FORMULATION AND EVALUATION OF EFFERVESCENT TABLETS … · Effervescent compositions in the form of...

Palanisamy P et al. IRJP 2011, 2 (12), 185-190

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY, 2(12), 2011

INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online www.irjponline.com Research Article

FORMULATION AND EVALUATION OF EFFERVESCENT TABLETS OF ACECLOFENAC

Palanisamy P*1, Rabi Abhishekh1, D Yoganand Kumar2 1Vinayaka Mission’s College of Pharmacy, Vinayaka Missions University, Salem, Tamil Nadu, India

2Trainee Research Associate, Pharmacokinetics/Biostatistics, Axis Clinicals Ltd, Hyderabad, Andhra Pradesh, India

Article Received on: 05/10/11 Revised on: 30/10/11 Approved for publication: 19/11/11 *E-mail: [email protected] ABSTRACT Recently, fast-dissolving drug delivery systems have started gaining popularity and acceptance as new drug delivery systems, because they are easy to administer and lead to better patient compliance. Usually, elderly people experience difficulty in swallowing the tablet. Aceclofenac is a NSAID which has greater inhibitory action against the inducible form of cyclooxygenase (COX-2) which is implicated in the inflammatory response against the constitutive form of this enzyme (COX-1) inhibition. The aim of this study was to formulate Effervescent tablet with sufficient mechanical integrity and to achieve faster disintegration in the water. Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use. Effervescent compositions in the form of tablets comprising a therapeutic agent, a granulating agent, a micro particulate effervescent component and an effervescent system which dissolve rapidly in water to yield an effervescent solution containing a completely dissolved therapeutic agent and a process for their preparation. Key Words: Effervescent Tablets, COX-1,COX-2 Aceclofenac. INTRODUCTION As per revised definition proposed to US FDA “Effervescent tablet is a tablet intended to be dissolved or dispersed in water before administration”. It generally contains in addition to active ingredients, mixture of acids/acid salts (citric, tartaric, malic acid or any other suitable acid or acid anhydride) and carbonate and hydrogen carbonates (sodium, potassium or any other suitable alkali metal carbonate or hydrogen carbonate) which release carbon dioxide when mixed with water. Occasionally, active ingredient itself could act as the acid or alkali metal compound necessary for effervescent reaction. Effervescent tablets are uncoated tablets that generally contain acid substances and carbonates or bicarbonates and which react rapidly in the presence of water by releasing carbon dioxide. They are intended to be dissolved or dispersed in water before use. The aim of this study is to develop and physico-chemically evaluate the Effervescent Tablets of Aceclofenac. To enhance the onset of action of Aceclofenac and increase the solubility of Aceclofenac. To enhance the bioavailability of drug. To achieve better patient compliance, To Avoid the First Pass Effect,They should have satisfactory property, Tablet having the greater bioavailability than other dosage form, The stability of Effervescent tablets can be increased, The effervescent tablets require strictly humid control area. The Effervescent tablets can not be made in a normal area where the humidity and temperature condition not maintained. Fast onset of action. - Effervescent tablet have major advantage that the drug product is already in solution at the time it is consumed, thus the absorption is faster and more complete than with conventional table faster absorption means faster onset of action effervescent drug are delivered to the stomach at a pH that is just right for absorption many medication travel slowly through the gastrointestinal tract or have absorption that is hampered by food or other drug. No need to swallow tablet - effervescent medications are administered in liquid form so they easy to take as compared to tablets or capsule the number of people who cannot swallow tablet or who dislike swallowing tablet and capsule is growing with an effervescent dosage form, one dose can usually delivered in just 3 or 4 ounces of water. Good stomach and intestinal tolerance - effervescent tablet dissolve fully in a buffered solution. Reduced localized contact in the upper gastrointestinal tract leads to less

irritation and greater tolerability buffering also prevent gastric acids from interacting with drug themselves, which can be a major cause of stomach. More portability - effervescent tablet is more easily transported than liquid medication because no water is added until it is ready to use. Improved palatability - drugs delivered with effervescent base, taste better than most liquids, mixture and suspensions superior taste masking is achieved by limiting objectionable characteristics and complementing formulations with flavor and fragrances. The effervescent tablet essentially include flavoring so they taste much better than a mixture of non effervescent powder in water moreover, they produce fizzy tablets, which may have better consumption appeal than the traditional dosage form.More consistent response - drugs delivered with effervescent technology have predictable and reproducible pharmacokinetics profile that are much more consistent than the tablets or capsule.Accurate dosing - researchers have been shown that effervescent tablets enhance the absorption of number of active ingredients compared to conventional formulations. This is because the carbon dioxide created by the effervescent reaction can enhance active ingredient permeability due to an alteration of paracellular pathway. the paracellular pathway is the primary route of absorption of hydrophilic active ingredients in which the solutes diffuse into the intercellular space between epithelial cells. it is postulated that the carbon dioxide widens the intercellular space between cell which leads to greater absorption of active ingredients (both hydrophilic and hydrophobic).the increased absorption of hydrophobic active ingredients could be due to the non polar carbon dioxide gas molecules partition into cell membrane, thus creating an increased hydrophobic environment, which would allow the hydrophobic active ingredients to be absorbed. Conventional tablets are often associate with slower onset of action and also undergoes first pass metabolism. Effervescent tablet avoid the first pass metabolism and also produce rapid onset of action. Oral liquid also provide rapid onset of action but required carefully handling. MATERIALS AND METHODS Aceclofenac was procured by Shri Krishna Pharmaceuticals (India),Citric acid, Fumaric acid, Sodium Citrate, Sodium benzoate was gifeted by (Thomas baker, Mumbai),Tartaric acid ,Sodium Bicarbonate was gifted by (Lar Chamical, Mumbai), Polyethlene



glycol-6000 was gifted by (Supreme Chemicals Mumbai), Polyvinylpyrolidone-K-30 was gifted by (Nan hangs industrial co.itd), Simethicone was gifted by (Nouveam exports pvt. Ltd. navi, Mumbai), Acesulfame potassium was gifted by Shanghai fortune way co.Ltd, Mumbai,India. Preformulation Preformulation is a branch of pharmaceutical sciences that utilizes biopharmaceutical principles in the determination of physicochemical properties of a drug substance. The goal of pre-formulation studies is to choose the correct form of the substance, evaluate its physical properties and generate a through understanding of the material’s stability under various conditions, leading to the optimal drug delivery system. The pre formulation study focuses on the physiochemical parameters that could effect the development of efficacious dosage form. These properties may ultimately provide a rationale for formulation design. Also it will help in minimizing problems in later stages of drug development, reducing drug development costs and decreasing product’s time to market. It gives the information needed to define the nature of the drug substance and provide framework for the drug combination with pharmaceutical excipients in the dosage form. Objective: The overall objective of Preformulation testing is to generate information useful to the formulation in developing desired, stable and bioavailable dosage forms. Scope: The use of pre formulation parameters maximizes the chances in formulating an acceptable, safe, efficacious and stable product. Pre formulation encompasses at least following tests: - Determination of melting point The melting point of Aceclofenac was determined by using Thermocal melting point apparatus. Solubility Aceclofenac is practically insoluble in water, freely soluble in acetone, soluble in alcohol. Angle of Repose (qqqq) The frictional force in a loose powder or granules can be measured by angle of repose. Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and horizontal plane.

tan q = h / r q = tan-1 (h/r)

Where, q is the angle of repose h is height of pile

r is radius of the base of pile Table 1 Relationship between Angle of Repose (qqqq) and flow properties

Angle of repose (qqqq) (degrees) Flow <25 Excellent

25-30 Good 30-40 Passable >40 Very poor

Method A funnel was filled to the brim and the test sample was allowed to flow smoothly through the orifice under gravity. From the cone formed on a graph sheet was taken to measure the area of pile, thereby evaluating the flowability of the granules. Height of the pile was also measured.

Bulk Density Bulk density is defined as the mass of a powder divided by the bulk volume. The bulk density of a powder depends primarily on particle size distribution, particle shape, and the tendency of the particles to adhere to one another. Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity of accurately weighed powder (bulk) from each formula, previously shaken to break any agglomerates formed was introduced into a 25 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 seconds interval. The taping was continued until no further change in volume was noted. LBD and TBD were calculated using following formula;

Weight of the powder LBD = --------- (a) Volume of the packing

Weight of the powder

TBD = ---------- (b) Tapped volume of packing

Tapped Density After measuring the bulk volume the same measuring cylinder was set into tap density apparatus. The tap density apparatus was set to 300 taps drop per minute and operated for 500 taps. Volume was noted as (Va) and again tapped for 750 times and volume was noted as (Vb). If the difference between Va and Vb not greater than 2% then Vb is consider as final tapped volume. The tapped density is calculated by the following formula.

Tapped density = Weight of powder / Tapped volume Percentage Compressibility The compressibility index of the granules was determined by Carr’s compressibility index. Grading of the powders for their flow properties according to Carr’s Index is shown in.

Table 2 Grading of the powders for their flow properties according to Carr’s Index

Consolidation Index (Carr %) Flow

5-15 Excellent 12-16 Good 18-21 Fair to passable 23-35 Poor 33-38 Very poor >40 Very Very poor

(%) Carr’s Index can be calculated by using the following formula

TBD – LBD Carr’s Index (%) = x 100 ----- (c) TBD Drug –Excipients IR compatibility study Compatibility study of drug with excipients were carried out by keeping the drug and excipients at 40oc + 75% RH and observed after every seven days for the physical observation and finalized excipients were confirmed by IR studies. The pure drug and its formulation along with excipients were subjected to IR studies. In the present study, the potassium bromide pellet was employed using Prestige 21 Shimadzu FTIR Spectrometer .



Table 3 Composition of effervescent Tablets Aceclofenac (Dry granulation) Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 Aceclofenac 100 100 100 100 100 100 100 100 100

Citric acid (anhydrus) 300 410 980 1245 980 980 980 1045 1045 Tartaric acid 210 120 520 545 1045 1045 1045 540 740 Ascorbic acid 200 210 - - - - - - -

Sodium bicarbonate 720 860 1480 1480 1480 1940 1480 1980 1980 Sodium carbonate 230 435 240 240 240 240 780 240 240

Sodium citrate - - 15 15 15 - - - - Sodium benzoate - - 20 20 20 25 20 20 20

Mannitol - 220 - - - - - - - PEG-6000 30 - - - - - - - - PVP-K-30 15 20 20 60 - 60 115 80 100

Acesulphum potassium - - - - 20 20 20 20 25

Table 4 Composition of Effervescent Tablets Aceclofenac (Wet Granulation) Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Aceclofenac 100 100 100 100 100 100 100 100 100 Citric acid (anhydrus) 300 410 980 1245 980 980 980 1045 1045 Tartaric acid 210 120 520 545 1045 1045 1045 540 740 Ascorbic acid 200 210 - - - - - - - Sodium bicarbonate 720 860 1480 1480 1480 1940 1480 1980 1980 Sodium carbonate 230 435 240 240 240 240 780 240 240 Sodium citrate - - 15 15 15 - - - - Sodium benzoate - - 20 20 20 25 20 20 20 Mannitol - 220 - - - - - - - PEG-6000 30 - - - - - - - - PVP-K-30 15 20 20 60 60 115 80 100 Simethicone - - - 15 15 - 60 25 50 Acesulphum potassium - - - - 20 20 20 20 25

EVALUATION OF EFFERVESCENT TABLETS Uniformity of thickness Test The maximum thickness of the formulation was found to be 6.09 mm. The minimum thickness of the formulation was found to be 5.6 mm. Hardness test The hardness of the tablet was found to be 2.0 to 4.0 Kg/cm2. Friability test The maximum friability of the formulation was found to be 0.34%. The minimum friability of the formulation was found to be 0.28%. The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable.

Weight Variation Test All the formulated (F1 to F9) tablets were passed weight variation test as the % weight variation was within the IP limits of ± 5.0% of the weight. The weights of all the tablets were found to be uniform with low standard deviation values. The prepared formulation complies with the weight variation test. Tablet Disintegration Test Disintegration time was found to be 82 to 120 sec from all formulations, F6 has minimum in vitro Effervescent time, but its hardness is not good so we select formula F8. PH of the solution Test PH of solution prepared putting tablets into water was affected by storage condition due to liberation of CO2 .

Table 5 Evaluation Of The Powder Blend Batch Code Bulk density Tapped density Angle of repose Percent

Compressibility F1 0.509 0.543 31.45 16.06 F2 0.565 0.546 30.45 14.85

F3 0.587 0.632 31.78 15.85

F4 0.543 0.587 25.98 15.96

F5 0.534 0.532 30.87 15.75

F6 0.578 0.654 31.64 16.84

F7 0.521 0.587 30.60 15.43

F8 0.576 0.598 28.98 15.65

F9 0.565 0.543 27.67 15.53



STANDARD CURVE OF ACECLOFENAC

y = 0.0321xR2 = 0.9996

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 2 4 6 8 10 12

CONCECTRATION

AB

SO

RB

AC

E(%

)

Linear

Table 6 Evaluation Of Tablet Parameter

Batch code Thickness (mm)

Hardness (kg)

Friability

Weight variation

Disintegration Time(sec.)

ph of solution

F1 5.6 5.00 FAIL PASS 120 7.22

F2 5.46 5.00 FAIL PASS 116 7.42

F3 5.65 5.00 FAIL PASS 98 7.56

F4 5.76 3.00 0.30 PASS 79 7.61

F5 5.92 3.00 0.34 PASS 82 7.67

F6 5.9 3.00 0.29 PASS 87 7.67

F7 5.97 2.00 FAIL PASS 82 7.71

F8 5.89 3.00 0.28 PASS 97 7.80

F9 5.88 3.00 0.30 PASS 107 7.91

Table 7 Observation Of Effervescent Tablet

Batch code Dry granulation Wet granulation

F1 Only half of the tablet was showing effervescence and sticking problem also occurred. Capping problem and less effervescence

F2 Sticking problem, less effervescence Capping problem and less effervescence

F3 Sticking problem, less effervescence Capping problem and less effervescence

F4 Sticking problem, less effervescence Very quick effervescence, the tablet surface was rough

F5 Tablet gives good effervescence, but the some particles

settle at the bottom of the solution, sticking problem also occurred.

Tablet gave good effervescence solution become some what clear and with less capping problem

F6 Tablet gives good effervescence but the tablet surface found rough and sticking problem also 0cour

Tablet gives good effervescence but the capping also as such.

F7 The tablet gives good effervescence, capping problem but the some particles become settled down, the hardness also

not good

The tablet gives good effervescence, no capping problem and the solution become found to be clear,

hardness of tablet not good

F8 The tablet found to be good hardness but the capping problem somewhat occurs, solution found to be not clear

The tablet gives good effervescence; no capping problem and the solution become found to be clear,

hardness of tablet also good compared to other batches.

F9 Tablet gives good effervescence, but the some particles

settle at the bottom of the solution, sticking problem also occurred.

Tablet gives slow effervescent. The other properties like hardness, appearance are satisfactory.

UV SPECTRA: Aceclofenac in 0.1 N Methanol shows maximum absorption at 273 nm. PREPARATION OF STANDARD CALIBRATION CURVE OF ACECLOFENAC Principle of the Aceclofenac exhibits peak absorbance at 273 nm in 0.1 methanol instrument used: jasco, UV spectrophotometer, Japan model series-135.

Table 8 Standard Calibration curve CONCENTRATION

(µ/ml) ABSORBANCE

(nm) 1 0.032 2 0.064 3 0.098 4 0.129 5 0.166 6 0.193 7 0.222 8 0.255 9 0.288 10 0.320

Slope-0.0321 R2 =0.9996

Standard Curve Of Aceclofenac

U.V. Spectrum Of Aceclofenac



Table 9 In Vitro Dissolution Study

S.N. Time (min)

Absorbance(nm) Conc. (µg

/ml)

Amount Present

in 900 ml

%Drug Release

0 0 0 0 0 0 1 1 0.0317 0.988 89 89 2 2 0.0360 1.122 101.01 101.01 3 3 0.0367 1.146 103.21 103.21 4 4 0.0367 1.144 103.02 103.02 5 5 0.0366 1.143 102.89 102.89

Stability Studies Since the period of Accelerated stability testing can be as long as 3 months for the effervescent tablet. Therefore it is essential to devise a method that will help rapid prediction of long-term stability of drug. The accelerated stability testing is defined as the validated method by which the product stability may be predicted by storage of the product under conditions that accelerate the change in defined and predictable manner. The stability studies of formulated tablets were carried out at 40 oC, RH 75% and at room temperature for one month. The effects of temperature and time on the physical characteristics of the tablet were evaluated for assessing the stability of the prepared formulations. Table 10 Stability study Disintegration Time of Formulation F8, at 400/75%RH

Parameter Initial After 15 day Afyer 30 day Disintegration Time(min) 97 95 95

Table 11 Stability study of in-vitro dissolution for formulation F8, at 400/75%RH

Time Initial After 15 days After 30 days 0 0 0 0 1 89.00 89.00 89.00 2 101.01 101.01 100.01 3 103.21 103.00 103.00 4 103.02 103.00 102.89 5 102.89 102.30 102.00

Table 12 Disintegration Time of Formulation F8, at Room Temperature

Parameter Initial After 15 day Afyer 30 day

Disintegration Time (min) 97 96 95

Table 13 In-vitro dissolution for formulation F8, at Room Temperature

Time Initial After 15 days After 30 days 0 0 0 0 1 89.00 89.00 89.00 2 101.01 101.01 100.01 3 103.21 103.15 103.00 4 103.02 103.00 102.89 5 102.89 102.50 102.50

SUMMARY AND CONCLUSION The study was undertaken with an aim to formulate effervescent tablet of Aceclofenac. Aceclofenac act by reducing production of prostaglandin which involved in pain and fever process, by inhibiting the cyclooxygenase enzyme. In present work an attempt has been made to formulate an effervescent tablet containing immediate release Aceclofenac using various acids and bases. The effervescent tablets were prepared by different techniques such as Direct compression, Wet granulation. The prepared tablets were evaluated for content uniformity and physical parameters. Capping and sticking problems were observed by Direct Compression Method. So the surface of tablets was not uniform. But with the help of wet granulation technique the powder become free flowing and the compression of the tablets so good as compared to the direct

compression. Capping and sticking problems by the direct compression method is the reason behind the selection of the wet granulation method. Wet granulation method provided the acids and bases protections from the environmental moisture and by this capping problem were reduced. At the time of manufacturing of effervescent tablets humidity and temperature should be maintained, strictly. The effervescent tablets were formulated using different acids and bases. PVP K30 as a binder and sodium benzoate as a lubricant were used in formulation of effervescent tablets. There are nine formulations that contain the Citric acid, Tartaric acid, Sodium bicarbonate, and Sodium carbonate were formulated. These nine formulations were evaluated for hardness, friability, and weight variation, effervescent time.

Table 14 Parameter Of Formula No.

Parameters F8

Disintegration time (sec.) 98

% Drug release within 1 min. 89

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Source of support: Nil, Conflict of interest: None Declared

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