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).
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The Theory and practice of industrial pharmacy; 3rd ed, pp.293-302.
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ER Tablet; An Important Tool for Oral Controlled Release Dosage Forms
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and Lee; Controlled Drug Delivery, 2nd Edition. pp: 12-31.
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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