design and development of valsartan antihypertensive by factorial designs

Design and development of valsartan tablet formulation for antihypertensive by 2 factorial design

Design and Development of Valsartan Tablet Formulations for Antihypertensiveby 2 Factorial designsKurmana Reshma(614289801004)By

Under the guidance ofMr.Taraka Rama Rao M.Pharmacy., Ph.DSri venkateswara college of pharmacy1(2014-2016)

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Many of modern drugs belong to class-I category under Biopharmaceutical Classification System (BCS) which are characterized by low solubility and high permeability.

Bioavailability is the most important property of a dosage form. Its ability of a dosage form to deliver active ingredient to its site of action in an amount sufficient to elicit the desire pharmacological response.

These drugs are insoluble in water and aqueous fluids in the pH range 1.0-7.5 and exhibit low and variable dissolution rate and bioavailability

INTRODUCTION2

Dosage form related factors which can be produces profound difference in the bioavailability including formulation and manufacturing variables such as particle size, chemical form, solubility of drug, type and quantity of excipients used

Very poor aqueous solubility of the drug also gives rise to difficulties in the formulation of solid dosage forms and leads to poor and variable dissolution rate and oral bioavailability.

The drug in solid dosage form most undergoes dissolution before its available for absorption from GIT. Dissolution forms rate limiting step in the absorption of drugs from solid dosage forms especially when the drug is poorly soluble.

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PLAN OF THE RESEARCH WORK Survey of literature related to the topic and framing of objectives and hypothesis for the investigation.

Procurement of drugs and excipients

Analytical methods:

standardization of UV-spectrophotometric method for the estimation of Valsartan validation of the method for linearity, accuracy and precision inference by the excipients and percent recovery.

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Evaluation of flow properties

Development of Valsartan tablet formulations.

Preparation of Valsartan tablets by wet granulation method as per 2 factorial design employing CD ,Binders (PVP, Gelatin) and Disintegrants (Potaostarch ,CCS)

Evaluation of tablets Prepared for drug content, hardness, friability, disintegration time and dissolution rate.

Estimation of various dissolution parameters from the dissolution data

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The dissolution data were analyzed as per zero order and first order kinetic model.

The dissolution efficiency ( DE30 ) and dissolution rate constant (K1 ) values analyze as per ANOVA of 2 Factorial designs.

Comparision of Dissolution data with Marketed product (Valent80)

Publication of research papers.

Thesis preparation and submission

OBJECTIVES

The objective of the present study is to evaluate the effect of commonly used -cyclodextrin, binders, and Disintegrants on the dissolution rate of Valsartan tablets.

The study is conducted as per 2 factorial designs to evaluate the individual main effect and combined effect of the three factors involved.

In the present study 2 factorial designs that use in the formulation of Valsartan tablets each at two levels for investigated individual /combined effects.

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The three factors such as Factor A -cyclodextrin (0, 1:2 ratio of drug: CD), Factor B binders (PVP3.2%, Gelatin 2% ) Factor C contain of Disintegrants (Potato starch 10%, Cross carmellose sodium 5%) each factor studied at two levels as given below.

*PVP Poly vinyl Pyrrollidone, CCS Cross carmellose sodium

Name of FactorLow levelHigh level

A) -Cyclodextrin _1:2 drug B) BinderPVP (3.2%)Gelatin (2%)C) DisintegrantPotato starch(10%)CCS (5%)

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To evaluate the individual and combined effect of the factors involved 2 factorial design needs the following eight selected combination of the three factorsS.noTreatments(Formulations)Factor AFactor BFactor C1.F_PVPPotato starch2.Fa1:2 -CDPVPPotato starch3.Fb_GelatinPotato starch4.Fab1:2 -CDGelatinPotato starch5.Fc_PVPCCS6.Fac1:2 -CDPVPCCS7.Fbc_GelatinCCS8.Fabc1:2 -CDGelatinCCS

*PVP Poly vinyl Pyrrollidone, CCS Cross carmellose sodium, CD Cyclo dextrin9

10LITERATURE REVIEW

RESEARCH ON FACTORIAL DESIGNS FOR FORMULATION DEVELOPMENT STUDIES

1. Diva Sangalio et al., Studied, Factorial design in the feasibility of producingMicrocelMC101pelletsbyextrusion/spheronization., International Journal of Pharmaceutics., 115 (1995), 53-60.

2. Nevin Celebi et al., The preparation and evaluation of Salbutamol sulphate containing poly (lactic acid-co-glycolic acid) microspheres with factorial design-based studies., International Journal of Pharmaceutics., 136 (1996), 89 -100.

3. Huiquan Wu et al., Quality-by-Design (Qbd) An integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and process design space development of naproxen., International Journal of Pharmaceutics.,405 (2011) ,6378.

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4. M. Kincl et al.,Application of experimental design methodology in development and optimization of diclofenac sodium drug release method., International Journal of Pharmaceutics., 291 (2005), 3949.

5. Mahesh N. Padamwar et al., Development of vitamin loaded topical liposomal formulation using Factorial design approach: Drug deposition and stability., International Journal of Pharmaceutics., 320 (2006), 3744.

6. Yun-Seok Rhee et al., Optimization of ibuprofen gel formulations using experimental design technique for enhanced transdermal penetration.,InternationalJournalofPharmaceutics., 364, (2008), 1420.

13 7. Helena Marie Lindholm Larsen et al., Formation of Mannitol hemihydrate in freeze-dried protein formulationsA design of experiment approach., International Journal of Pharmaceutics. ,(2014), 45 52.

8.Inayat Bashir Pathan et al., Formulation design and optimization of novel mouth dissolving tablets for Venlafaxine hydrochloride using Sublimation technique., journal of pharmacy research (2013) .,593-598.

9. Hetal Patel et al., Dissolution rate improvement of telmisartan through modified MCC pellets using 3 full factorial design, Saudi Pharmaceutical Journal., 2015, 1-9.

14VALSARTAN - A DRUG PROFILE

Category: Antihypertensive Mechanism of Action: Effectively inhibits the AT mediated vaso constructive and aldosterone secreting effects of angiotensin-II and results in a decrease vascular resistance and blood pressure.

Empirical formula: CHNOMolecular weight: 435.51876 g/moleMelting point: 116-117CDescription: White fine powder.Solubility : water insoluble and soluble in ethanol/methanol.

Pharmacokinetics

Extent of absorption :50% Bioavailability:25% Protein binding : 94-97%bound to serum proteins.1% serum albumin. Excreted unchanged in urine : Feces (83%) and urine (13%)Half life : 4-6 hoursDose: 80 to 320 mg once daily.

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ANALYTICAL METHODMETHOD USED FOR THE ESTIMATION Of VALSARTANA spectrophotometric method based on the measurement of absorbance at 250 nm in phosphate buffer pH 6.8 for use in the present study for the estimation .15Calibration curve for the estimation of Valsartan (n=6)Calibration curve for the estimation of ValsartanS.noValsartanConcentration(g/ml)AbsorbanceRelative standard deviation (RSD)1.0002.20.0800.043.40.1440.014.60.2410.025.80.2960.016.100.3870.021

DISCUSSION:The method obeys Beers law in the concentration range 1-10g/ml. The low relative standard deviation (RSD) value ensure reproducibility of method The results of interference study indicated that none of the exceipients use in the study interference.

16 EXPERIMENTALPreparation of Valsartan Tablets: The compressed tablets containing 80 mg of Valsartan were prepared by wet granulation method

S.noName of the ingredients( mg) FormulationsFFFbFabFcFacFbcFabc 1.Valsartan8080808080808080 2.DCP1852518020197.537.5192.532.5 3.-cyclodextrin -160 -160 -160 -160 4.PVP88 - -88 -5Gelatin - -55 - -5 - 5.Potato starch25252525 - - - -Cross carmellose Sodium - - - -12.512.512.512.5 6.Talc88888888 7.Magnesium stearate 88888888 Total315315315315315315315315

Formula for Valsartan tablet Formulation Prepared

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EVALUATION OF TABLETS All the tablets were prepared by Conventional wet granulation method tablets were evaluated for

Content uniformity Hardness Friability Disintegration time Dissolution rate studies 17

DISSOLUTION RATE STUDIES

Apparatus: (LABINDIA) DS 8000 Stirrer : Paddle Stirrer Speed : 50 RPM Dissolution media: pH 6.8 Phosphate Buffer Assay: 250 nm at UV visible spectrophotometer Sampling Time Intervals: 10min, 20 min, 30 min, 40 min, 50 min, 60 min18

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DATA ANALYSIS The Data analyzed as per first order/ zero order kinetic model

Analyzed as per Analysis of variance (ANOVA) of 23Factorial Design to find out individual and combined effect of three factors involved based on the Dissolution rate constant (K1) and DE30

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20S.noFormulationsAngle of repose ()Bulk density(gm/cm)Tapped densityCarrs index(%)1.F113.470.310.4711.592.Fa14.80.420.388.823.Fb16.20.400.398.694.Fab16.80.380.318.825.Fc17.30.390.3711.566.Fac18.70.420.4010.147.Fbc17.90.450.4711.548.Fabc18.10.410.4011.42

Flow properties of Granules

21S.noFormulationsDrug content(%)Hardness(Kg/cm)Friability(%)Disintegration time (min)1.F198.75.10.904.82.Fa99.25.30.704.43.Fb99.14.50.694.54.Fab98.95.00.813.85.Fc98.35.50.711.06.Fac99.35.80.812.37.Fbc98.25.90.782.78.Fabc99.45.70.922.83

Physical Properties of Valsartan tablets Prepared

22 Dissolution Profile of Valsartan Tablets Prepared Employing as per 2 Factorial Design Formulations ( F1 ) (n=4)

Time(min)Percent drug dissolved (%)XSD

Trail-ITrail-IITrail-IIITrail-IV000000108.9010.758.097.0418.6951.562011.4114.17511.3810.8311.9481.503012.9517.47514.6614.3314.8531.894018.0120.9118.0817.7018.671.495020.62521.7520.418.4820.313751.36024.06124.924.92524.92424.700.42

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Dissolution Profile of Valsartan Tablets Prepared Employing as per 23 Factorial Designs (F1).

24Dissolution Profile of Valsartan Tablets Prepared Employing as per 2 Factorial Design Formulations (Fa) (n=4)Time(min)Percent drug dissolved (%)X SD


25 Dissolution profile of Valsartan Tablets Prepared Employing as per 2 Factorial Design formulations (Fa) (n=4).

26Time(min)Percent drug dissolved (%)XSD

Trail-ITrail-IITrail-IIITrail-IV0000001013.7613.2126.97528.3120.561.12018.1218.1230.2531.62524.522.43020.7923.8844.74734.093.64027.27526.3053.57551.2742.402.15029.8829.8858.8857.1247.20.56040.3356.42562.27561.2755.823.6

Dissolution Profile of Valsartan tablets Prepared Employing as per 2 Factorial Design Formulations (Fb) (n=4).

27 Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fb) (n=4).



Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fab) (n=4).

29 Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fab) (n=4).



Dissolution Profile of Valsartan tablets prepared Employing as per 2 Factorial Design Formulations (Fc) (n=4).

31 Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fc) (n=4).

32 Time (min)Percent drug dissolved (%)XSD


Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fac) (n=4).

33 Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design Formulations (Fac) (n=4).



Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fbc) (n=4).

35 Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fbc) (n=4).


Trail-ITrail-IITrail-IIITrail-IV0000001013.7315.6820.0220.7317.5423.32025.6724.4827.2627.9826.3451.53040.6837.3944.5143.0741.4131.24052.9254.1350.7654.453.051.655071.6773.5772.7364.4570.6054.16097.5797.296.9897.5 97.54.4

Dissolution profile of Valsartan tablets prepared Employing as per 2 Factorial Design formulations (Fabc) (n=4).

37 Dissolution profile of Valsartan tablets prepared Employing) as per 2 Factorial Design formulations (Fabc) (n=4).

38TimeminMean Percent drug dissolved (%)F1FaFbFabFcFacFbcFabc000000000108.6951.511.051.420.561.117.751.920.982.922.411.224.150.817.533.32011.941.514.232.224.522.419.512.834.192.235.08.4.235.481.926.341.53014.851.816.381.734.093.525.051.951.321.943.592.446.172.741.411.24018.671.419.831.941.902.133.032.361.782.758.542.459.291.652.981.65020.311.323.5952.247.220.548.631.974.893.173.11.1.70.581.470.604.16024.700.429.1971.055.823.662.942.790.171.386.112.494.110.597.54.4

Dissolution Profile of Valsartan Tablets Prepared Employing as per 2 Factorial Design Formulations (F1- Fabc) (n=4)

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39 Dissolution Profiles of Valsartan Tablets Prepared Employing as per 2 Factorial Designs (F1- Fabc).

40 First order Dissolution Profile of Valsartan Tablets Prepared Employing as per 2 Factorial Designs formulations (F1- Fabc).

41S.n0FormulationPD30 (%)tK1 10 3(min-1)DE30 (%)1F117.4751hr47.02824.339.34251.270752Fa18.81hr35.1669.39511.16851.50403Fb47.032min51.74437.6520.71257.47384Fab34.1744min18.36719.62217.591259.5125Fc53.6822min4.34392.228326.94252.41136Fac45.6734min1.810840.424424.5415.78717Fbc5427min3.3702.55527.574.06048Fabc44.537min2.12440.888021.493252.006

Dissolution Parameters of Valsartan Tablets Prepared Employing 2 Factorial Designs

42Source of variablesDegrees of Freedom(n-1)Sum of SquaresMSS= SS/DF*F=MSS/ESS*Total311756.755756.6695-Treatments71735.59247.94281.142Error2421.16570.88191Fa1317.52317.52360.04Fb14814.2574814.2575458.9602Fab135.490335.490340.24Fc14794.654794.655436.7275Fac1116.281116.281131.852Fbc14147.324147.324702.7Fabc16.75286.75287.657

ANOVA of Dissolution Efficiency (DE30) of Valsartan Tablets Prepared by Employing 23 Factorial Designs

F 0.05., (7, 24) = 2.42, (1, 24) = 4.26.

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43Source of variablesDegrees of freedom (n-1)Sum of SquaresMSS= SS/DF*F=MSS/ESS*Total31584,018,1028188,392,936.4-Treatments78784,965,7681254,995,1103.67273Error248200947,665341,706152.71Fa12,338,125,8922,338,125,8928.8425Fb13037,195,1493037,195,1498.88832Fab12089,379,7342089,379,7346.11455Fc16055,052,8056055,052,80517.72005Fac11,613,365,6691,613,365,6697.21500Fbc12,254,66,36552,2546636557.5982Fabc11825,513,2711825,513,2719.3423

ANOVA of Dissolution rate constant (K1) of Valsartan Tablets Prepared by Employing 23 Factorial Designs

F 0.05., (7, 24) = 2.42, (1, 24) = 4.26.

44S.noTime (min)Percent Drug Dissolved (%)Fabc (Rt)*Valent 80 (Tt)*Rt-Tt(Rt-Tt)210000021015.6817.671.993.96932024.4826.381.93.6143037.3939.371.983.920454054.1358.1341665073.5778.374.823.0476097.2100.02.87.84 Rt=302.45 (Rt-Tt) = 17.47( Rt-Tt)2 = 58.3794

Comparison of Dissolution Profile of Valsartan Optimize Formulation (Fabc)and Marketed Product (Valent 80) by f1, f2 .*Rt, Tt = Individual/mean percent dissolved at each point t.

45Difference Factor (f1) f1= {[S t=1n |Rt-Tt|] / [S t=1n Rt ]} x100f1= 17.47/302.45 x100f1 = 5.776

Similarity Factor (f2)f2= 50 log {[1+ (1/n) t=1 n (Rt-Tt)2 ]-0.5 100}f2= 50log {[1+ (1/6) (Rt-Tt) 2]-0.5 100f2 = 1+ 58.3794/6f2 = 1/9.7299f2 =75.291

Dissolution Profile of Valsartan Optimize Formulation (Fabc) and Marketed Product (Valent 80)

RESULTS AND DISCUSSION 46

The main objective of the investigation is valsartan tablet formulation was employed by 23 Factorial Design employing Cyclodextrin, Binders, Disintegrants are the three factors are using this study.

Two levels of the three factors used such as Factor A ( Cyclodextrin are 0%,1:2 ratio drug: Cyclodextrin)

The two levels of the Factor B (Binders) are Poly Vinyl Pyrrollidone 3.2%, Gelatin 2% of drug content,

The two levels of Factor C (Disintegrant) are Potato Starch 10%, Cross Carmellose Sodium 5% of drug content.

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The results obtained from evaluation of granules such as Angle of repose, Bulk density, and True density in all the formulations.

The angle of repose values was found to be 13.47-18.7 respectively all formulations shows the angle of repose produce good flow properties.

Bulk density found between 0.31-0.45gm/cm3 the true density found between 0.31-0.47gm/cc respectively,

The compressibility index was found to be 8.82-11.59 %, it exhibits excellent to good flow properties.

48 All the tablets prepared evaluated for drug content hardness, friability, disintegration time

The hardness of the tablets was in the range 4.5-5.7kg/cm2.

The friability was less than 0.90% in all the cases.

The Valsartan content of tablets prepared was within 1002.5%

The Disintegration time was in the range 1.0 min -4.8 min

The valsartan tablet formulation Fc disintegrate rapidly with in 1min, all other tablets are the slowly 2.3-4.8min respectively.

All Valsartan tablets prepared were good quality and fulfill the official specifications of uncoated tablets (IP).

49The dissolution data were analyzed as per zero order and first order kinetic in all the cases r value in the first order model higher than those in zero order model

Many variables were observed in the dissolution rate the variation observed may be due to formulation variables.

The dissolution parameters such as dissolution rate constant (K1) and dissolution efficiency (DE30) were subjected to Analysis of Variance (ANOVA) to find out the significance of individual main and combined effect of the three factors involved.

50The results of ANOVA of dissolution rate constant (K1) indicated that the individual main effect of the three factors such as Factor A ( Cyclodextrin), Factor B (Binder) and Factor C ( Disintegrant) and combined effect of the three factors are significant (P < 0.05) due to the Binders, Disintegrants use and inclusion of Cyclodextrin has significantly influence the dissolution rate of valsartan tablets.

The results of ANOVA of DE30 values indicates that the individual main effect of three factors such as Factor A (Cyclodextrin), Factor B (Binder) and Factor C (Disintegrant) and combined effect of the three factors are significant (P < 0.05) thus the Binder, Disintegrant and Cyclodextrin influence the dissolution efficiency of Valsartan tablets.

51The increasing order of dissolution rate observed with various formulations was Fabc > Fbc > Fc > Fac > Fab > Fb > Fa > F1.

Valsartan tablets formulations Fabc formulated employing Cyclodextrin (1:2) (Factor A) and Gelatin (2%) as a Binder (Factor B) and Cross Carmellose Sodium (5%) as Disintegrant (Factor C) gave highest dissolution rate of Valsartan (97.5% in 60 min).

The dissolution profile of optimize formula (Fabc) and Marketed product of valsartan tablets (Valent80) in each case were compare by difference factor (f1) and similarity factor (f2).

The values of f1 and f2 indicated similarity of the dissolution profile of optimize formula (Fabc) and Marketed product (Valent80) of valsartan tablets to meet comparable dissolution profile with commercial tablets (Valent80).

52SUMMARY AND CONCLUSIONS The individual main effect and combined effect of commonly used Cyclodextrin, Binders, disintegrants on the dissolution rate of valsartan tablets were studied in 23 factorial designs employing selected combinations of three factors ( Cyclodextrin, Binders, disintegrants)

All the prepared granules were studied for flow properties such as bulk density, true density, compressibility index to achieve excellent to good flow properties.

All the valsartan tablets were prepared good quality with regard to drug content, hardness, friability and disintegration time to fulfill official (IP) specifications of uncoated tablets.

The valsartan tablets dissolution from all the tablets prepared followed first order kinetic model.

53 Many variations were observed in all the dissolution parameters of tablets prepared due to formulation variables.

The ANOVA of dissolution rate (K1) indicates the individual main effect and combined effect of Cyclodextrin, Binders, disintegrants on the dissolution rate constant (K1) are significant (P < 0.05).

The ANOVA of dissolution efficiency (DE30) indicates that individual main effect and combined effect of Cyclodextrin, Binders, disintegrants on the dissolution efficiency (DE30) are significant (P < 0.05).

Valsartan tablets formulations Fabc formulated employing 1:2 ratio of Cyclodextrin (Factor A) and Gelatin (2%) as a Binder (Factor B) and Cross Carmellose Sodium (5%) as Disintegrant (Factor C) gave highest dissolution rate of Valsartan 97.5% in 60 min.

54The increasing order of dissolution rate observed with various formulations was Fabc > Fbc > Fc > Fac > Fab > Fb > Fa > F1.

The optimize Valsartan tablets (Fabc) formulated employing1:2 ratio of Cyclodextrin, Gelatin (2%) and Cross Carmellose Sodium (5%) are compare to the marketed product (Valent 80). The differential factor (f1) valued found 5.776 and similarity factor (f2) value found 75.291.

Differential factor (f1) and similarity factor (f2) indicate identical/similar dissolution profile comparable to marketed product ( Valent 80)

55 PAPERS PUBLISHED

1. K. Reshma and Ch.Taraka Ramarao, Pharmaceutical Formulation Development Process by Factorial Design, Optimization and ANOVA Techniques: An Review,

European Journal of Biomedical and Pharmaceutical sciences (EJBPS) 2016, VOLUME 3, ISSUE 10, 108-115.2. Research Paper for CommunicationK. Reshma and Ch.Taraka Ramarao,

Design and Development of Valsartan tablets formulation for Anti hypertensive by 23 Factorial Design, Asian Journal of Pharmaceutical Sciences.

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design and development of valsartan antihypertensive by factorial designs

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