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INTERNATIONAL RESEARCH JOURNAL OF PHARMACY www.irjponline.com ISSN 2230 – 8407

Research Article

FORMULATION DEVELOPMENT OF IRBESARTAN (POORLY WATER-SOLUBLE DRUG) IMMEDIATE RELEASE TABLETS

Abbaraju Prasanna Lakshmi*, Meka Anand Kumar, M. Vamshi Krishna, K.Annie Vijetha, G. Ashwini

Omega College of Pharmacy, Ghatkesar, Edulabad, Andhra Pradesh, India

Article Received on: 06/12/11 Revised on: 10/01/12 Approved for publication: 18/02/12 *Email: prasanna1707@gmail.com ABSTRACT The aim of the present study is to increase the solubility of poorly water soluble drug Irbesartan by using surfactants and formulating into immediate release tablets by using super disintegrants. Surfactants such as sodium lauryl sulfate, polysorbate, and poloxamer 800 are used for increasing the solubility of drug in water by micellisation technique. Super disintegrant such as croscarmellose sodium was used for fast disintegration. Physical properties for granules such as Bulk density, Tapped density, Hausners ratio, % compressibility, % LOD and physical characteristics for Irbesartan IR tablets such as weight variation, friability, hardness, thickness, disintegration, in-vitro dissolution were studied. % cumulative drug release of formulation T3 (having 2% Tween 80) matched with the innovator product Avapro and the similarity factor between innovator and T3 was 97. KEY WORDS: Irbesartan, Polysorbate, poloxamer, sodium lauryl sulphate. INTRODUCTION Solubility and dissolution are the key parameters for the therapeutic effect of a drug. Solubility is one of the important parameter to achieve desire concentration of drug in systemic circulation for pharmacological response1. More than 92% of the drugs listed in U.S pharmacopeia are having poor solubility. It is commonly recognized in the pharmaceutical industry that on average more than 40% of newly discovered drug candidates are having poor solubility. Micronization, Nanonization, salt formation, use of surfactants2,3,4, solvent deposition, eutectic mixture, solid dispersion and molecular encapsulation are the several methods for enhancement of solubility of the drugs5. Surfactant acts as an absorption enhancer and hence increases both dissolution and permeability of the drug6. They enhance the dissolution rate by promoting wetting and penetration of dissolution fluid into the drug particles. Both ionic and nonionic surfactants were used for solubility enhancement. Among the ionic surfactants, anionic surfactants have high solubility than cationic. Further enhancement of dissolution can be done by using super disintegrants. Super disintegrants, disintegrate the tablet rapidly which enhances the dissolution rate of the drug7. Irbesartan is an angiotensin II receptor antagonist used in the treatment of hypertension. It may also delay progression of diabetic nephropathy and also indicated for the reduction of renal disease progression in patients with type 2 diabetes8, hypertension and micro albuminuria or proteinuria. According to BCS classification Irbesartan belongs to class II9. Since it has poor solubility in water, methods has been developed for enhancement of solubility by using different types and concentrations of surfactants by which the solubility of Irbesartan has been increased. The present work is to optimization of Irbesartan immediate release tablets and comparing the best with the innovator product by varying the concentration and type of surfactants.

MATERIAL AND METHODS Materials Irbesartan(Aarey Drugs and Pharmaceuticals Ltd, Andhra Pradesh), Lactose Monohydrate ( Surya Pharmaceuticals Ltd, Himachal pradesh), Croscarmellose sodium(Sun Pharmaceuticals Inds Ltd, Gujarath), Pregelatinized starch (Bliss GVS Pharma Ltd,Mumbai), Sodium Lauryl Sulphate (Neuland Laboratories, Andhra Pradesh), Poloxamer 800 (Neuland Laboratories, Andhra Pradesh), Polysorbate(Neuland Laboratories, Andhra Pradesh), Aerosil 200(Sd fine chemicals, Mumbai), MCC (Avicel 101) (Ozone International, Mumbai), Magnesium state(Rexer pharma private Ltd, cherlapally). Solubility studies of Irbesartan Weigh accurately 300mg (i.e. highest dose of Irbesartan) of Irbesartan (API) and transfer it in to 250ml flask containing media (0.1N HCl, 0.01N HCl, pH 3.0Citrate buffer, pH4.5 Acetate buffer, pH 6.8 Phosphate buffer) and the flask is subjected to sonication at 37°C for 1hr. The solution was filtered and supernatant solution is collected. From this solution 1ml is pipette out and it was diluted to 10ml with water, and the absorbance was checked at 220 nm for 3 times and the average value of the absorbance was taken for calculations to get concentration of drug. Method of preparation Sift Irbesartan, Lactose, Croscarmellose Sodium, Aerosil, Pregelatinized starch, through # 30 mesh and dissolve different surfactant as per table in water. Transfer material into rapid mixing granulator and granulated by mixing with surfactant solution and dried in FBD at 55-60ºC and checking to LOD <2.0%, then Sift granules through #24 mesh and Sift the extra granular MCC, Cross careamellose sodium, Aerosil through #30 mesh and blend the material. Sift magnesium stearate through #60 mesh and added to the blend. The blend was compressed by using 15.6x7.8mm punch in 16 station, single rotary compression machine. Prototype Formulation In this formulation three different types of surfactants were used at three different percentages 0.5%,1%,2%. The different formulas and different ratios of surfactants were given in the below table.

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TABLE1: FORMULATION OF DIFFERENT CONCENTRATION OF SURFACTANTS S.No Ingredients mg/tab (0.5%) Trail-1 mg/tab (1%) Trail-2 mg/tab (2%) Trail-3

S1 P1 T1 S2 P2 T2 S3 P3 T3

1. 2. 3. 4. 5. 6. 7. 8. 9.

Irbesartan LactoseMonohydrate

Cross careamellose sodium Pregelatinized Starch Sodium lauryl sulfate

Poloxamer80 Polysorbate Aerosil 200

Purified water.

300.0 76.5 15.0 90.0 3.0 - -

12.0 q.s

300.0 76.5 15.0 90.0

- 3.0 -

12.0 q.s

300.0 76.5 15.0 90.0

- -

3.0 12.0 q.s

300.0 76.5 15.0 90.0 6.0 - -

12.0 q.s

300.0 76.5 15.0 90.0

- 6.0 -

12.0 q.s

300.0 76.5 15.0 90.0

- -

6.0 12.0 q.s

300.0 76.5 15.0 90.0 12.0

- -

12.0 q.s

300.0 76.5 15.0 90.0

- 12.0

- 12.0 q.s

300.0 76.5 15.0 90.0

- -

12.0 12.0 q.s

Extragranular 1. 2. 3. 4.

MCC (Avicel101) Crosscarmelosesodium

Aerosil 200 Magnesium Stearate

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

78.0 15.0 4.5 6.0

Total Tablet Weight 600 600 600 600 600 600 600 600 600 MCC: Micro crystalline cellulose

Drug excipient compatibility studies Drug and excipients were weighed and sifted through sieve no 40 separately. The drug and excipient mixture were placed in glass vials and sealed with aluminum foil. These vials were placed in different temperature conditions (25⁰c/60%RH, 40⁰c/75%RH, 50⁰c/75%RH) for 15, 20 days. At the end of 15 and 30 days the samples were analyzed for physical change. Evaluation of physical characteristic of granules10 The granules were evaluated for % loss of drying, Bulk density, Tapped density, Compressibility and Hausners ratio. Evaluation of tablet properties11 The prepared tablets were evaluated for weight variation, friability by using Roche friabilator, Hardness (Monsanto hardness tester), Thickness (vernier calipers), disintegration (Electro lab India Ltd), and Dissolution (Schimadzu). Weight Variation Weight variation test is done by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weight with the average. Any deviation in the tablet weight indicates dose uniformity is not Friability Friability test was performed by taking 20 tablets. Pre weight of the individual tablet was taken before subjecting to friability test. Weighed tablet samples are transformed into friabilator and subjected to combined effects of abrasion and shock by revolving at 25rpm for 4min for 100revolutions. Samples are withdrawn after set time completions and loose dust powder was removed from the tablet and final weight is noted and substituted in the formulae. % friability= Initial weight-Final weight x 100 Initial weight Hardness 20 tablets were selected randomly from a batch and hardness was tested by placing the tablet between two anvils, and the crushing strength that causes the tablet to break is noted. Thickness Thickness of the tablets was measured by using vernier calipers. Mean and standard deviation were calculated.

Disintegration Disintegration was performed for finding out the time taken for tablets to broken down from large particle into small particles. Test was performed by using. Tablets was placed in 6 glass tubes (1 tablet in each tube) and immersed in simulated gastric fluid at 37⁰c±2⁰c. Dissolution Drug release studies were done by using USP type 11 apparatus (paddle type). 900ml of dissolution medium was transferred into round bottomed beaker and the temperature was maintained at 37⁰c±2⁰c and 50rpm. At regular time interval 5ml sample was withdrawn and replaced with fresh dissolution medium. Removed sampled was diluted and observed in UV spectrophotometer at 220nm. Assay of tablets12 Estimation of drug content in tablet was carried out by using UV/Visible spectrophotometer at 220-nm. Procedure Weigh and finely powder not fewer than 10 Tablets. Transfer an accurately weighed portion of the powder, equivalent to about 15 mg of Irbesartan, to a 100-mL volumetric flask. Add methanol up to about three-fourths of the volume of the flask. Sonicate for 15 minutes, with stirring at 5-minute intervals. Dilute with methanol to volume, and pass a portion of this solution through a glass microfiber membrane filter having a 0.45-µm or finer porosity. RESULTS AND DISCUSSION

TABLE 2: SOLUBILITY STUDY OF IRBESARTAN

S.No Dissolution Medium mg/250ml mg/900ml 1 SGF 297.34 1070.64

2 0.1N HCl 307.7 1107.73

3 0.01N HCl 98.58 354.9

4 pH 3.0 Citrate buffer 41.85 150.64

5 pH 4.5 Acetate buffer 26.09 93.91

6 pH 6.8 Phosphate buffer 212.22 764

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TABLE 3: DRUG AND EXCIPIENT COMPATIBILITY STUDY S.NO Name of the substance D:E

Ratio 25°C/60%RH 40°C/75%RH 50°C/60%RH

Initial 15

days 30

days 15

days 30

days 15

days 30

days 1 Irbesartan As such no change NCC NCC NCC NCC NCC NCC 2 Lactose Monohydrate 1:2 no change NCC NCC NCC NCC NCC NCC 3 Avicel PH 101 1:2 no change NCC NCC NCC NCC NCC NCC 4 Croscarmellose sodium 1:1 no change NCC NCC NCC NCC NCC NCC 5 Colloidal Silicon Dioxide 1:0.25 no change NCC NCC NCC NCC NCC NCC 6 Magnesium stearate 1:0.25 no change NCC NCC NCC NCC NCC NCC 7 Carnauba wax 1:1 no change NCC NCC NCC NCC NCC NCC 8 Poloxamer 188 2:1 no change NCC NCC NCC NCC NCC NCC 9 SodiumLauryl Sulphate 2:1 no change NCC NCC NCC NCC NCC NCC 10 Sodium Starch Glycollate 1:1 no change NCC NCC NCC NCC NCC NCC 11 Starch 1500 1:5 no change NCC NCC NCC NCC NCC NCC 12 Tween 80 2:1 no change NCC NCC NCC NCC NCC NCC

D:E : Drug Excipient ratio, NCC (No conformational change), RH: Relative Humidity.

TABLE 4: PHYSICAL CHARACTERISTICS OF INNOVATOR Parameters Observation

Colour White Shape Caplet Weight 601±1.14

Thickness 7.0±0.1 Hardness 115-120 Length 15.3 Width 7.1

Disintegration time 2min

TABLE 5: PHYSICAL CHARACTERISTICS OF GRANULES Trial No.

%LOD Bulk density (gm/cm2)

Tapped density ( gm/cm2)

% Compressibility Hausner Ratio

S1 1.56 0.487 0.565 13.80 1.160 S2 1.64 0.469 0.531 11.67 1.132 S3 1.46 0.5 0.545 8.0 1.09 P1 1.71 0.444 0.558 20.43 1.25 P2 1.52 0.486 0.567 14.2 1.166 P3 1.62 0.443 0.554 20.03 1.25 T1 1.47 0.469 0.531 11.67 1.132 T2 1.74 0.51 0.543 6.07 1.064 T3 1.65 0.485 0.567 12.13 1.138

TABLE 6: PHYSICAL CHARACTERISTICS OF IRBESARTAN IR TABLETS:

Trial Weigh variation ( mg)

Friability (%)

Hardness (Newton’s)

Thickness (mm)

Disintegration (min)

Drug content (%)

S1 602±2.35 0.14 110 - 120 7.2±0.1 7.30 99.8 S2 601±2.04 0.12 110 - 120 7.1±0.1 7.27 101 S3 603±2.03 0.17 110 - 120 7.2±0.1 7.29 99.6 P1 602±2.06 0.2 110 – 120 7.3±0.1 2.40 99.9 P2 604±2.41 0.24 110 – 120 7.1±0.1 2.36 100.2 P3 602±2.13 0.26 110 – 120 7.1±0.1 2.24 99.5 T1 601±2.35 0.23 110 – 120 7.2±0.1 2.14 99.8 T2 604±2.15 0.24 110 – 120 7.2±0.1 2.02 99.9 T3 602±2.38 0.28 110 – 120 7.2±0.1 1.50 100.1

Fig 1: Comparing dissolution profile of innovator and trial S1, P1 and

T1

Fig 2: Comparing dissolution profile of innovator and trial S2, P2 and

T2, T3

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Fig 3: comparing dissolution profile of innovator and trial S3, P3 and

TABLE 7: SIMILARITY FACTOR OF DIFFERENT

FORMULATIONS SNO Trails Similarity factors

1 S1 19.1

2 P1 42.9

3 T1 48

4 S2 20

5 P2 56

6 T2 68.4

7 S3 22

8 P3 63

9 T3 97

RESULTS AND DISCUSSION Preformulation studies are conducted for pure drug Irbesartan; it revealed that the drug exhibits poor flow properties and compressibility. To enhance the flow property wet granulation method is used for the preparation of Irbesartan immediate release tablets. The drug content in the formulation is within the limits and it was given in the table 6. Solubility of Irbesartan in different media is given in the table2. Solubility is high in 0.1 N HCl compared to other medium. So the dissolution studies were conducted in 0.1 N HCl. Physical properties of granules such as bulk density, tapped density, hausners ratio, %LOD, and compressibility were found to be within the range. All the formulations shown good flow properties and the results were shown in the table 5. Drug excipient compatibility studies showed that there was no interaction or physical change between the drug and excipient. The selected excipient was found to be compatible with the drug. The evaluated IR tablets weight variation was within the range of 601±2.04-604±2.41, friability falls between 0.2-0.17, hardness and thickness of the tablets were found to be between 110-120 and 7.1-7.2. Disintegration time of all the nine formulations was 7.30, 7.27, 7.29, 7.40, 2.36, 2.24, 2.14, 2.20, 1.50min. Among all the formulations, T3 disintegrated within 1.50 min. the

disintegration concentration in all the formulation was same but the disintegration was varied in the formulation due to the change in the concentration and type of surfactant. Dissolution studies of all the formulations are compared with the marketed product AVAPRO. 2% polysorbate (formulation T3) showed the same release profile as that of the marketed product AVAPRO. The comparative release rate profile of marketed product and T3 were shown in fig 3. 2% of polysorbate has the capability to form micelles, which enhances the solubility of the drug. This infers that as the concentration of surfactant increases the micellar concentration increases, as micellar concentration of surfactant increases the rate of release of the drug is increased due to the fast absorption of the dissolution medium by the tablets and greater disintegration, which enhances the drug release. Surfactant helps in solubility of drug and dissolution rate also. The similarity factor of different formulations with innovator product has been checked. Among all the formulation the similarity factor between formulator T3 and innovator is found to be 97. The similarity factor for all the formulations and innovator were given in table7. REFERENCES 1. D.M. Brahmankar, Sunil B.Jaiswal. Biopharmaceutics and pharmacokinetics- A treatise. Absorption of drugs. 2nd ed. Delhi: Vallabh Prakashan; 2009: 24‐ 27. 2. K.G.H. Desai, A. R. Kulkarni, Aminabhavi TM., et al. Solubility of rofecoxib in the presence of methanol, ethanol and sodium lauryl sulfate at (298.15, 303.15 and 308.15) k. Journal of Chem. Eng 2003; 48(4): 942–945. 3. C. Liu, K. G. H. Desai, and C. Liu., et al. Solubility of valdecoxib in the presence of Ethanol and Sodium lauryl sulfate at (298.15, 303.15 and 308.15) k. Journal of Chem. Eng. Data 2004; 49(6): 1847–1850. 4. K.G.H. Desai and H. J. Park, et al. Solubility studies of valdecoxib in the presence of carriers, co-solvents and surfactants. Drug Development Research 2004; 62(1): 41–48. 5. D.M. Brahmankar, Sunil B.Jaiswal. Biopharmaceutics and pharmacokinetics- A treatise. Bioavailability and Bioequivalence. 2nd ed. Delhi: Vallabh Prakashan; 2009; 349‐ 357. 6. A.A. Noyes, W.R. Whitney, The rate of solution of solid substances in their own solutions, J. Am. Chem. Soc.1897;19: 930-934., 7.P.S Mohanachandran, P.G Sindhumol, T.S Kiran.et al., Superdisintegrants: An Overview, International J pharm sci. 2011; 6(1): 105-109. 8. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB. et al., "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes".N Engl J Med. 2001; 345(12): 851–60. 9. Amidon GL, Lennernäs H, Shah VP, Crison JR et al., "A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability" Pharm. Res 1995; 12 (3): 413–20. 10. Carr, R.L. et al ., “Evaluating flow properties of solids”. chem Engg 1965; 72: 162-168. 11. Leon lachman, Herbert A. Lieberman, “The theory and practice of industrial pharmacy”, In: Gilbert S. Banker and Neil R. Anderson. Tablets. 3rd ed. Bombay: Varghese publishing house; 1990; 297-302. 12. Hobart H. Willard, Lynne L. Merritt, John A. Dean, Frank A. settle. et al., Instrumental methods of analysis. U Visible instrumentation.7th edition, Noida: India Binding House; 2007; 121‐140.

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