formulation development and evaluation of venlafaxine hcl sustained

Research Article

FORMULATION DEVELOPMENT AND EVALUATION OF VENLAFAXINE HCl SUSTAINED RELEASE MATRIX TABLET

RAHUL THORAT1, PURUSHOTTAM PATIL*1, RASHMI AAGE2, PRASHANT PURANIK1, VIRAJ SALVE1

1Govt.College of Pharmacy, Aurangabad. 431005, 2Y. B. Chavan College of Pharmacy, Aurangabad. 431001 (M.S) India. Email: [email protected]

Received: 27 Jun 2013, Revised and Accepted: 30 July 2013

ABSTRACT

Objectives: The purpose of research work is to prepare Sustained Release Dosage Form (SRDF) of Venlafaxine HCl. As its half life is 5-6 Hrs and having good solubility (BCS Class I) it is suitable candidate for sustained release tablet dosage form.

Method: It was formulated to matrix tablet by direct compression method using Carbopol 971P and Ethyl cellulose as sustaining polymers. Differential Scanning Calorimetry (DSC) study shows that drug and other excipients are compatible with each other. The effects of polymers concentration on drug release profile were investigated. A 32 full factorial design was applied to systemically optimize the drug formulation. Concentration of Carbopol 971P and Ethyl cellulose are selected as independent variables and % Cumulative release of drug for 3 and 24 hrs (Q3,Q24) were selected as dependent variables.

Results: All precompressional and post compressional parameters were within official limit. Batch F5 containing Carbopol 20% and Ethyl cellulose (20cps) 10 % shows drug release upto 95.47 % in 24 Hrs selected as optimized batch. ANOVA data shows models were significant. Drug release kinetics study shown that it follows Korsmeyer Peppas model (r2=0.9922) and release exponent (n=0.4365) shows mechanism is Fickian type.

Conclusion: Hence by formulating its sustained release matrix tablets of 24 Hrs creates new hope for patient as improving patient compliance and decreasing frequency of administration.

Keywords: Sustained release matrix tablet, Venlafaxine HCl, Carbopol 971P, Ethyl cellulose etc.

INTRODUCTION[1-7]

SRDF provides the initial release of the drug sufficient to provide a therapeutic dose soon after administration and then a gradual release over an extended period. Recently, SRDF became a very useful tool in medical practice offering a wide range of actual and perceived advantages to the patients. The basic rational for sustained drug delivery is to alter the drug release and also to formulate such dosage form that improves patient compliance. To target chronic diseases it is the best suitable dosage form.An appropriate formulation can make the absorption, distribution, metabolism and elimination (ADME) profile of a drug much more favourable. Venlafaxine HCl is an orally active serotonin noradrenalin reuptake inhibitor used in the treatment of major depressive disorders. The successful treatment of depression depends on the maintenance of effective drug concentration level in the body for which a constant and uniform supply of drug is desired. It is a highly water soluble drug (Class I) with the biological half life of 5 Hrs thus requires two to three time daily dosing to maintain plasma drug concentration. So providing its slow release to maintain therapeutic level is the major need of this formulation.

MATERIALS AND METHODS

Materials

Venlafaxine HCl was received as a gift sample from Lupin Research Park, Aurangabad. Ethyl cellulose was gifted from Colorcon Asia Pvt ltd, Goa. MCC PH102 was obtained from Signet Chemicals, Mumbai. Carbopol 971P, PVP K30, Magnesium stearate, Talc were purchase from Dipa Chemicals, Aurangabad. All other chemical and reagent were of analytical grade.

Methods

A) Drug identification and drug-excipients compatibility study[8-23]

1) Melting Point

Melting point of Venlafaxine HCl was determined by taking a small amount of sample in a capillary tube closed at one end and placed in

Digital melting point apparatus. (Veego Digital Melting point apparatus) The melting point was recorded.

2) UV Spectrum and Calibration curve of Venlafaxine HCl

The UV spectrum of Venlafaxine HCl was obtained using Shimadzu UV1700. Accurately weighed 25 mg of the drug was dissolved in sufficient quantity of buffer pH 6.8 and volume made upto 25 ml known as stock solution (1000 µg/ml). 1ml of aliquot was withdrawn and volume was made upto 100 ml using buffer pH 6.8 to obtain the concentration of 10µg/ml. Subsequently aliquots were removed to give 2-10µg/ml. The resultant solution was scanned from 400 to 200 nm.

3) Fourier Transform Infra-Red Spectra (FTIR)

The drug sample was placed in FTIR cuvette. The drug sample was scanned over the range of 4000-400 cm-1on an FTIR (Prestige 21 SHIMADZU). The FTIR spectra of drug sample were recorded. Similarly, the procedure repeated by dispersing a sample {drug, drug and polymer (1:1) as well as mixture of drug and polymers (1:1:1:1)} in FTIR cuvette.

4) Differential Scanning Calorimetry (DSC)

The thermal behaviour of Venlafaxine HCl was studied using Shimadzu DSC TA60 WS Thermal Analyzer. Accurately weighed samples of (For drug 6.06 mg) were hermetically sealed in aluminium pan and heated at a constant rate of 20°C/min over temperature range of 100 to 300°C. The DSC thermogram was recorded. The physical mixtures of drug with polymers for compatibility studies were prepared by triturating drug and drug and polymers (1:1) in a dried mortar for 5 min and kept as it is for 24 hrs.

B) Preparation of Tablet[24-25]

Matrix tablets of Venlafaxine HCl were prepared by direct compression method using 10 mm flat-faced punch 10mm of 12 stations (Lab Press Machinery Pvt. Ltd, Ahmadabad, India.) The active ingredient and the excipients were passed through 60 mesh sieve and thoroughly mixed using a polybag for 10 minutes. PVP K30 was used as binding agent and magnesium stearate, talc were added

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491 Vol 5, Suppl 3, 2013

AAccaaddeemmiicc SScciieenncceess

Patil et al. Int J Pharm Pharm Sci, Vol 5, Suppl 3, 757-765

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to the above blend as flow promoters and further mixed for another 10 minutes. In all the formulations the amount of Venlafaxine HCl

was kept constant (75mg) Table 1 shows different matrix tablets of Venlafaxine HCl using Carbopol 971P and Ethyl cellulose.

Table 1: Formulation of 32 Factorial Design Batches

Ingredients (mg) / batch F1 F2 F3 F4 F5 F6 F7 F8 F9 Venlafaxine HCl 75 75 75 75 75 75 75 75 75 Carbopol 971P 45 45 45 60 60 60 75 75 75 Ethyl cellulose (20cps)

15 30 45 15 30 45 15 30 45

PVP K30 9 9 9 9 9 9 9 9 9 MCC 102 146 131 116 131 116 101 116 101 86 Mg. Stearate 5 5 5 5 5 5 5 5 5 Talc 5 5 5 5 5 5 5 5 5 Total 300 300 300 300 300 300 300 300 300

C) Evaluation of flow properties for Factorial blend[26-32]

The quality of tablet depends upon the quality of powder from which it is prepared. The powder of factorial batches were evaluated for Bulk density, Tapped density, Carr’ index (compressibility), Angle of repose and Hausner’s ratio. The evaluated parameters of powder are reported in the Table 4.

1) Bulk density

Apparent bulk density ( b) was determined by pouring the blend into a graduated cylinder. The bulk volume (Vb) and weight of the

powder (M) was determined. The bulk density ( b) was calculated using following formula:

Bulk Density = M / Vb

2) Tapped density

The measuring cylinder containing a known mass of blend (M) was tapped for a fixed time (100 tapping). The minimum volume (Vt) occupied in the cylinder and weight of the blend was

measured. The tapped density ( t) was calculated using following formula.

Tapped Density = M / Vt

3) Carr’s index

The Carr’s index is expression that shows the compressibility of the powder. It is calculated by using the formula,

Carr’s Index = [(Tapped Density – Bulk Density) / Tapped Density] x 100

4) Hausner’s ratio

The Hausner’s ratio (H) is an indication of flowability of the powder. It is calculated by the formula,

5) Angle of repose

It is a maximum angle possible between the surface of pile and the horizontal plane. The lesser the angle of repose, more is the free flowing powder and vice-versa. The angle of repose for the powder of each formulation was determined by the method.

D) Evaluation of Tablets

Tablets are evaluated for following official and non official tests.

1) Appearance

The appearance, colour and any other flaws like chips, cracks, surface texture etc. are other important morphological characteristics were observed.

2) Weight variation test

Five tablets were taken and average weight of the tablet was determined. The tablets were weighed individually and the weight variation was determined

3) Hardness

Tablet hardness is defined as force required to crushing the tablet in diametric compression test. The hardness was measured with Monsanto hardness tester.

4) Friability

Twenty tablets were weighed and subjected to friability test in Roche friabilator. The pre-weighed sample was placed in friabilator which revolves at 25 rpm for 4 min. dropping the tablets through a distance of 6 inch with each revolution. This process was repeated for all formulations and the percentage friability was calculated.

5) Drug content

Randomly selected 1 tablet from each batch was crushed in a mortar and pestle. The crushed powder equivalent to 100 mg of Venlafaxine HCl was taken and dissolved in 100 ml of buffer pH 6.8 (1000µg). Then filtered through Whattman filter paper No 42. The concentration of Venlafaxine HCl was determined by measuring the absorbance at 225nm. Aliquots were taken from stock solution and diluted with buffer pH 6.8 and analyzed by UV-Visible Spectrophotometer (UV-1700 SHIMADZU).

6) In vitro drug release study[33-37]

The drug release rate from Venlafaxine HCl SR matrix tablets (n=3) was determined using USP apparatus type II (Labindia, India). The dissolution test was performed using 900 ml of 0.1N HCl for first 2 Hrs and then buffer pH 6.8 for remaining 22 hrs at 37 0.5C and 50 rpm. The drug release and drug release kinetics was calculated by PCP disso ver. 3.0. The cumulative drug release of all 9 batches is reported in the Tables 6 and Fig. 6 resp.

E) Statistical analysis by Design Expert Software

A 32 full factorial design was selected and the 2 factors were evaluated at 3 levels, respectively. The percentages of Carbopol 971P (X1), Ethyl cellulose (X2) were selected as independent variables and the dependent variables were Q3, Q24. The data obtained were treated using Stat Ease Design Expert 7.1.6 software and analyzed statistically using analysis of variance (ANOVA) (Table 7, 8). The data were also subjected to 3-D response surface methodology to study the interaction of Carbopol 971P (X1), Ethyl cellulose (X2) on dependent variables. (Fig. 7, 8)

F) Kinetics analysis of drug release

To analyze the mechanism of drug release from the tablet the In vitro dissolution data were fitted to zero order, first order, Higuchi release model, Hixson and Crowell powder dissolution method and Korsmeyer Peppas model by using PCP Disso Version 3 software, and the model with the higher correlation coefficient was considered to be the best model. The observations summarized in the Table 9.

b

t


759

RESULTS AND DISCUSSION[38-50]

A) Drug Identification and drug-excipients compatibility study

1) Melting Point

The melting point of Venlafaxine HCl was determined on Digital melting point apparatus was found to be 213º-216ºC which is in good agreement with reported melting point.

2) UV Spectrum and Calibration curve of Venlafaxine HCl

The UV spectrum of Venlafaxine HCl solution (10µg/ml) exhibited wavelength of absorbance maximum at 225 nm which complies with the reported and calibration curve shows r2=0.999

3) Fourier Transform Infra Red Spectrophotometer (FTIR)

In all physical mixtures of drug and polymer, there was neither masking of single characteristic peak nor existence of additional peak in the spectra. (Fig. 2, 3 and Table 2) so we can conclude that drug and polymers are compatible with each other.

4) Differential scanning calorimeter (DSC)

The endothermic peak at 210.94ºC of blend can be attributed as that of Venlafaxine HCl. (214.67 ºC) Thus the thermogram showed that

the Venlafaxine HCl, Carbopol 971P, Ethyl cellulose are compatible with each other since there is no significant difference in endothermic peak of pure drug (Table 3) and physical mixture of drug with other excipients.

C) Evaluation of flow properties for Factorial blends

1) Bulk density

The bulk density of powder is important parameter in the compressibility of the powder. The bulk density was between 0.410 to 0.437gm/cm3.

2) Tapped density

The tapped density of powder is important parameters in the compressibility of the powder. The tapped density was found to be 0.497 to 0.567 gm/cm3.

3) Carr’s index

The Carr’s index is indicator of compressibility. The value below 21 % shows fair to passable compressibility. It was found to be 16.32 to 23.50 %.indicating passable compressibility.

Fig. 1: UV Spectrum and Calibration curve of Venlafaxine HCl

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 2 4 6 8 10 12

Ab

sorb

ance

Conc. ug/ml


760

Fig. 2: FTIR spectrum of Venlafaxine HCl

Fig. 3: FTIR spectrum of Factorial tablet

Table 2: Fourier Transform Infrared spectral assignments with excipients

S. No. Functional Group Reported Values Venlafaxine HCl Factorial Tablet 1 OH 3300-3400 3321.42 3321.42 2 C6H5 1500-1600 1514.12 1514.12 3 Aliphatic CH 2800-3000 2943.37 2936.21 4 C-O-C 1000-1200 1039.63 1039.63


761

0.00 5.00 10.00

Time [min]

-30.00

-20.00

-10.00

0.00

10.00

mW

DSC

100.00

200.00

300.00

C

Temp

210.17 x100COnset

220.41 x100CEndset

205.85 x100CStart

223.09 x100CEnd

214.67 x100CPeak

-640.29 x100mJ

-105.66 x100J/g

Heat

-30.98 x100mWHeight

File Name: Venlaflaxine.tadDetector: DSC60Acquisition Date 12/11/08Acquisition Time 12:55:56Sample Name: VenlaflaxineSample Weight: 6.060[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]20.00 300.0 0

Thermal Analysis Result

Venlaflaxine.tadVenlaflaxine.tad

TempDSC

Fig. 4: DSC Thermogram of Venlafaxine HCl

0.00 2.00 4.00 6.00 8.00

Time [min]

-20.00

-10.00

0.00

mW

DSC

100.00

200.00

300.00

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201.99 x100COnset

216.63 x100CEndset

187.39 x100CStart

221.25 x100CEnd

210.94 x100CPeak

-278.64 x100mJ

-24.53 x100J/g

Heat

-12.64 x100mWHeight

File Name: V+Blend.tadDetector: DSC60Acquisition Date 13/02/07Acquisition Time 14:50:30Sample Name: V+BlendSample Weight: 11.360[mg]Annotation:

[Temp Program]Start Temp 100.0Temp Rate Hold Temp Hold Time[C/min ] [ C ] [ min ]30.00 300.0 0

Thermal Analysis ResultV+Blend.tadV+Blend.tad

TempDSC

Fig. 5: DSC Thermogram of physical mixture

Table 3: DSC compatibility of drug and mixture

S. No. Parameters Venlafaxine HCl Physical Mixture 1 Peak obtained oc 214.67 210.94

Table 4: Powder Flow properties of factorial batches

Batch Bulk Density (gm/cm3)

Tapped Density (gm/cm3)

Carr’s Index (%)

Hausner’s Ratio Angle of Repose (0)

F1 0.423± 0.26 0.512± 0.19 17.38± 1.09 1.21± 0.09 27.12± 1.21 F2 0.419± 0.07 0.499± 0.07 16.32±1.78 1.19± 0.04 29.24± 1.05 F3 0.437±0.19 0.567±0.01 22.92± 1.02 1.24± 0.08 25.36± 1.29 F4 0.417± 0.01 0.494± 0.05 16.59± 1.35 1.18± 0.048 25.12± 1.01 F5 0.413± 0.06 0.497± 0.36 16.90± 1.81 1.20± 0.126 26.42± 1.23 F6 0.420± 0.21 0.527± 0.005 20.30± 2.13 1.25± 0.043 28.54± 1.12 F7 0.431± 0.01 0.521± 0.013 17.27± 1.23 1.20± 0.094 27.18± 1.32 F8 0.428± 0.17 0.535± 0.028 20.00± 1.62 1.25± 0.060 29.36± 1.14 F9 0.41± 0.01 0.536± 0.031 23.50± 1.26 1.30± 0.041 27.48± 1.26

All values are mean±SD, n=3


762

4) Hausner’s ratio

The Hausner ratio is another parameter indicating the flow properties. It was found to be 1.18 to 1.30 indicating good to passable flowability.

5) Angle of repose

The angle of repose can be correlated with type of flow of powder. The angle of repose 20 to 30º indicates the good flow while the angle of repose more 30º indicates poor flow properties and angle of repose below 20º indicates excellent flow properties. The angle of repose was found to be within the range of 25.12º to 29.36º indicating good flowability.

D) Evaluation of Tablets

The tablets from the factorial batches were evaluated for different evaluation parameters of tablets.

1) Appearance

The tablets from all factorial batches were white, circular. The surface texture was smooth. The thickness of tablets of factorial batches was 3.12 to 3.24 mm and it was found to be within limit of deviation from average value (not more than 5%).

2) Weight variation

For tablet weighing 300 mg or more, not more than two tablets differ from the average weight by 5% deviation. The weight variation within limits indicates uniformity in tablet compression and consequently content of drug in a unit.

3) Hardness

The hardness is important characteristics to be evaluated for handling and transportation properties of the tablets. The hardness of tablets was found to be 6.3 to 8.0 Kg/cm2which indicate good handling and transportation characteristics.

4) Friability

The friability is important characteristics to be evaluated for handling and transportation properties of the tablets. The friability of tablets was less than 0.5% which indicates good handling and transportation characteristics.

5) Drug content

The drug content of the nine formulations was found to be between 97.22 to 101.89% (i.e. variation of ±4%). The value ensures good uniformity of the drug content in the tablet.

6) In vitro drug release studies

In vitro drug release study was carried out using USP dissolution apparatus II in 0.1N HCl for first 2 Hrs and then buffer pH 6.8 for a period of remaining 22 Hrs.

The formulations F5, F6 and F8 comprising of Carbopol 971P 60mg, 60mg, 75mg resp. and Ethyl cellulose 30 mg, 45 mg, 30 mg resp. showed improved drug release upto 24 hrs and minimum burst release with more than 80% release in 24 hrs. Hence formulation with comparatively lower polymer concentration (F5) was selected as optimized formulation. Formulation containing combination of Carbopol 971P and Ethyl cellulose retarded the drug release upto 24 Hrs, but showed 41 to 50% drug release in first 3 Hrs in initial batches which were not appropriate. This burst release may be due to high water solubility of drug and more time required for wetting of tablet. This problem was overcome by increasing the Conc. of Polymers.

E) Statistical analysis by Design Expert Software

i) ANOVA study

The Q3, Q24 for the 9 batches (F1-F9) showed a wide variation (i.e., 35.32-50.28% and 84.69-102.37% resp). Data clearly indicates that the Q3, Q24 values are strongly dependent on the selected independent variables. The coefficients of X1 X2 were found to be significant at p <0.05, hence confirmed the significant effect of all the variables on the selected responses.

Table 5: Evaluation of Venlafaxine HCl SR matrix tablets

Batch Appearance Weight variation* mg ± SD

Hardness (Kg/cm2) ±SD

Friability# % Thickness (mm) ±SD

Drug content (%mg) ±SD

F1 White, circular, 10mm 300±0.47 6.3±0.28 0.61±0.02 3.18±0.12 99.03±0.14 F2 White, circular, 10mm 300±0.81 6.7±0.5 0.71±0.04 3.20±0.220 97.03± 1.11 F3 White, circular, 10mm 300±1.69 7±0.31 0.65±0.09 3.18±0.03 100.02±0.45 F4 White, circular, 10mm 299±1.24 7.3±0.21 0.50±0.03 3.20±0.13 99.5±0.79 F5 White, circular, 10mm 300±0.47 7.6±0.28 0.49±0.06 3.24±0.11 98.5±0.49 F6 White, circular, 10mm 300±1.24 8±0.5 0.57±0.09 3.20±0.12 98.1± 0.49 F7 White, circular, 10mm 300±0.94 7.5±0.28 0.69±0.07 3.18±0.25 101.89± 0.83 F8 White, circular, 10mm 300±81 7±0.5 0.82±0.03 3.12±0.15 97.22± 0.36 F9 White, circular, 10mm 300±0.47 7.8±0.5 0.78±0.07 3.16±0.03 98.62± 0.52

* n=20, #n=10, All values are mean ± SD [

Table 6: Percent cumulative drug release of formulation F1 to F9

Time (Hrs) Cumulative Drug Release (%) F1 F2 F3 F4 F5 F6 F7 F8 F9

0.5 14.07 ±0.10

10.76 ±0.03

14.25 ±0.06

11.70 ±0.14

16.60 ±0.12

8.094 ±0.05

13.73 ±0.07

10.53 ±0.04

9.547 ±0.07

1 23.42±0.09 16.96±0.10 19.85±0.09 18.42±0.13 21.95±0.06 15.43±0.11 22.66±0.12 15.38±0.11 16.51±0.14 2 37.60

±1.44 30.98 ±0.04

29.90 ±1.43

29.81 ±0.01

28.61 ±0.07

22.50 ±0.15

32.08 ±0.14

29.88 ±0.05

22.57 ±0.13

3 50.02±1.40 47.52±0.02 41.73±1.53 50.28±0.12 38.14±0.19 36.82±0.10 42.73±0.24 38.08±0.05 35.32±0.37 4 67.57

±1.50 55.67 ±0.09

48.02 ±1.37

57.23 ±0.05

49.99 ±0.20

41.66 ±0.22

45.07 ±0.03

44.12 ±0.19

47.66 ±0.03

6 73.36 ±1.13

61.87 ±0.08

62.29 ±1.27

64.37 ±0.08

57.13 ±0.16

57.80 ±0.11

54.82 ±0.15

53.90 ±0.08

52.28 ±0.07

8 79.85±1.32 67.16±0.27 71.47±1.20 70.47±0.02 71.40±0.12 66.20±0.38 73.92±0.17 72.95±0.06 65.36±0.34 12 83.74

±1.40 74.36 ±0.35

78.65 ±1.22

73.73 ±0.24

76.31 ±0.60

72.91 ±0.25

80.88 ±0.01

77.49 ±0.22

75.41 ±0.25

16 91.17±1.66 87.49±0.40 86.03±1.19 83.42±0.01 82.34±0.14 82.17±0.27 86.64±0.09 84.36±0.44 79.74±0.41 24 102.3±1.54 97.37±0.28 93.28±1.37 99.33±0.06 95.47±0.32 86.83±0.37 93.23±0.14 89.81±0.14 84.69±0.26

All values are mean ± SD, n=3


763

Fig. 6: Percent cumulative drug release of formulation F1 to F9

Table 7: Analysis of variance for Q3

Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non Significant Model 237.81 2 118.91 21.45 0.0018 A-C 92.28 1 92.28 16.65 0.0065 Significant B-EC 145.53 1 145.53 26.26 0.0022 Residual 33.25 6 5.54 - - Cor total 271.06 8 - - - R Squared 0.8773 - Adj R-Squared 0.8364 Pred R-Squared 0.7853 Adeq Precision 13.018

Table 8: Analysis of variance for Q24

Source Sum of Squares Degrees of Freedom Mean Square F Value P Value Model Significant/Non Significant Model 260.05 5 52.01 21.58 0.0147 A-C 106.60 1 106.60 44.23 0.0069 Significant B-EC 151.30 1 151.30 62.78 0.0042 R- Squared 0.9729 Adj R- Squared 09279 Pred R- Squared 0.7082 Adeq Precision 14.574

Fig. 7: Response surface plot for Q3

Design-Expert® SoftwareFactor Coding: Actualdiso 3hr

Design points above predicted valueDesign points below predicted value50.41

35.32

X1 = A: cX2 = B: ec

15.00

21.00

27.00

33.00

39.00

45.00

45.00

51.00

57.00

63.00

69.00

75.00

30

35

40

45

50

55

d

iso

3

hr

A: c B: ec


764

Fig. 8: Response surface plot for Q24

Table 9: Model fitting data of Venlafaxine HCl SR matrix tablet (Optimized batch F5)

S. No. Formulation Models R N K 1

F5

Zero Order 0.5964 0.4365

24.597 First Order 0.9566

Matrix 0.9754 Korsmeyer Peppas 0.9922 Hixon Crowell 0.8866

ii) 3-D Response surface plot

The response surface plots showed that various combinations of independent variables X1, X2 may satisfy any specific requirement (i.e. maximum drug release upto 24 hrs and minimum burst release in 3 hrs) while taking into consideration of various factors involved in dosage form.

F) Kinetics analysis of drug release

The results shown that the factorial design batches follows Korsmeyer Peppas model. The R value of Korsmeyer Peppas was found close to one (0.9922) the slow release of the drug from the matrix may be due to the formation of viscous gel of Carbopol 971P. The n values were found to be less than 0.5 (0.4365) indicating that the mechanism is diffusion controlled or Fickian type as shown in Table 9.

CONCLUSION

The drug has elimination half life of 5(±2) hours shows that it is a suitable candidate for sustained release formulation. Advantage of this formulation over others is that it is easy to prepare and cost effective. Optimum concentration of Carbopol 971P and Ethyl cellulose based formulations was found to provide the desired release (95.47%) with a reduced frequency of administration. Release Kinetics shows it follws Korsmeyer Peppas model and mechanism is diffusion controlled or Fickian type. Thus, the Objective of the project was to formulate a sustained release matrix type tablet of Venlafaxine Hydrochloride meant for once-a-day administration.

ACKNOWLEDGEMENT

The authors are grateful to Lupin Research Park, Aurangabad for providing Venlafaxine HCl as gift sample and Dr. S.S. Khadabadi Principal Goverment College of Pharmacy, Aurangabad for necessary support and valuable guidance.

REFERENCES

1. Lachman L, Liberman HA. The Theory and Practice of Industrial Pharmacy. 3rd ed., Varghese Publishing House, Bombay: 293-330.

2. Remington. The Science and Practice of Pharmacy. 21st ed, Vol. 1; 2005: 889-905.

3. Ansel H, Nicholas G. Ansels Pharmaceutical dosage forms and drug delivery system.9th edn. Lippincott Williams and Wilkins: 225-256.

4. Gartlehner G, Gaynes BN, Hansen RA et al. Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians. Ann Int. Med Nov 18, 2008; 149(10): 734-50.

5. Hamilton M. A rating scale for depression, Journal Neural Neurosurgery Psychiatry. 1960; 23: 56-63.

6. American Psychiatric Association. Arlington (VA): Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Part B: Background Information and Review of Available Evidence: c2010.

7. B. Prasanthi. Modulation of drug release kinetics of a highly water soluble drug from hydrophilic matrices. JGTPS, April-June 2012; Vol 3: 698-704.

8. Indian Pharmacopoeia. The Indian Pharmacopoeia Commission, Ghaziabad. Government of India Ministry of Health & Family Welfare. 2007; Vol 1and 2: 135-142, 43-46.

9. British Pharmacopoeia. The Department of Health, Social Services and Public Safety. 2009; Volume I & II, Ph Eur monograph: 2119.

10. Kanfer I, Walker R. Marcel Dekker. Experimental Formulation Development, 2005: 81-92.

11. Ahmed S, Naini V. Marcel Dekker Scale-Up, Process Validation and Technology Transfer. 2005: 92-111.

12. Quanyin Gao and Dilip R. Analytical Methods Development and Methods Validation for Solid Oral Dosage Forms. Marcel Dekker 2005: 42-46.

Design-Expert® SoftwareFactor Coding: Actualdiso 24hr

Design points above predicted valueDesign points below predicted value102.37

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13. Donald L. Wise. Handbook of Pharmaceutical Controlled Release Technology. Marcel Dekker 2000: 159-161.

14. Patel R, Baria A. Formulation development and process optimization of theophylline sustained release matrix tablet. International Journal of Pharmacy and Pharmaceutical Sciences, Oct-Dec. 2009; 1(2):30-42.

15. Modi S. Sustained release drug delivery system: a review. International Journal of Pharmaceutical Research and Development, 2011; 2: 147-159.

16. Gaikwad D, Jadhav R. Formulation and Evaluation of Sustained Release Tablet of Aceclofenac by Film Coating. IJRPB, Jan-Mar 2011; 2 (1): 310-318.

17. Bhosale R, Raut R. Formulation and evaluation of ion exchange resin tablet of propranolol. IRJP, 3(4); 416-422.

18. Keraliya R, Patel C. Osmotic drug delivery systems a part of modified release dosage form. International Scholarly Research Network, ISRN Pharmaceutics, 2012: 1- 9.

19. Shivhare U, Adhao N. Formulation development, evaluation and validation of sustained release tablets of Aceclofenac. International Journal of Pharmacy and Pharmaceutical Sciences, Oct-Dec. 2009; 1(2):74-80.

20. Chauhan M, Satish A, Patel A. Concise review on sustained drug delivery system and its opportunities, Am. J. PharmTech Res, 2012; 2 (2): 228-238.

21. Charman SA, Charman WN, Rathbone MJ. Modified release drug delivery technology. NewYork : Marcel Dekker.2003: 4.

22. Kamboj S, Gupta G, Oberoy J. Matrix Tablets: An Important Tool for Oral Controlled-Release Dosage Forms. Pharmainfo net, 2009; 7: 3-16.

23. Nokhodchi A, Shaista R. The role of oral controlled release matrix tablets in drug delivery systems. BioImpacts, 2012; 2(4): 175-187.

24. H. Doddayya H, Patil S. Effect of gum rosin and ethyl cellulose on in vitro release of Venlafaxine hydrochloride from hydrophilic matrix tablets. International Journal of Pharmaceutical & Biological Archives 2011; 2(3): 980-988.

25. Wilson B, Patel H. Design and evaluation of sustained release matrix tablets of levofloxacin for effective treatment of microbial infections. International Journal of Drug Delivery2011; 3: 305-314.

26. J Villanova et al. Design of prolonged release tablets using new solid acrylic excipients for direct compression. European Journal of Pharmaceutics and Biopharmaceutics 2011; 79: 664–673.

27. Sinha et al. Novel Lannea Woodier gum matrices for controlled release of drugs. Carbohydrate Polymers 2011; 83: 1492–1498.

28. S. Strübing et al. Characterization of poly (vinyl acetate) based floating matrix tablets, Journal of Controlled Release 2008; 12: 149–155.

29. Y.S.R. Krishnaiah et al. A three-layer guar gum matrix tablet for oral controlled delivery of highly soluble metoprolol tartrate. International Journal of Pharmaceutics 2002; 241: 353–366.

30. X. Wei et al. Sigmoidal release of Indomethacin from pectin matrix tablets: Effect of in situ crosslinking by calcium cations. International Journal of Pharmaceutics 2006; 318: 132–138.

31. M. Ishida et al. A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules. International Journal of Pharmaceutics 2008; 359: 46–52.

32. Chavan S, Anantwar S. Design and evaluation of oncedaily sustained release matrix tablets of Nicorandil. International Journal of Pharmacy and Pharmaceutical Sciences, 2011; 3(2): 13-18.

33. B.Prasanthi, D Raju. Modulation of drug release kinetics of a highly water soluble drug from hydrophilic matrices. Journal of

Global Trends in Pharmaceutical Sciences April-June 2012; Vol.3, Issue 2: 698-707.

34. Dokoumetzidis, P. Macheras. A century of dissolution research: From Noyes and Whitney to the Biopharmaceutics Classification System. International Journal of Pharmaceutics 2006; 321: 1–11.

35. Siewert M. FIP guidelines for dissolution testing of solid oral products. Joint report of the section for official laboratories and medicines control services and the section of industrial pharmacists of the F.I.P: 1-12.

36. Guideline on quality of oral modified release products. European Medicines Agency 2012: 3-15.

37. Pontius A. EUFEPS, Revision of BE Requirements for Modified Release Products - Dissolution Testing Barcelona. Feb. 2011:1-35.

38. S.I. Pather et al. Sustained release theophylline tablets by direct compression Part 1: formulation and in vitro testing. International Journal of Pharmaceutics 1998; 164: 1–10.

39. E. Sundy, M. Paul Danckwerts. A novel compression-coated doughnut-shaped tablet design for zero-order sustained release. European Journal of Pharmaceutical Sciences 2004; 22: 477–485.

40. V.K. Gupta et al. Controlled-release tablets from carrageenans: effect of formulation, storage and dissolution factors. European Journal of Pharmaceutics and Biopharmaceutics 2001; 51: 241-248.

41. Y Krishnaiah, R Karthikeyan. Three-layer guar gum matrix tablet formulations for oral Controlled delivery of highly soluble trimetazidine dihydrochloride. Journal of Controlled Release 2002; 81: 45–56

42. G.A. Abdelbary, M.I. Tadros. Extended release matrix tablets based on hydrophilic interpolymer complexes and a hydrophobic waxy polymer. European Journal of Pharmaceutics and Biopharmaceutics 2008; 69: 1019-1028.

43. S. Limmatvapirat et al. Modulation of drug release kinetics of shellac-based matrix tablets by in-situ polymerization through annealing process. European Journal of Pharmaceutics and Biopharmaceutics 2008; 69: 1004–1013.

44. Marta Casas, Carmen Ferrero. Synthesis and characterization of new copolymers of ethyl methacrylate grafted on tapioca starch as novel excipients for direct compression matrix tablets. European Polymer Journal, 2009; 45: 1765–1776.

45. Celine Valeria Liew, Lai Wah Chan. Evaluation of sodium alginate as drug release modifier in matrix tablets. International Journal of Pharmaceutics 2006; 309: 25–37.

46. Jiménez-Martínez et al. Sustained delivery of captopril from floating matrix tablets. International Journal of Pharmaceutics 2008; 362: 37–43.

47. E. Castellanos Gil et al. Subcoating with Kollidon VA 64 as water barrier in a new combined native dextran/HPMC–cetyl alcohol controlled release tablet. European Journal of Pharmaceutics and Biopharmaceutics 2008; 69: 303–311.

48. Katzhendler et al. United States patent. Zero order Sustained release matrix tablet of Carbamazepine. Patent No 5980942; Nov. 9: 1999.

49. Odidi et al. United States patent. Sustained release matrix tablet pharmaceutically acceptable salts of Diclofenac. Patent No US 6312724B1; Nov 6: 2001.

50. Xiuli W, Ningyun S, Baojian W. Sigmoidal release of Indomethacin from pectin matrix tablets: Effect of in situ cross linking by calcium cations. International Journal of Pharmaceutics 2006; 318: 132–138.

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