate Surfactant
04 MCC-102 Diluent
05 Magnesium stearate Lubricant 06 Polyvinylpyrrolidone K-30 Binder
www.wjpps.com Vol 8, Issue 8, 2019. 1673 Table 2: Formulation batches for IR tablets.
Sr. No. Name F1 F2 F3 F4 F5 F6 F7 F8 01 Drug 20 20 20 20 20 20 20 20 02 SSG 15 15 15 15 15 15 15 --- 03 Croscarmellose --- --- --- --- --- --- --- 15 04 SLS --- --- 5 5 5 8 12 5 05 MCC-102 138 149 144 144 149 146 142 144 06 Mg. Stearate 4 2 2 --- --- 2 2 2 07 PVPK-30 20 10 10 10 5 5 5 10 08 Aerosil --- --- --- 2 2 --- --- --- 09 Talc 4 4 4 4 4 4 4 4
FTIR Spectroscopy Study
The drug sample of Rivaroxaban was mixed with IR grade KBr in the drug: KBr ratio of 1:100. This mixture was compressed to form pellets by applying 10 tons of pressure in the hydraulic press. The pellets were scanned over a wave number range of 4000 to 400 cm-1 in FTIR instrument (Perkin Elmer, Spectrum Bx) and spectral analysis was done.
Preparation of immediate release tablets of Rivaroxaban
The IR tablets of Rivaroxaban were prepared by the direct compression method by using double rotary tablet press machine (Rimek Mini II MT 12 station). The drug, polymers and other excipients used in immediate (IR) release were passed through sieve 40# and 60# before their use in the formulation.
Rivaroxaban, MCC-102, SLS, SSG, Mg stearate, PVPK-30 and Talc were sifted through 40 # and collected in polybag. Then Magnesium stearate was shifted through 60 # sieve and collected in polybag.
Tablet compression parameters
Punch Upper – 7mm round punch Lower- 7mm round, plain Appearance Round tablet
White, plane on one side and another side is embossed. Avg. Weight 199mg ± 0.05
www.wjpps.com Vol 8, Issue 8, 2019. 1674 Evaluation of immediate release tablets of Rivaroxaban
Appearance
The general appearance of tablet is its visual identity and all over elegance, shape, color, surface textures. These all parameters are essential for consumer acceptance.
Thickness
The thickness of the tablets was determined by using vernier calipers. Randomly 10 tablets were selected for determination of thickness and expressed in Mean± SD and unit is mm. Hardness
The hardness of tablet is an indication of its strength against resistance of tablets to capping, abrasion or breakage under conditions of storage, transportation and handling before usage. Measuring the force required to break the tablet across tests it. Hardness of 10 tablets (randomly) from whole batch was determined by Monsanto hardness tester. Hardness is measured in kg/cm².
Weight variation
The weight variation test is carried out in order to ensure uniformity in the weight of tablets in a batch. The total weight of 20 tablets randomly from whole batch was determined and the average was calculated. The individual weights of the tablets were also determined accurately and the weight variation was calculated.
Friability test
Friability is the loss of weight of tablet in the container due to removal of fine particles from the surface during transportation or handling. Roche friabilator was employed for finding the friability of the tablets. Roche friabilator is rotated at 25rpm for 4 minutes for 100rounds. The tablets were degusted and weighed again. The percentage of weight loss was calculated using the formula.
Here,
www.wjpps.com Vol 8, Issue 8, 2019. 1675 W1 = Final weight (After test)
Disintegration test
The USP device to test disintegration uses six glass tubes that are ―3 long, open at the top, and held against 10‖ screen at the bottom end of the basket rack assembly. One tablet is placed in each tube and the basket rack is positioned in 1 liter beaker of distilled water at 37± 2°C, such that the tablets remain below the surface of the liquid on their upward movement and descend not closer than 2.5cm from the bottom of the beaker.
Wetting Time
The wetting time of the tablets was measured using a simple procedure. Five circular tissue papers of 10cm diameter were placed in a petri dish containing 0.2% w/v solution of amaranth (10ml). One tablet was carefully placed on the surface of the tissue paper. The time required for development color due to amaranth (water soluble dye) on the upper surface of the tablets was noted as the wetting time.
Water Absorption Ratio
A small piece of tissue paper folded twice was placed in a small petri dish containing 6ml of water. A tablet was put on the paper. The wetted tablet was then weighed. Water absorption ratio, R was determined by using following formula.
Here,
R = Water absorption ratio
Wb = Weight of tablet before water absorption Wa = Weight of tablet after water absorption Drug content
www.wjpps.com Vol 8, Issue 8, 2019. 1676 Dissolution Study
In vitro release of rivaroxaban from tablets was monitored by using 900 ml of 0.1 N HCL, at 37 ± 0.5°C and 75 rpm using programmable dissolution tester USP II. Aliquots of 10 ml were withdrawn from the dissolution apparatus at time intervals of 5,10,20,30,40,50,60 min and the samples were replaced with fresh dissolution medium. Absorbance of these solutions was measured at 267 nm. The percent drug release was calculated using the calibration curve of the drug in acetate buffer pH 4.5+0.4% SLS.
RESULT AND DISSCUSION
Evaluation of powder blend of immediate release tablet
Powder blend of immediate release tablet evaluated for different parameters and results for the same shown in table 26, and it was observed that Compressibility index (%) was in the range of 22.73 to 31.34, Hausner’s ration in the range of 1.29 to 1.41. From these observation it was concluded that the blend of immediate release tablet has good flow properties and compressibility.
Table 3: Evaluation of pre compression parameter. BATCH NO. Bulk density (gm/ml) Tapped density(gm/ml) Angle of repose (θ) Carr’s Index (%) Hausner’s ratio % C.R F1 0.466±0.2081 0.607±0.01 21.19±0.89 31.34 1.30 70.65% F2 0.466±0.100 0.661±0.06 20.42±0.78 24.89 1.41 67.14% F3 0.633±0.057 0.646±0.06 19.72±0.53 9.84 1.02 85.08% F4 0.500±0.100 0.682±0.17 18.15±0.24 27.61 1.36 76.29% F5 0.566±0.152 0.738±0.12 18.41±0.53 20.13 1.30 82.35% F6 0.533±0.057 0.660±0.16 19.51±0.40 15.66 1.23 78.24% F7 0.533±0.023 0.665±0.03 24.57±0.15 23.46 1.28 99.37% F8 0.566±0.057 0.733±0.07 21.07±0.47 22.73 1.29 82.30%
Evaluation parameters of immediate release tablet was found to be satisfactory. Flow of powder blend shows good flow property, Bulk density, Angle of repose, Carr’s index and Hausner’s ratio was also found to be within range. F7 batch shows best results as compared to all other batches.
Fourier transformed infrared spectroscopy (FTIR) studies
www.wjpps.com Vol 8, Issue 8, 2019. 1677 Figure 2: FTIR Spectrum of Rivaroxaban.
Table 4: FTIR Spectra of Rivaroxaban.
Sr. No. Peak Observed Functional group 1 3355.11 N-H (2°-amines) 2 1737.00 C=O stretch(ester) 3 1643.72 C=O stretch(amide)
www.wjpps.com Vol 8, Issue 8, 2019. 1678 Figure 3: FTIR spectrum of Rivaroxaban and SSG.
Figure 4: FTIR spectrum of Rivaroxaban and SLS.
www.wjpps.com Vol 8, Issue 8, 2019. 1679 Figure 6: FTIR Spectrum of Rivaroxaban and Talc.
www.wjpps.com Vol 8, Issue 8, 2019. 1680 The compatibility of rivaroxaban with various excipients was studied by Fourier Transform Infrared Spectroscopy. In the present study, results of FTIR were successfully employed to assess the compatibility of rivaroxaban with the excipients. No concrete evidence of interaction was observed between rivaroxaban and the excipients like MCC-102, SSG, SLS, PVPK-30, Mg. Stearate and Talc concluded that there is no interaction between drug and excipients.
Table 5: Evaluation of post compression parameters. BATCH NO. Average Hardness (kg/cm² ) Average Weight Variation (%) Friability (% w/w) Average thickness (mm) Dt (Sec) Wetting time (Sec) Water absorption ratio F1 3.91±0.5 198±2.26 0.26±0.04 3.86±0.14 151±1.01 136±4.16 18.63±2.28 F2 3.48±0.9 199±0.76 0.27±0.02 3.81±0.17 154±1.62 147±2.53 18.79±2.96 F3 3.84±0.7 199±0.53 0.27±0.02 3.85±0.18 159±1.08 130±4.98 16.86±5.19 F4 3.59±0.8 199±2.21 0.27±0.03 3.78±0.14 158±1.32 131±3.45 19.58±2.65 F5 3.75±0.6 199±0.75 0.23±0.04 3.80±0.18 157±2.15 149±5.02 27.91±6.55 F6 3.44±0.6 199±0.40 0.22±0.02 3.85±0.15 158±2.94 150±5.14 19.88±1.17 F7 3.91±0.5 199 ±0.05 0.26±0.01 3.88±0.15 241±0.34 111±1.02 17.79±0.07 F8 3.71±0.5 198±1.43 0.23±0.03 3.86±0.17 157±2.01 128±6.50 19.28±2.51
All parameters of compressed immediate release tablet were found to be satisfactory. Average weight was found to be within limit. Thickness was found to be in range 3.88±0.15. Hardness and friability were found to be in appropriate range. F7 batch shows best results as compared to all other batches.
www.wjpps.com Vol 8, Issue 8, 2019. 1681 Figure 8: Cumulative release of Prepared tablet (900ml, 75rpm).
Figure 9: Dissolution of IR tablets containing different concentration of PVP K-30.
www.wjpps.com Vol 8, Issue 8, 2019. 1682 CONCLUSION
The present study was aimed to develop a formulation of immediate release tablet of Rivaroxaban close similar to marketed product by applying a simple manufacturing process such as direct compression. The direct compression process is cost effective and less time consuming. The formulated immediate release tablet was evaluated for different physical and chemical parameters of the immediate release tablet. From the above study it was concluded that the formulation F7 was showing good physical parameters in terms of flow ability and compressibility and the in vitro drug release for F7 is higher and dissolution pattern is close similar to marketed product.
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