Formulation and Evaluation of Extended Release Tablets of Alfuzosin HCl

 

Praveen Kumar Uppala*, Madhusha Reddy Y.

K.V.K College of Pharmacy, Affiliated to Jawaharlal Nehru Technological University, Hyderabad.

*Corresponding Author E-mail: praveen.chintu32@gmail.com, madhusha.reddy@gmail.com

 

ABSTRACT:

Developing oral extended release tablets for highly water soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. The present work is focused on controlling the release of highly water soluble Alfuzosin HCl from hydrophylic matrices prepared using hypermellose.

 

Alfuzosin HCl tablets were prepared by direct compression method using hypermellose  polymer to control release of highly water soluble drug  alfuzosin HCl which is having short half life primarily used as antihypertensive drug. The formulations developed from F1 to F8 .With in these formulations F8was found to have optimised drug release of 86% for 20 hours, the kinetic release studies were conducted  for the  optimised formulation and the best fit model was found to be Higuchi( diffusion ) model.

     

KEYWORDS: Alfuzosin HCl, extended release, hypermelose.

 

 


INTRODUCTION:

Oral drug delivery is the most widely used route of administration among all the routes of administration that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form.

 

Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient compliance and cost effective manufacturing process.1   The dissolution rate of a drug from its dosage form is considered as an important parameter in the bioavailability. The rate determining step in the absorption of orally administered hydrophilic drugs is the rate of drug permeation through the biomembrane.

 

These immediate release dosage forms have some limitations such as 2, 3

1)      Drugs with short half-life require frequent administration, which increases chances of missing dose of drug leading to poor patient compliance.

2)      The unavoidable fluctuations in the drug concentration may lead to under medication or over medication as the CSS values fall or rise beyond the therapeutic range.

3)      The fluctuating drug levels may lead to  adverse effects especially of a drug with small therapeutic index, whenever over medication occurs.

 

Administration of the conventional dosage form by extra vascular route does not maintain the drug level in blood for an extended period of time. The short duration of action is due to the inability of conventional dosage form to control temporal delivery.

 

Fig. 1.A hypothetical plasma concentration-time profile from conventional multiple dosing and single doses of sustained and controlled delivery formulations. (MSC=maximum safe concentration, MEC = minimum effective concentration).

 

Extended Release Dosage Forms4

Are designed to release their medication at a predetermined rate, duration and location to achieve and maintain optimum therapeutic blood levels.

e.g: prolonged release, controlled release, slow release and sustained   release

 

Fig 2 Theoretical drug concentration profile following multiple dosing of a drug as an immediate-release form every 8 hours (–) and as an extended-release form once every 24 hours (---).

 

MATERIALS AND METHODS:

List of materials:

S.no

Name

Functional category

Sources

1

Lactose monohydrate, NF

Diluent

DMV international

2

Microcrystalline cellulose, NF

Diuent

DMV international

3

Guar Gum, NF

Ratecontrolling polymer

Lucid collaid

4

Hydroxypropyl methylcelluose, USP (methocel k100M)

Ratecontrolling polymer

Colorcon

5

Povidone, USP

Binder

BASF

6

Pregelatinized starch,NF

Binder

DMV international

7

Magnesium stearate, NF

Lubricant

Ferrow

8

Colloidal silicon dioxide, NF

Glidant

Degussa

 

Analytical Method Development For Drug Estimation:

Standard graph of Alfuzosin hydrochloride:

Conc.(µg/ml)

Area response

10

568.815

20

1151.332

30

1742.388

40

2294.868

50

2840.067

 

METHODOLOGY:  

Drug excipient compatibility study:       

S.no

Composition details

Ratio

1

D+ Lactose Monohydrate (DCL 11)

1:10

2

D+ Microcrystalline Cellulose (Vivapur101)

1:10

3

D+ Dicalcium Phosphate (Calipharmd)

1:10

4

D+ Methyl Cellulose (HPMCK100 Premium)

1:5

5

D+ Methyl Cellulose (Methocel E5 LV Permium)

1:5

6

D+ Guargum (Lucid 7500 cps)

1:1

7

D+ Xantahn Gum (Xantural75)

1:1

8

D+ Alginic Acid (Protacidf120nm)

1:1

9

D+ Colloidal Silicon Dioxide (Aerosil 200M)

1:0.25

10

D+ Talc

1:0.25

11

D+ Magnesium Stearate

1:0.25

12

D+ Hydrogenated Castor oil(Cutina HR)

1:0.25

13

D+ Sodium Stearyl Fumarate

1:0.25

Standard curve for Alfuzosin HCL was observed in 0.01N Hcl.

 

FORMULATION DEVELOPMENT:

INNOVATOR PRODUCT CHARACTERISATION:

Innovator product characterization of XATRAL XL 10mg prolonged release               tablets (Alfuzosin HCl ER tablets) 10mg.

S. No

Parameters

Results

1

Description

Round bewail edged trilayer tablets with two layers, outer layers in yellow color and middle colorless layer.

2

Innovator

Sanofi Aventis, UK

3

Strength

10mg

4

Shape

Round

5

Size(mm)

8.05mm

6

Thickness(mm)

7.01mm,7.00mm

7

Hardness(kp)

7.7kp, 6.9kp

8

Color

Two yellow color layers and one colorless layer

9

Average weight

362.3mg

10

Label claim

Each tablet contains 10mg of Alfuzosin HCl in a sustained release formulation

11

Pack

Blister

12

Water by KF(%w/w)

4.51

13

Assay(%w/w)

101.7

 

TABULATION AND GRAPHS:                                                                                                          

Preformulation Studies of API:

s.No

API Characterisation

results

1

Physical Appearance

White, hygroscopic and crystalline powder

2

Bulk density

0.184

3

Tapped Density

0.328

4

Carr’s index

43.82

5

Haussner’s Ratio

1.8

6

Particle size Distribution

D10

D50

D90

7.7

20.8

52.4

7

Solubility

Solvent media

Solubility

0.01n HCl PH=2

192( mg/ml)

Acetate buffer PH .=4.5

172( mg/ml)

Phosphate buffer PH=6.8

159( mg/ml)

Phosphate buffer PH.=10

123( mg/ml)

 

CONCLUSION:

The value of compressibility index above 25%, 15-25%, less than15% indicate poor flowability, optimum flowability and high flowability respectively. As Alfuzosin hydrochloride value is more than 25% it exhibits poor flow5.

 

10.2 Preformulation studies of formulations

(I)Physical parameters of the blend:

S.No

Parameter

AFZ

(F001)

AFZ

(F002)

AFZ

(F003)

AFZ

(F004)

1

Bulk density

(gm/ml)

0.345

0.359

0.342

0.361

2

Tap density

0.467

0.462

0.480

0.500

3

Compressibility index

28.52%

28.61%

28.76%

27.71%

4

Hausner ratio

1.407

1.381

1.403

1.383

 

 


Physical parameters of the blend:

S. No

Parameter

AFZ (F005)

AFZ (F006)

AFZ (F007)

AFZ (F008)

1

Bulk density(gm/ml)

0.341

0.334

0.355

0.334

2

Tap density

0.469

0.464

0.501

0.473

3

Compressibility index

27.273%

27.907%

29.070%

29.310%

4

Hausner ratio

1.375

1.387

1.410

1.415

 

Particle size distribution:

S. No

Sieve No

% Retentions

(AFZF001)

% Retentions

(AFZF002)

% Retentions

(AFZF003)

% Retentions

(AFZF004)

1

#20

3.1%

3.8%

2.4%

3.5%

2

#40

9.5%

10.6%

9.6%

9.5%

3

#60

8.0%

7.6%

8.8%

8.5%

4

#80

10.0%

9.2%

6.4%

9.0%

5

Receiver

69.4%

68.8%

72.8%

69.5%

 

Particle size distribution:

S.No

Sieve  No

% Retentions

(AFZF005)

% Retentions

(AFZF006)

% Retentions

(AFZF007)

% Retentions

(AFZF008)

1

#20

4.0%

2.0%

3.2%

3.5%

2

#40

11.2%

9.2%

9.2%

12.5%

3

#60

8.0%

8.0%

8.0%

7.5%

4

#80

10.0%

10.8%

8.8%

6.5%

5

Receiver

66.8%

70.0%

70.8%

70.8%

 

Compression parameters:                                                                                                                                                                                                                  

S.No

Parameters

AFZ(F001)

AFZ(F002)

AFZ(F003)

AFZ(F004)

1

Description

White to off white colored round shaped tablet

White to off white colored round shaped tablet

White to off white colored round shaped tablet

White to off white colored round shaped tablet

2

Tooling

8.8mm round shaped

8.8mm round shaped

8.8mm round shaped

8.8mm round shaped

3

Weight of 10 tablets(gm)

3.4910

3.5210

3.5108

3.5193

4

Weight of individual tablets(mg)

348.8, 351.9, 349.4, 346.4, 348.4

348.8, 351.9, 349.4, 346.4, 348.4

349.9, 351.5, 351.6, 351.6

349.0, 352.2, 353.0, 347.0

5

Hardness(kp)

9.7, 9.1, 9.4, 10.6, 9.5

12.1, 10.6, 11.0, 10.9, 10.8

9.7, 9.1, 9.4, 10.6, 9.5

9.5, 9.6, 9.6, 9.0, 10.2

6

Thickness(mm)

5.45-5.57

5.65-5.75

5.70-5.75

5.65-5.75

7

Friability(%w/w)

0.13%

0.15%

0.14%

0.15%

 

Compression parameters:                                               

S.No

Parameters

AFZ(F005)

AFZ(F006)

AFZ(F007)

AFZ(F008)

1

Description

White to off white colored round shaped tablet

White to off white colored round shaped tablet

White to off white colored round shaped tablet

White to off white colored round shaped tablet

2

Tooling

8.8mm round shaped

8.8mm round shaped

8.8mm round shaped

8.8mm round shaped

3

Weight of 10 tablets(gm)

3.538

3.4916

3.4916

3.4930

4

Weight of individual tablets(mg)

357.3, 356.5, 355.8, 360.2

352.7, 351.2, 348.4, 348.7, 349.3

352.7, 351.2, 348.4, 348.7, 349.3

348.8, 351.9, 349.4, 346.4, 348.4

5

Hardness(kp)

12.2, 11.6, 11.7, 12.2, 10.7

12.1, 10.6, 11.0, 10.9, 10.8

12.1, 10.6, 11.0, 10.9, 10.8

11.2, 10.7, 10.6, 12.0, 10.7

6

Thickness(mm)

5.45-5.57

5.30-5.40

5.30-5.40

5.45-5.55

7

Friability(%w/w)

0.13%

0.13%

0.13%

0.15%


 

Solubility conclusion:

The solubility of Alfuzosin hydrochloride drug substance in phosphate buffer of PH. =10 is about 123(mg/ml). Calculated dose solubility volume 10 mg(highest strength)/ 123( mg/ml)=0.08 ml < 250ml.

 

Therefore Alfuzosin hydrochloride is considered a highly soluble drug according to the Biopharmaceutical classification system6.

 

FORMULATION TRAILS:

Initial trails started for Alfuzosin HCl ER tablets 10mg using  with some of the excipients similar to brand product  the formulation details are below

 

Dissolution studies on innovator product:

Based on office of generic drugs recommendations the following dissolution condition was selected for evaluation purpose.


Alfuzosin HCl (mg)

Microcrystalline cellulose (mg)

Hydroxyl propyl methyl cellulose (mg)

Guar gum (mg)

Xantham gum (mg)

Silica, colloidal anhydrous (mg)

Magnesium stearate (mg)

Purified water (mg)

10

234 .00

100.00

-

-

2.00

4.00

Q.S

10

229.00

105.00

-

-

2.00

4.00

Q.S

10

204.00

100.00

30.00

-

2.00

4.00

Q.S

10

194.00

105.00

300

-

2.00

4.00

Q.S

10

184.00

110.00

40.00

-

2.00

4.00

Q.S

10

174.00

115.00

45.00

-

2.00

4.00

Q.S

10

154.00

115.00

45.00

20.00

2.00

4.00

Q.S

10

164.00

115.00

45.00

10.00

2.00

4.00

Q.S

 

COMPARATIVE DATA OF VARIOUS FORMULATIONS

S.

NO

INGREDIENTS

F001

(%)

F002

(%)

F003

(%)

F004

(%)

F005

(%)

F006

(%)

F007

(%)

F008

(%)

1

Alfuzosin HCl

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

10.00

(2.85)

2

Microcrystalline cellulose

(vivapur101

234.00

(66.85)

229.00

(65.42)

204.00

(58.28)

194.00

(55.42)

184.00

(52.57)

174.00

(49.71)

154.00

(44.00)

164.00

(46.85)

3

Hydroxyl propyl methyl cellulose (methocel K100 premium)

100.00

(28.57)

105.00

(30.00)

100.00

(28.57)

105.00

(30.00)

110.00

(31.42)

115.00

(32.85)

115.00

(32.85)

115.00

(32.85)

4

Guar Gum(apcol ultra guar)

-

-

30.00

(8.57)

35.00

(10.00)

40.00

(11.42)

45.00

(12.85)

45.00

(12.85)

45.00

(12.85)

5

Xantham gum

-

-

 

-

 

 

-

 

 

   -

 

   -

20.0

(5.71)

10.0

(2.85)

5

Purified water

q.s

q.s

q.s

q.s

q.s

q.s

q.s

q.s

6

Silica, colloidal anhydrous

2.00

(0.57)

2.00

(0.57

2.00

(0.57)

2.00

(0.57)

2.00

(0.57)

2.00

(0.57)

2.00

(0.57)

2.00

(0.57)

7

Magnesium stearate

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

4.00

(1.14)

 

Total weight

350.00

350.00

350.00

350.00

350.00

350.00

350.00

350.00

 

 Dissolution profile in 0.01N Hcl, pH 4.5 Acetate buffer, pH 6.8 phosphate buffer:

Dissolution media

0.01N Hcl

pH 4.5 Acetate buffer

pH 6.8 phosphate buffer

Volume

900ml

900ml

900ml

Apparatus

Paddle(with sinkers)

Paddle(with sinkers)

Paddle(with sinkers)

Speed

100 rpm

100 rpm

100 rpm

Time

1,2,6,12,20 hrs

1,2,6,12,20 hrs

1,2,6,12,20 hrs

 

Dissolution profile:

Product

% Drug released

1hr

2hr

6hr

12hr

20hr

Cummulative % drug release of Xatral XL prolonged release tablets 10mg in 0.01N Hcl

20

28

52

80

97

Cummulative % drug release of Xatral XL prolonged release tablets 10mg in pH 4.5 Acetate buffer

19

28

52

81

98

Cummulative % drug release of Xatral XL prolonged release tablets 10mg in pH 6.8 phosphate buffer

17

24

40

57

74

 

 


Dissolution profiles of innovator in 0.01N HCl, pH 4.5 Acetate buffer, pH 6.8 Phosphate buffer:

 

CONCLUSION:

From the innovator product characterization and dissolution studies the following conclusions were drawn.

     Xatral XL 10mg prolonged release tablets (Alfuzosin Hcl ER tablets)  are trilayered tablets with drug layer in one of the layers and polymers in other two layers7.

     Xatral XL 10mg prolonged release tablets show 20% drug release in 1st hour,28.0%  drug release in 2nd hour, 52.0% drug release in 6th hour, 80.0% drug release in 12th hour, 97.0% drug release in 20th hour8.

     Xatral XL 10mg prolonged release tablets assay value is 101.7%.

 

Dissolution profiles of Formulations Developed:

Medium

0.01N Hcl

pH 6.8 phosphate buffer

Volume

900 ml

900 ml

Speed

100 rpm

100 rpm

Apparatus

Paddle with sinkers

Paddle with sinkers

 

Dissolution profile of innovator, F001, F002

 

Dissolution profile of innovator, F003, F004, F005

 

 


Dissolution profile: Monolithic tablet Formulation

Product

% Drug released

1hr

2hr

6hr

12hr

20hr

Cumulative % drug release of Xatral XL prolonged release tablets 10mg

20

28

52

80

97

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F001)

30

42

66

88

100

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F002)

28

40

68

85

98

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F003)

24

36

62

84

95

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F004)

24

34

61

80

95

Cummulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F005)

21

31

55

76

91

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F006)

20

30

54

74

90

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg (AFZ F007)

17

26

48

68

85

Cumulative % drug release of Alfuzosin HCl ER tablets 10mg  (AFZ F008)

18

28

50

70

86

 


F001:  the monolithic matrix tablets have shown faster dissolution than brand which could be reduced by increasing the polymer(HPMC) concentration

 

F002 the monolithic matrix tablets have shown faster dissolution than brand which could be reduced by increasing the polymer(HPMC) concentration and add the guar gum 

 

F003: In this strategy the monolithic matrix tablets with guar gum have shown faster dissolution than brand which could be reduced by increasing the polymer concentration.

 

F004: In the second strategy the monolithic matrix tablets with guar gum of AFZF004 have shown faster dissolution than brand which could be reduced by increasing the polymer concentration from 35mg/tablet to 40mg/ tablet and HPMC from 105-110mg/tablet compared to AFZ F004.

 

F005: Almost same dissolution profiles were observed with AFZ F005 batches.  monolithic tablet formulation development was continued.

 

F006: Almost same dissolution profiles were observed with AFZ F006 batches. So further development of monolithic tablet was carried out by using another rate controlling polymer xanthan gum.

 

F007: The dissolution profiles of AFZ F007 were slower when compared to brands dissolution profile which could be improved by using less polymer concentration

 

F008: AFZ F008 batch with xanthan gum 10mg/tablet showed comparable dissolution profile with the brand product, so this formula was finalized for execution of batches

 

DISSOLUTION CHROMATOGRAMES BY HPLC

 

Dissolution profile comparison (similarity and dissimilarity factors):

Time

(hrs)

Innovator

Trail F008

Rt-Tt

(Rt-Tt)2

F2=58.56

1

20

18

-2

4

2

28

28

0

0

6

52

50

-2

4

12

80

70

-10

100

F1 =10.12

20

97

86

-11

121

 

Sum=277

Sum=252

Sum=-25

Sum=229

 

FORMULAS:

F1 = {[ Σn t=1 (Rt-Tt)] / Σn t=1 Rt } ×100

F2 =50×log{[1+(1/n)  Σn t=1 (Rt-Tt)2]×100}

 

RESULTS:

Similarity factor (F2) = 58.56

Dissimilarity factor (f1) =10.12

 

Drug excipient compatibility study:  

CONCLUSION:

There was no interaction between drug and polymers, drug and excipients. So the selected excipients were found to be compatible with Alfuzosin Hydrochloride10

 

DRUG EXCIPIENT COMPATABILITY STUDIES:            

FTIR Graphs:

 

IR spectrum of Alfuzosin HCl

 

IR spectrum of HPMC K 100M:

 

IR spectrum of optimized formulation (F008):

 

CONCLUSION:                                                                                                                     

The main objective of present investigation is to formulate and evaluate Alfuzosin ER tablets10mg. The dissolution profile was found to be influenced by concentration of polymer. The ideal extended release formulation should release NLT 75% of drug in 0.01N Hcl within 24 hrs11.

 

The formulation prepared with Guar Gum, Xanthan Gum and HPMC K100 M as polymers yielded the required release of Alfuzosin HCl. Stability studies were studied for optimized formulation and dissolution studies and assay conducted for optimized formulations after stability studies12.Release kinetics was studied for all formulations and drug release followed first order in all cases and the mechanism of drug release followed Higuchi mechanism. The selected formulation AFZF008 was compared with the marketed formulation (XATRAL). The comparison of final optimized product with innovator was done by using similarity factor (F2) and dissimilarity factor (F1).

 

REFERENCES:

1)      Leon Lachman, Herbert A. Libermann, The Theory and practice of industrial pharmacy; 3rd ed, pp.293-302.

2)      Robinson and Lee; Controlled drug delivery; fundamentals and applications, 2nd ed. Marcel Dekkar; New York :1978.pp 24-26

3)      Brahmankar DM, Jaiswal.SB. Biopharmaceutics and Pharmacokinetics A Treatise. 1st Edition.

4)      Chein YW. Novel Drug Delivery Systems.2nd edition: Marcel Dekker; New York.

5)      Pharmainfo.net ER Tablet; An Important Tool for Oral Controlled Release Dosage Forms

6)      Banker GS, Rhodes ET. Modern Pharmaceutics. 3rd Edition; Marcel Dekker; Matrix Tablets: An Important Tool for Oral Controlled Release Dosage. New York 1996. pp.678-721

7)      Robinson and Lee; Controlled Drug Delivery, 2nd Edition. pp: 12-31.

8)      S.J. Carter, Powder flow and Compaction, Cooper and Gunn’s Tutorial Pharmacy 6th edition, CBS Publishers and Distributers, New Delhi, 217, 2000. 

9)      Pharmapedia.com. Tablet: Manufacturing methods-granulation- pharmapedia.htm. 

10)    Dilip M. Parikh, “Theory of Granulation,” Hand book of Pharmaceutical Granulation Technology, Marcel Dekker INC, New York, pp.8, 15, 16,152.

11)    Swarbrick J, Boylan J.C, “Granulation”, Encyclopaedia of   Pharmaceutical Technology, Marcel Dekker INC, New York, 1992, vol-7, pp-121-123.

12)    Aulton M.E, 2nd ed, Granulation Pharmaceutics; The Science of Dosage Form Design, Churchill Livingstone, Edin Burgh, Second Edition, pp. 187,188.

 

 

Received on 14.10.2013       Modified on 15.12.2013

Accepted on 28.01.2014     ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. and Tech. 6(2):April- June  2014; Page 91-98