International Journal of Innovative Pharmaceutical Sciences and Research

Transcription

1 International Journal of Innovative Pharmaceutical Sciences and Research FORMULATION AND EVALUATION OF MONTLUKAST SODIUM EXTENDED RELEASE MATRIX TABLET 1 G.Rajini*, 2 Dr N. Srinivas Malla reddy institute of pharmaceutical sciences, Maisammaguda, Dhulapally, (Post Via Hakimpet, secunderabad , Telangana, INDIA Abstract Montelukast is a leukotriene receptor antagonist used for the maintenance treatment of asthma, chronic asthma attacks, and to relieve symptoms of seasonal allergies. It is usually administered orally once a day. Montelukast is a CysLT1 antagonist; it blocks the action of leukotriene D4 (and secondary ligands LTC4 and LTE4) on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene and results in less inflammation. Montelukast biological half life is 2.5 to 5.5 hrs, thereby decreasing bioavailability up to 64%. So in order to improve the bioavailability and efficacy we have designed extended release tablets. Keywords: Montelukast Sodium, Extended release Matrix Tablet. Corresponding Author: G.Rajini Deparment of Pharmaceutics Malla reddy institute of pharmaceutical sciences Secunderabad , Telangana, INDIA rajini1803@gmail.com Mobile: Available online: November Issue 2815

2 INTRODUCTION Oral drug delivery is the most widely utilized route of administration among all the routes of administration that has been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient compliance and cost effective manufacturing process. The dissolution rate of a drug from its dosage form is considered as an important parameter in the bioavailability. The rate determining step in the absorption of orally administered hydrophilic drugs is the rate of drug permeation through the biomembrane [1]. In other words, absorption of such drugs is said to be permeation rate limited or Tran s membrane rate limited. Pharmaceutical products designed for oral delivery are mainly conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. MATERIALS AND METHODS MATERIALS Montelukast sodium was obtained as gift sample from Divis laborataries ltd,india. HPMC k100m CR and HPMC k4 m, Polyox 303 wsr, Ethyl cellulose 7 cps, were received as gift samples from Colorcon,goa. Xanthan gum was received as gift samples from CPKELCO, Carbopol 71 G NF was received as gift samples from LUBRIZOL and all other chemicals/solvents were procured from market are of analytical grade. DETERMINATION OF SOLUBILITY: Excess drug was added carefully using a spatula to 10 ml of the aqueous buffer in a conical flask, while stirring until a heterogeneous system (solid sample and liquid) was obtained. The solution containing excess solid was then capped, and stirred at 150 rpm at the room temperature for 24 hours. Then the solution containing excess solid was filtered using 0.22 µm PVDF filter, appropriate dilutions were then made and analyzed using UV spectrophotometer. MELTlNG POINT DETERMINATION: Melting point of the drug sample was determined by capillary method by using melting point apparatus. The reported and observed melting points. PARTICLE SIZE DISTRIBUTION: grams of montelukast sodium was taken and added to an assembly of sieves consisting ASTM sieve numbers # 30,40, 60, 80,100,120 base. Then assembly was closed and kept on sieve shaker and started analysis. Weights retained were checked for every 5 minutes and process was continued until Available online: November Issue 2816

3 variation in weights retained was not more than 5% or 0.1 gram. 20 minutes was set as end point based on the observation. Calculations were made to obtain cumulative percentage weight retained and tabulated. FLOW PROPERTIES: ANGLE OF REPOSE [2] The flow property was determined by measuring the Angle of Repose. In order to determine the flow property, the Angle of Repose was determined. It is the maximum angle that can be obtained between the free standing surface of a powder heap and the horizontal. Angle of repose= tan-¹ (h/r) Where, h = height, r = radius. BULK DENSITY [2] Bulk density is ratio of given mass of powder and its bulk volume. Bulk density was determined by measuring the volume of known mass of powder sample that has been passed through the screen in to graduated cylinder or through volume measuring apparatus in to cup. Bulk density = M / V 0 Where M= mass of the powder; V 0 =bulk volume of the powder. TAPPED DENSITY [2] A known quantity of powder was transferred to a graduated cylinder and volume V0 was noted. The cylinder fixed to a density determination apparatus, tapped for 500 times then reading was observed. The density is achieved by mechanically tapped by a measuring cylinder containing the powder sample. After observing the initial volume the cylinder is mechanically tapped and volume reading were taken until little further volume changes is observed. Tap density = M / V r Where M = mass of the powder, V r = final tapping volume of the powder. COMPRESSIBILITY INDEX AND HAUSNER S RATIO [2] Basic methods for the determination of compressibility index and Hausner s ratio: While there are some variations in the method of determining the compressibility index and Hausner s ratio, the basic procedure is to measure the unsettled apparent volume,(v O ), and the Available online: November Issue 2817

4 final tapped volume, (V f ), of the powder after tapping the material until no further volume changes occur. The compressibility index and the Hausner s ratio are calculated as follows: Compressibility index = 100 Vo-V f /Vo Hausner s ratio = Vo/V f Where, V o = apparent volume, V f = final tapped volume. Alternatively, the compressibility index and Hausner s ratio may be calculated using measured values of bulk density and tapped density as follows: Compressibility index = 100 tapped density / bulk density Hausner s ratio = tapped density / bulk density DRUG-EXCIPIENTS COMPATIBILITY STUDY [3] FOURIER TRANSFORMATION INFR-RED (FTIR) ANALYSIS: Fourier-transform infrared (FTIR) spectra of the Drug and polymer were obtained on Alpha Booker FTIR (Tokyo, Japan). The spectra were scanned over the wave number range of 4200 to 400 cm 1 PREPARATION OF MONTLUKAST SODIUM EXTENDED RELEASE MATRIX TABLETS: Table 1: COMPOSITIONS OF MONTLUKAST SODIUM TABLETS Ingredients mg/tablet F1 F2 F3 F4 F5 F6 F7 Drug HPMC k4m HPMCk100m Carbopol Polyox Xanthan gum PVP Iso propyl alcohol q.s q.s q.s q.s q.s q.s q.s MCC Magnesium stearate EC Talc Available online: November Issue 2818

5 Extended Release matrix tablets of montelukast sodium were prepared by wet granulation method. The compositions of the ingredients are shown in the Table (3). Wet granulation is a process of using a liquid binder or adhesive to the powder mixture. Non-aqueous solvent like Iso propyl alcohol is chosen as solvent with poly vinyl Pyrrolidone (PVP K-30) as binder. Once the solvent evaporates and powders have formed a densely mass, then the granulation is milled which results in formation of granules. At first process started with 2% binder solution. EVALUATION OF TABLETS: The quantitative evaluation and assessment of a tablets chemical, physical and bioavailability properties are important in the design of tablets and to monitor product quality. There are various standards that have been set in the various pharmacopoeias regarding the quality of pharmaceutical tablets. These include hardness, thickness, friability, weight variation and invitrodissolution characters. HARDNESS [4] Tablets require a certain amount of strength or hardness and resistance to friability, to withstand mechanical shocks of handling in manufacture, packing and shipping. The hardness of tablet was measured by Monsanto hardness tester. The tablets from each batch were used for hardness studies and results are expressed in Kg/cm 2. THICKNESS [5] It can be dimensionally described & controlled. The thickness of a tablet is only variables. Tablet thickness can be measured by micro-meter or by other device. Tablet thickness should be controlled within a ± 5% variation of standard value. Thickness of tablet is important for uniformity of tablet size. Thickness was measured using Vernier caliper. It was determined. FRIABILITY [6] Friction and shock are the forces that most often cause tablets to chip, cap or break. The friability test is closely related to tablet hardness and designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator. METHOD A number of tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are weighed and the weight compared with the initial Available online: November Issue 2819

6 weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked. The percentage friability was determined by the formula: % friability = (W 1 -W 2 ) / W 1 X 100 W 1 = Weight of tablets before test W 2 = Weight of tablets after test by checking ten tablets from each formulation. WEIGHT VARIATION TEST [7] This is an in process quality control test to ensure that the manufacturers control the variation in the weight of the compressed tablets, different pharmacopoeia specify these weight variation tests.. These tests are primarily based on the comparison of the weight of the individual tablets (xi) of a sample of tablets with an upper and lower percentage limit of the observed sample average (x-mean). The USP has provided limits for the average weight of uncoated compressed tablets. These are applicable when the tablet contains 50mg or more of the drug substance or when the latter comprises 50% or more, by weight of the dosage form. METHOD: Twenty tablets were weighed individually and the average weight was calculated. The individual tablet weights are then compared to the average weight. Not more than two tablets should differ in their average weight by more than percentages stated in USP. No tablet must differ by more than double the relevant percentage. CONTENT UNIFORMITY TEST [8] The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch. Due to increased awareness of physiological availability, the content uniformity test has been included in the monographs of all coated and uncoated tablets and all capsules intended for oral administration where the range of size of the dosage form available include 50mg or smaller sizes. METHOD: Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content Available online: November Issue 2820

7 and the 10th tablet may not contain less than 75% and more than 125% of the labeled content. If these conditions are not met, remaining 20 tablets assayed individually and none may fall outside of the 85 to 115% range. DISSOLUTION [9] Dissolution is a process by which the disintegrated solid solute enters the solution. The test determines the time required for a definite percentage of the drug in a tablet to dissolve under specified conditions. Dissolution Parameters Medium : 900ml, 6.8 Phosphate buffer, 0.1N HCl Apparatus : paddle (USP-II) RPM : 50 Temperature : 37 o C Time Points : 1,2,4,6,8,12, hr PROCEDURE: In vitro dissolution for SR tablets were done initially in 0.1N HCL for 2hrs and next in 6.8 phosphate buffer for 10hrs. 5ml of sample was withdrawn at predetermined time intervals replacing with an equal quantity of drug free dissolution fluid. The samples withdrawn were filtered through 0.45µ membrane filter, and drug release in each sample was analyzed by was analyzed at 285 nm for the presence of model drug, using a UV-visible spectrophotometer. DRUG RELEASE: The drug release from the montelukast sodium tablets was investigated in a USP-II (paddle) apparatus, 900 ml of Phosphate buffer ph 6.8 (50 rpm, 37 C). At predetermined time intervals, 5- ml samples were withdrawn and diluted to suitable concentration and then analyzed with UV spectrophotometer at λmax=285 nm. DISINTEGRATION TIME [10] For a drug to be absorbed from a solid dosage form after oral administration, it must first be in solution, and the first important step toward this condition is usually the break-up of the tablet; a process known as disintegration. The disintegration test is a measure of the time required under a given set of conditions for a group of tablets to disintegrate into particles which will pass through a 10 mesh screen. Generally, the test is useful as a quality assurance tool for conventional dosage forms. Available online: November Issue 2821

8 METHOD The U.S.P. device to test disintegration uses 6 glass tubes that are long open at the top and 10 mesh screens at the bottom end. To test for disintegration time, one tablet is placed in each tube and the basket rack is positioned in a 1-L beaker of water, simulated gastric fluid or simulated intestinal fluid at 37 ± 20 C such that the tablet remain 2.5 cm below the surface of liquid on their upward movement and not closer than 2.5 cm from the bottom of the beaker in their downward movement. Move the basket containing the tablets up and down through a distance of 5-6 cm at a frequency of 28 to 32 cycles per minute. Floating of the tablets can be prevented by placing perforated plastic discs on each tablet. According to the test the tablet must disintegrate and all particles must pass through the 10 mesh screen in the time specified. If any residue remains, it must have a soft mass. If one or two tablets fail to disintegrate, the test is repeated using 12 tablets. DRUG RELEASE KINETICS [11, 12] ZERO-ORDER MODEL Drug dissolution from dosage forms that do not disaggregate and release the drug slowly can be represented by the equation Qt = Q0 + K0t Where Qt is the amount of drug dissolved in time t, Q0 is the initial amount of drug in the solution (most times, Q0 = 0) and K0 is the zero order release constant expressed in units of concentration/time. To study the release kinetics, data obtained from in vitro drug release studies were plotted as cumulative amount of drug released versus time. Application: It is used to describe the drug dissolution of several types of modified release pharmaceutical dosage forms, as in the case of some Transdermal systems, as well as tablets with low soluble drugs in coated forms, osmotic systems, etc. FIRST ORDER MODEL The first order equation describes the release from systems where the dissolution rate is dependent upon the concentration of the dissolving species. Release behavior generally follows the following first order equation: Log C= Log C o -kt/2.303 Where C is the amount of drug dissolved at time t, Available online: November Issue 2822

9 C o is the amount of drug dissolved at t=0 and k is the first order rate constant. A graph of log cumulative of % drug remaining vs time yields a straight line. The pharmaceutical dosage forms following this dissolution profile, such as those containing watersoluble drugs in porous matrices, release the drugs in a way that is proportional to the amount of drug remaining in its interior, in such way, that the amount of drug released by unit of time diminishes. HIGUCHI MODEL The first example of a mathematical model aimed to describe drug release from a system was proposed by Higuchi in Initially conceived for planar systems, it was then extended to different geometrics and porous systems. This model is based on the hypothesis that initial drug concentration in the is much higher than drug solubility. Drug diffusion takes place only in one dimension (edge effect must be negligible); Drug particles are much smaller than system thickness; swelling and dissolution are negligible; drug diffusivity is constant; and Perfect sink conditions are always attained in the release environment. In a general way the Higuchi model is simply expressed by following equation Q = K H - t 1/2 Where, K H is the Higuchi dissolution constant. The data obtained were plotted as cumulative percentage drug release versus square root of time.. KORSMEYER-PEPPA MODEL: It derived a simple relationship which described drug release from a polymeric system equation. To find out the mechanism of drug release, first 60% drug release data were fitted in Korsmeyer-Peppas model, Mt / M = Kt n Where Mt / M is a fraction of drug released at time t, k is the release rate constant and n is the release exponent. The n value is used to characterize different release for cylindrical shaped matrices. In this model, the value of n characterizes the release mechanism of drug. STABILITYSTUDIES [13,14,15] Stability of the drug product composition is equally important as that of its drug release profile throughout the shelf period of the product. The product capability to withstand the accelerated conditions to prevent the drug degradation determines the stability of the product. Selected Formulation was subjected to stability studies as per ICH guidelines. Available online: November Issue 2823

10 Following conditions were used for Stability Testing C/60% RH analyzed every month for period of three months C/75% RH analyzed every month for period of three months C/75% RH analyzed every month for period of three months. RESULT & DISCUSSION STANDARD CALIBRATION CURVE: Table 2: Calibration data of montelukast sodium in 0.1N HCl Fig.1: Standard graph of montlukast sodium in 0.1 N HCl Concentration (mcg/ml) Absorbance (nm) Table 3: Calibration data of montelukast sodium in 6.8 ph buffer Fig. 2 : Standard graph of montelukast sodium in 6.8 ph buffer Concentration (mcg/ml) Absorbance (nm) Standard graph of montelukast sodium at 285 nm has shown good linearity with R 2 values in 6.8 P H phosphate buffer which suggests that it obeys the Beer-Lambert s law. Available online: November Issue 2824

11 Fig 3: Absorption maxima of montelukast sodium These were analyzed at 285 nm and calibration curve was plotted taking concentration in µg/ml on X- axis and absorbance units on Y-axis. FLOW PROPERTY: Table 4: flow properties of montelukast sodium Parameter F1 F2 F3 F4 F5 F6 F7 Angle of repose(θ) Bulk density Tapped density Compressibility Index Hausner s Ratio Inference: Formulations F1, F2, F3, F5 showed good flow properties and formulations F4, F6, F7 showed fair flow properties. Formulations F1, F3, F4, F5, F6 showed fair compressibility index and formulation F2 showed good compressibility index and formulation F8 showed poor compressibility index, formulations F7, showed passable compressibility index. DRUG POLYMER INTERACTION STUDY BY USING FTIR From the spectra of Montelukast sodium, combination of Montelukast sodium with excipient, it was observed that all characteristic peaks of Montelukast sodium were present in the combination spectrum, thus indicating compatibility of the drug and excipient. IR spectra are shown in Fig:16 Available online: November Issue 2825

12 Fig 4: FTIR spectrum of Montelukast sodium Fig 5: FTIR spectra of optimized formulation F4 EVALUATION STUDIES OF TABLETS Table 5: Evaluation studies of montelukast sodium Weight Thickness Hardness Friability Drug Formulation variation (mm) (kp) (%) content (%) F F F F F F F Table 6: In-vitro drug release profile of different formulations of drug TIME (hrs) F1 F2 F3 F4 F5 F6 F Available online: November Issue 2826

13 Fig.6: Dissolution graph of montelukast sodium formulations Based on the dissolution profile, it was confirmed that the formulation (F4) showed maximum drug release up to 12hrs. KINETIC ANALYSIS OF DISSOLUTION DATA Table 7: Release kinetics for optimized (F4) formulation of Montelukast sodium Time (Hrs) T Log T % CRD Cumulativ e % Drug Retained Log Cumulative % Drug Released Log Cumulative % Drug Retained Available online: November Issue 2827

14 Fig 7: zero order release graph of F4 Fig 8: First order release graph of F4 Fig 9: Higuchi model graph of F4 Fig 10: Peppas model of F4 Table 8: Stability dissolution profile of F4 for 1 st and 2 nd month Fig. 11: Stability Dissolution Profile of F4 for initial&1 st month TIME (hr) F4 initial F4 1 st month CONCLUSION Extended release tablets of a model drug was formulated and evaluated with different polymers. Formulations with HPMC k100m and HPMC k4m polymers has successfully extended the drug release up to 12 hours and they are formulated in 1:1 ratio with drug by using wet granulation. Formulation prepared by wet granulation with 2%PVP -k 30 as the binder containing xanthan Available online: November Issue 2828

15 gum as the polymer in 1:1 ratio with drug has successfully extended the drug release up to 12 hours. Formulation prepared by wet granulation with 5%PVP -k 30 as the binder containing Polyox 303 wsr as the polymer in 1:1 ratio with drug has successfully extended the drug release up to 12 hours. Formulations containing HPMC and Carbopol 71 GNF polymers prepared by wet granulation with 2% binder concentration showed enhancement of compressibility index Hardness effect was observed on all the formulations when compressed with low and high hardness.formulations has successfully extended the drug release up to 12 hours when compressed with 5-6kp hardness. Effect of diluents on drug release was observed. Water soluble diluents like lactose cause marked increase in drug release rate. The reason behind that was water soluble filler in matrices stimulate the water penetration in to inner part of matrix, due to increase in hydrophilicity of the system, causing rapid diffusion of drug, leads to increased drug release rate. Smallest particle size, hydrophobicity of dicalcium phosphate has minimum porosity and maximum release retardation. This result indicated hydrophilicity and hydrophobicity of fillers had significant effect on release profile. Optimized tablets followed anomalous type drug release involving the diffusion, erosion, dissolution and swelling mechanism. Release kinetics of optimized formulations was following zero order drug release. REFERENCES 1. A Herbert Lieberman, Leon Lachman, Joseph B. Schwartz, Pharmaceutical dosage forms Tablets, Vol.1, 2&3.second edition. 2. Brahmankar, D.M. and Jaiswal, S.B. Biopharmaceutics and Pharmacokinetics A Treatise. 1st edn., Vallabh Prakashan, New Delhi, 1995, 35, Mohd Abdul Hadi, Lokeswara Babu V, Narottam Pal, Srinivasa Rao A. Formulation and evaluation of Sustained release Matrix tablets of Montelukast Sodium. International Journal of Pharmacy. 2012; 2(3): Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in., the theory and practice of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in., the theory and practice of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in., the theory and practice of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in., the theory and practice Available online: November Issue 2829

16 of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in., the theory and practice of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in. the theory an practice of Industrial Pharmacy,3 rd edition, page no: Leon Lachman, Herbert A.Liberman,Joseph L.Kang.,Tablets in the theory and practice of Industrial Pharmacy,3 rd edition, page no: Higuchi T. J Pharm Sci. 1963; 52: Korsmeyer RW, Gurny R, Doelkar EM, Buri P, Peppas NA. Int J Pharma. 1983; 15: USP-32-NF-27; The United States Pharmacopoeia; 2008; The European Pharmacopoeia; 2000;2.9:15; 4.6: USP-32-NF-27; Tablet Friability; TheUnited States Pharmacopoeia; General Information; 2008; 3; Hayashi T, Kanbe H, Okada M, Suzuki M, Ikeda Y. Int J Pharm. 2005; 304: Available online: November Issue 2830