9 Formulation, optimization and evaluation of sustained release...

Chapter 9 Formulation and evaluation of sustained release atenolol

Modi Darshan A. 126 Ph.D Thesis

9 Formulation, optimization and evaluation of sustained release layer of atenolol

Atenolol is a cardioselective β-blocker widely prescribed for asymptomatic condition

such as hypertension. It is poorly absorbed from the lower gastrointestinal tract. The

oral bioavailability of atenolol was reported to be 50%.1 The human jejunal

permeability and extent of absorption is low.2 Thus, it seems that an in gastric

residence time may increase the extent of absorption and bioavailability of drug. The

recommended adult oral dosage of atenolol is 50 mg twice daily for the effective

treatment of hypertension. However, fluctuations of drug concentration in plasma may

occur, resulting in side effects or a reduction in drug concentration at receptor side. As

the drug is effective when the plasma fluctuations are minimized, therefore sustained

release dosage form of atenolol is desirable. The short biological half life of drug (6 to

8 hr) also favors development of sustained release formulations.

There are several approaches have been reported for prolonging the residence time of

drug delivery system in a particular region of the gastrointestinal tract, such as

floating drug delivery systems, swelling and expending systems, polymeric

bioadhesive systems, swelling and expanding systems, modified shape systems, high

density systems and other delayed gastric emptying devices.3 The objective of the

present investigation is to formulate floating sustained release tablets of atenolol to

increase the gastric retention for better absorption and extend the drug release up to 12

hr.

9.1 Experimental material

Atenolol was a gift sample from Zydus Cadila HealthCare Ltd, All HPMC grade

polymers were procured from Chemdyes Corporation, Ahmedabad. All other

chemicals and reagents used were of analytical grade.

9.2 Preparation of atenolol as sustained release layer4

Atenolol was prepared as sustained release by using hydrophilic polymer hydrophobic

polymers as well as natural polymers. Wet granulation method was employed by

using organic solution Iso Propyle Alcohol (IPA) as a vehicle and Poly Vinyl

Pyrolidine K–30 (PVP K- 30) as a binder. Hydrophilic polymer Hydroxy Propyle

Methyle Cellulose (HPMC) of different viscosity grades was selected as hydrophilic

polymer, Eudragit RSPO and Carbopol were selected as hydrophobic polymers and

Xanthan gum and Guar gum were selected as natural polymers to retard the release

rate.



Table 9.1: Preliminary screening of formulation of sustained release layer of

atenolol using natural, hydrophillic and hydrophobic polymers

Ingredients

(mg)

Batches

SR1 SR2 SR3 SR4 SR5 SR6

Atenolol 50 50 50 50 50 50

HPMC K4M 30 - - - - -

HPMC K100M - 30 - - - -

Carbopol - - 30 - - -

Guar gum - - - 30 - -

Eudragit RSPO - - - - 30 -

Xanthan gum - - - - - 30

PVP K-30 15 15 15 15 15 15

DCP 200 200 200 200 200 200

Mg stearate 5 5 5 5 5 5

IPA Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Total 300 300 300 300 300 300

Table 9.2: Preliminary screening of formulation of sustained release layer of

atenolol using hydrophilic polymers

Ingredients

(mg)

Batches

SR7 SR8 SR9 SR10

Atenolol 50 50 50 50

HPMC K4M 60 90 - -

HPMC K100M - - 60 90

PVP K-30 15 15 15 15

DCP 170 140 170 140

Mg stearate 5 5 5 5

IPA Q.S. Q.S. Q.S. Q.S.

Total 300 300 300 300

Accurately weighed atenolol, polymers and Dibasic Calcium Phosphate (DCP) were

passed through 20 # sieve. Slurry of PVPK - 30 IP (5 % w/w) was prepared in IPA by

gentle stirring. All the above ingredients were mixed for 15 minutes. The paste was



added slowly in above mixer and made the lumpy mass. The prepared mass was

passed with sieve # 12 and dried it at 40oC for 1 h in an oven. Then passed this dried

mass through sieve # 20. After mixing, mg. stearate (20#) was added and mixed for 5

min. The prepared blend was compressed using 12 mm concave punch in rotary tablet

press machine.

9.3 Development of floating system5

Floating system was developed using gas generating agent. Different concentration of

sodium bicarbonate along with citric acid was used as gas generating agent.

Accurately weighed atenolol, HPMC K100M, sodium bicarbonate, citric acid and

DCP were passed through 20 # sieve. Slurry of PVP K-30 IP (5% w/w) was prepared

in IPA by gentle stirring. All the above ingredients were mixed for 15 min. The paste

was added slowly in above mixer and made the lumpy mass. The prepared mass was

passed with sieve # 12 and dried it at 40oC for 1 h in oven. Then passed this dried

mass through sieve # 20. After mixing, Mg. stearate (20#) was added and mixed for 5

min. The prepared blend was compressed using 12 mm concave punch in rotary tablet

press machine.

Table 9.3: Preliminary screening of gas generating agent

Ingredients

(mg)

Batches

FL1 FL2 FL3 FL4 FL5

Atenolol 50 50 50 50 50

HPMC K100M 90 90 90 90 90

Xanthan gum - - - - 60

Sod.bicarbonate 30 45 60 45 45

Citric acid - - - 30 30

PVP K30 (5%) 15 15 15 15 15

DCP 110 95 80 110 5

Mg stearate 5 5 5 5 5

IPA Q.S. Q.S. Q.S. Q.S. Q.S.

Total 300 300 300 300 300



9.4 Optimization of tablet formulation using 32full factorial design6

A statistical model incorporating interactive and polynomial terms was used to

evaluate the responses.

Y = b0 + b1X1+b2X2 + b12X1X2 + b11X12 +b22X2

2 [9.1]

Where, Y is the dependent variables, b0 is the arithmetic mean response of the nine

runs, and b1 is the estimated coefficient for the factor X1.

The main effects (X1 and X2) represent the average result of changing one factor at a

time from its low to high value. The interaction terms (X1X2) show how the response

changes when two factors are simultaneously changed. The polynomial terms (X1and

X2) are included to investigate non-linearity. HPMC K100M (X1) and sodium

bicarbonate (X2) were selected independent variables. The preparation and evaluation

method for tablets and amount of atenolol were kept constant for all trials.

A 32 randomized full factorial design was utilized in the present study. In this design

two factors were evaluated, each at three levels, and experimental trials were carried

out at all nine possible combinations. The design layout and coded value of

independent factor is shown in Table.

The factors were selected based on preliminary study. The concentration of HPMC

K100M (X1) and concentration of Sodium bicarbonate (X2) were selected as

independent variables.

Table 9.4: Full factorial design layout

Batch code X1 X2

F1 -1 -1

F2 -1 0

F3 -1 1

F4 0 -1

F5 0 0

F6 0 1

F7 1 -1

F8 1 0

F9 1 1



Model is fitted by carrying out multiple regression analysis and F-statistics to identify

statistically significant terms. The time required for 50% drug release (t50), release at

15 min (Q15), release at 360 min (Q360), FLT, and time required for 75% drug release

(t75) were selected as dependent variables.

Table 9.5: Coded values for concentration of HPMC K100M and concentration

of sodium bicarbonate

Coded values X1 (HPMC K100M) X2 (NaHCO3)

-1 20% 10%

0 25% 12.5%

+1 30% 15%

Table 9.6: Composition of factorial design batches

Ingredients

(mg)

Batches

F1 F2 F3 F4 F5 F6 F7 F8 F9

Atenolol 50 50 50 50 50 50 50 50 50

HPMC K100M 60 60 60 75 75 75 90 90 90

Xanthan gum 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5 37.5

Sod.bicarbonate 30 37.5 45 30 37.5 45 30 37.5 45

Citric acid 25 25 25 25 25 25 25 25 25

PVP K30 (5%) 15 15 15 15 15 15 15 15 15

DCP 77.5 70 62.5 62.5 55 47.5 47.5 40 32.5

Mg stearate 5 5 5 5 5 5 5 5 5

IPA Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S. Q.S.

Total 300 300 300 300 300 300 300 300 300

9.5 Evaluation of atenolol sustained release tablets7, 8

9.5.1 Physical parameters of atenolol sustained release tablets

As per I.P, prepared atenolol sustained release tablets were evaluated for various

parameters like weight variation test, hardness and friability as per procedure

described in sections 5.3. Results are shown in Table 9.7.



9.5.2 Floating property study9

The time taken for dosage form to emerge on surface of medium is called buoyancy

lag time (BLT). Duration of time for which the dosage form constantly emerges on

surface of medium called Total floating time (TFT). Floating characteristics of the

prepared formulations were determined by using USP 23 paddle apparatus at a paddle

speed of 50 rpm in 900 ml of a 0.1 N HCl solution at 37±0.2°C.

9.5.3 Dissolution studies for sustain release layer10

In-vitro dissolution tests were carried out using USP apparatus type II (ELECROLAB

TDT 06 T, Bombay). The dissolution medium consisted of 900 ml 0.1N HCl for first

two h and then replaced with phosphate buffer 6.8 for rest of the period maintained at

37 ± 0.50C and stirred at 50 RPM. Samples (10 ml) were withdrawn at predetermined

time intervals of 1, 2, 4, 6, 8, 10 and 12 hr. Equal amount fresh dissolution medium,

maintained at same temperature, was replaced immediately. Samples were analyzed

for drug content using UV-Visible spectrophotometer at 271 nm. It was made clear

that none of the ingredients used in the matrix formulation interfered with the assay.

Percentage drug release was computed from prepared standard curve. The release

study was conducted in the triplicate and mean values were plotted.

9.5.4 Swelling studies of sustain release layer

The extent of swelling was measured in terms of percentage weight gain by the tablet.

The swelling behaviors of the formulations were studied. One tablet from each

formulation was exposed to pH 6.8 phosphate buffers. At the end of 1 h, tablet was

withdrawn, soaked with tissue paper and weighed. Then for every 2 hr, weight of the

tablets were noted and the process continued till the end of 12 hr. Percentage weight

gain by the tablet was calculated using the formula.

S.I = (Mt -Mo/Mo×100)

Where, S.I = swelling index,

Mt = weight of tablet at time‘t’,

M0 = Initial weight of tablet.

9.5.5 Kinetic analysis11-16

Atenolol sustained release tablets were evaluated for kinetic analysis as per

description of section 6.3.4.



9.6 Results and discussion

9.6.1 Physical parameters

Table 9.7: Evaluation of physical parameters of formulations SR1-SR6

Batches

Evaluation parameters

Thickness

± S.D.

(mm)

(n = 5)

Hardness

± S.D.

(kg/cm2)

(n = 5)

Friability

(%)

(n = 10)

Weight

variation

(mg)

(n =20)

Drug

content

(%)

SR1 3.36 ± 0.03 4.9 ± 0.5 0.344 304.2 ± 10.2 96.24

SR2 3.35 ± 0.04 4.8 ± 0.8 0.298 305.4 ± 7.1 98.92

SR3 3.36 ± 0.02 4.9 ± 0.4 0.245 305.8 ± 5.4 101.5

SR4 3.32 ± 0.01 4.8 ± 0.7 0.156 301.3 ± 4.5 98.98

SR5 3.32 ± 0.04 4.8 ± 0.5 0.112 300.3 ±3.7 97.90

SR6 3.28 ± 0.02 4.8 ± 0.3 0.221 301.5 ± 8.1 99.52

For preliminary screening, atenolol sustained release layer was prepared using

different properties of polymers comprised of 6 batches. These all 6 different

formulations were evaluated for some pharmocotechnical physical characteristics like

weight variation, hardness, thickness and friability. After evaluating it was found that

none of the formulation deviated more than 5% of an average weight. It confirmed the

pharamcoepial limits for the same test. It was laso observed that friability of all the

formulations were below 1%, which also confirmed the specifications. Hardness was

found very even in all formulations.

After preliminary screening, tablets prepared using 20 and 30% concentration of

HPMC K4M and HPMC K100M as shown in table 9.7 and evaluated for hardness,

weight variation, friability and drug content. The average weight of tablet

formulations was within the range of 301-304 mg. So, all tablets passed weight

variation test as the weight variation was within the pharmacopoeial limits of 5% of

the weight. The weight of all the tablets was found to be uniform with low standard

deviation values. Hardness of all the batches was in the range of 4.8-4.9 kg/cm2 which

ensure good handling characteristic of all batches. The friability was less than 1% in



all the formulations ensuring that the tablets were mechanically stable. Drug content

for all the batches was found within the pharmacopoeial limits.

Table 9.8: Evaluation of physical parameters of batches SR7-SR10

batches


Thickness ±

S.D. (mm)

(n = 5)

Hardness

± S.D.

(kg/cm2)

(n = 5)

Friability

(%)

(n = 10)

Weight

variation

(mg) ± S.D.

(n =20)

Drug

content

(%)

SR7 3.34 ± 0.03 4.9 ± 0.3 0.424 301.5 ± 12.1 104.24

SR8 3.34 ± 0.04 4.9 ± 0.5 0.327 301.3 ± 7.7 101.92

SR9 3.35 ± 0.03 4.9 ± 0.3 0.431 304.7 ± 13.2 101.5

SR10 3.34 ± 0.02 4.8 ± 0.4 0.289 303.2 ± 10.2 99.78

After optimization of concentration of sustain release polymer i.e. HPMC K100M

attempt was made to prepare atenolol floating tablet using different concentration of

sodium bicarbonate alone as well as combination of it with citric acid. Prepared

batches were evaluated for floating lag time and other physical parameters

Table 9.9: Evaluation parameters of preliminary screening of floating approach

Batches


Thickness

± S.D.

(mm)

(n = 5)

Hardness

± S.D.

(kg/cm2)

(n = 5)

Friability

(%)

Wt

variation

(mg) ± S.D.

(n=20)

Drug

content

(%)

FLT

(min)

FL1 3.24 ± 0.02 4.9 ± 0.2 0.524 302.3± 2.2 98.24 36

FL2 3.32 ± 0.05 4.8 ± 0.3 0.627 302.5± 1.2 100.92 28

FL3 3.32 ± 0.02 4.9 ± 0.3 0.531 304.7± 2.5 99.54 24

FL4 3.34 ± 0.03 4.9 ± 0.4 0.589 303.1± 1.8 97.78 1.3*

FL5 3.20 ± 0.01 4.9 ± 0.2 0.427 301.8±2.7 95.63 1.5

*Complete erosion of tablet.



The average weight of tablet formulations was within the range of 302-304 mg. So, all

tablets passed weight variation test as the weight variation was within the

pharmacopoeial limits of 5% of the weight. The weight of all the tablets was found to

be uniform with low standard deviation values. Hardness of all the batches was in the

range of 4.8-4.9 kg/cm2 which ensure good handling characteristic of all batches. The

friability was less than 1%. All the batches were evaluated for floating property. Here

tablets prepared using Sodium bicarbonate alone has FLT within 24-36 min in which

FL3 batch shows least FLT because of higher concentration of Sodium bicarbonate

while it is highest in tablets prepared using less concentration of Sodium bicarbonate

i.e. 36 min in batch FL1. FLT more than 15 min was not desirable so to decrease the

FLT combination of Sodium bicarbonate and citric acid was used in batch FL4 which

shows FLT of 1.3 min.

9.6.2 In-vitro dissolution profile of atenolol

Table 9.10: Drug release profile of batches SR1-SR6

Time (h) Cumulative Drug Release (%)

SR1 SR2 SR3 SR4 SR5 SR6

0 0 0 0 0 0 0

1 82.43 ±0.17

65.85 ±0.63

51.65 ±0.34

62.40 ±0.33

53.82 ±0.23

56.71 ±0.23

2 91.03 ±0.49

86.74 ±0.69

74.11 ±0.40

80.68 ±0.53

74.03 ±0.49

74.96 ±0.53

4 97.48 ±0.51

93.08 ±0.54

97.13 ±0.59

98.25 ±0.47

96.51 ±0.45

92.47 ±0.41

6 98.07 ±0.48

98.36 ±0.87

100.88 ±0.39

98.90 ±0.36

99.38 ±0.53

98.07 ±0.50

All values are expressed as mean ± standard deviation, n=3.

Tablets prepared using 10% concentration of HPMC K4M, carbopol and guar gum

can sustained the drug release up to 5 hr while tablets prepared using HPMC K100M,

eudragit and xanthan gum can sustained the drug release up to 6 hr. Formulation

prepared using eudragit does not show swelling during dissolution study because of

hydrophobic nature of eudragit while tablets prepared using carbopol tend to stick at

the bottom of the dissolution apparatus as carbopol has mucoadhesive property so

chances of adhesion of floating tablet to the stomach wall prepared using carbopol.

For such reason eudragit and carbopol were not selected for further study. Tablets



prepared using guar gum sustained the drug release up to 5 hr. To sustain the drug

release up to 12 hr higher concentration of guar gum was required and as it is a

natural polymer its property may be differ depending on the manufacturer and

availability of raw material so Guar gum was not selected for further study. Xanthan

gum can sustain the drug release up to 6 hr and has good matrix integrity. So, it may

be used to maintain the matrix integrity of the floating tablet. HPMC K4M in 10 %

concentration sustain drug release up to 5 hr while HPMC K100M sustain the drug

release up to 6 hr as it has a higher viscosity than HPMC K4M, so combination of

both the polymers may be used if HPMC K100M alone cannot sustain the drug

release up to 12 hr.

Figure 9.1: Dissolution profile of atenolol for primary screening

From the in-vitro dissolution study and above mentioned reasons HPMC K4M and

HPMC K100M were selected for further study and tablets were prepared using 20%

and 30% concentration of both and evaluated for drug release study and other

evaluation parameters.

Tablets prepared using 20% concentration of HPMC K4M sustain the drug release up

to 7 hr and release 98.71%, while tablets prepared using 30% concentration of HPMC

K4M could sustain the drug release up to 8 hr and release 96.99% drug after 8 hr.

While tablets prepared using 20% concentration of HPMC K100M could sustain the

drug release up to 11 hr and release 97.26% drug while tablets prepared using 30%

concentration of HPMC K100M released 94.69% drug after 12 hr. So, increase in

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7

Cumulative Drug Re

lease (%

)

Time (hr)

SR1

SR2

SR3

SR4

SR5

SR6



concentration of polymer can sustain the drug release. Viscosity of HPMC K4M was

less compared to HPMC K100M and HPMC K100M can provide the drug release up

to 12 hr. Therefore, HPMC K100M was selected for further study and attempt was

made to prepare floating tablet.

Table 9.11: Dissolution profile of batches SR7-SR10 Time (min)

Cumulative Drug Release (%) SR7 SR8 SR9 SR10

0 0 0 0 0

1 39.13 ±0.50

33.68 ±0.56

22.92 ±0.47

19.07 ±0.45

2 84.60 ±0.49

64.75 ±0.33

35.61 ±0.53

32.18 ±0.35

4 93.20 ±0.23

86.76 ±0.32

52.41 ±0.70

48.47 ±0.31

6 97.62 ±0.56

96.23 ±0.29

64.89 ±0.60

59.95 ±0.46

8 - 96.99 ±0.80

78.08 ±0.55

77.03 ±0.57

10 - - 92.24 ±0.22

88.08 ±0.62

12 - - - 94.69 ±0.56


Figure 9.2: Dissolution profile of atenolol using HPMC as polymer

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cumulative Drug Re

lease (%

)

Time (h)

SR7

SR8

SR9

SR10



9.7 Optimization using 32 full factorial design9

9.7.1 Precompression parameters of factorial formulations

The blend of powder was prepared using all possible formulation of 32 full factorial

design and evaluated for evaluation parameters like Angle of Repose, Bulk density,

Tapped density, Carr’s index and Hausner’s ratio. The method for measurement of

angle of repose, bulk density, tapped density; Carr’s index and Hausner’s ratio are

given in section. Angle of repose of all batches varies from 23.1 to 28.3. Angle of

repose less than 30 indicates good flow property. Compressibility index vary from

17.4% to 25.5 % which shows good to fair compressibility. Hausner’s ratio varies

from 1.25 to 1.34. Hausner’s ratio between 1.2-1.4 indicates good compressibility.

Here all these results showed good flow property and compressibility which is

favorable for tablet compression.

Table 9.12: Evaluation of precompression properties of batches F1-F9

Batches Angle of

repose(θ)

Bulk density

(gm/cm3)

Tapped

density(gm/cm3)

Carr’s

index (%)

Hausner’s

ratio

F1 27.4±1.4 0.58±0.03 0.74±0.01 21.3±1.5 1.34±0.1

F2 25.3±1.4 0.56±0.04 0.72±0.04 24.6±1.3 1.27±0.3

F3 27.0±1.6 0.53±0.07 0.67±0.05 20.8±1.7 1.25±0.4

F4 23.1±1.3 0.56±0.06 0.68±0.04 21.0±1.5 1.31±0.2

F5 24.4±1.7 0.57±0.02 0.73±0.03 22.5±1.4 1.34±0.1

F6 26.2±1.4 0.54±0.03 0.74±0.05 25.5±1.3 1.27±0.6

F7 28.3±1.2 0.58±0.04 0.75±0.04 19.4±1.3 1.29±0.2

F8 27.7±1.5 0.57±0.08 0.75±0.03 17.4±1.6 1.25±0.6

F9 23.1±1.6 0.59±0.06 0.67±0.04 21.4±1.5 1.25±0.1


9.7.2 Physical parameters of factorial formulations

The average weight of tablet formulations was within the range of 300-304 mg. So, all

tablets passed weight variation test as the % weight variation was within the

pharmacopoeial limits of 7.5% of the weight. The weight of all the tablets was found

to be uniform with low standard deviation values. The mean tablet thickness (n=5)

were uniform in all batches with values ranging between 3.30-3.38 mm. These values



thus indicate uniformity within batch and batch to batch. The measured hardness of

tablets of each batch ranged between 4.8-4.9 kg/cm2. This ensures good handling

characteristics of all batches. The friability was less than 1% in all the formulations

ensuring that the tablets were mechanically stable. The percentage drug content of the

all batches was found between 93.16% to 104.5%, which was within acceptable limits

and indicating dose uniformity in each batch.

Table 9.13: Evaluation parameters of formulations F1-F9

Batches


Thickness ± S.D. (mm)

(n = 5)

Hardness ± S.D.

(kg/cm2) (n = 5)

Friability (%)

(n = 10)

Weight variation

(mg) (n=20)

Drug content

(%)

F1 3.32 ± 0.02 4.9 ± 0.4 0.369 302 ± 0.9 98.34

F2 3.34 ± 0.04 4.9 ± 0.7 0.398 304 ± 1.0 98.78

F3 3.35 ± 0.01 4.9 ± 0.5 0.445 304 ± 1.2 104.5

F4 3.32 ± 0.01 4.8 ± 0.7 0.356 301 ±0.6 94.98

F5 3.32 ± 0.03 4.9 ± 0.5 0.214 300 ±0.4 99.93

F6 3.32 ± 0.03 4.8 ± 0.4 0.231 301 ± 0.9 93.52

F7 3.30 ± 0.04 4.8 ± 0.6 0.246 302 ± 0.7 96.94

F8 3.30 ± 0.05 4.8 ± 0.5 0.287 300 ± 1.0 93.16

F9 3.38 ± 0.04 4.9 ± 0.3 0.312 304 ± 0.5 102.1

All values are expressed as mean ± standard deviation

9.7.2 Floating and water uptake studies of factorial formulations

The swelling capacity of HPMC, and gas generated from gas generating agent helped

the tablets to float. On immersion in 0.1N HCl at 37oC, the tablets floated and

remained buoyant without disintegration. All tablets float within 68-95 sec without

sinking. From the results of total floating time it can be concluded that all batches

showed duration of floating between 7 to 12 hr. This may be due to the amount of

hydrophilic polymer.



Table 9.14: Floating and water uptake property of formulations F1-F9

Batches Floating lag time

(Sec) (n=3)

Total floating

time (h)

Water uptake

(%)

F1 95±04 8 273.33

F2 87±05 7 240

F3 81±05 7 266.66

F4 84±01 <12 276.66

F5 79±06 <12 293.33

F6 61±02 11 270

F7 94±05 <12 310

F8 85±05 <12 293

F9 68±01 <12 300

Water uptake study was performed on all the batches for 12 hr. From the results, it

was concluded that swelling increased as time increased because the polymer

gradually absorb water due to hydrophilicity of polymer. The outer most hydrophilic

polymer hydrates and swells and a gel barrier are formed at the outer surface. As the

gelatinous layer progressively dissolves and/or is dispersed, the hydration swelling

release process is repeated towards new exposed surfaces, thus maintaining the

integrity of the dosage form. In the present study, the higher swelling index was found

for tablets of batch F7 containing higher concentration of HPMC K100M (30%).

Thus, the viscosity of the polymer had major influence on swelling process, matrix

integrity, as well as floating capability, hence from the above results it can be

concluded that linear relationship exists between swelling process and viscosity of

polymer.

9.7.3 In-vitro drug release study of factorial formulations

In-vitro drug release data and profile of prepared tablets are shown in table 9.15. In

the present study, HPMC K100M is hydrophilic in nature. In case of hydrophilic

matrix system, drug release involves penetration of solvent into the matrix, hydration

and swelling of the polymer and dissolution of the active ingredients and transfer of

the dissolved drug and soluble matrix components into the bulk.



Table 9.15: Cumulative percentage release of formulation of factorial formulation

Time (h)

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

0 0 0 0 0 0 0 0 0 0 1 54.27

±0.52 55.41 ±0.55

59.76 ±0.41

20.74 ±0.65

22.35 ±0.48

32.81 ±057

15.45 ±0.34

18.66 ±0.56

24.10 ±0.33

2 68.59 ±0.23

69.74 ±0.42

70.04 ±0.39

33.30 ±0.37

33.79 ±0.25

40.00 ±0.59

22.32 ±0.35

23.96 ±0.74

31.92 ±0.74

4 80.69 ±0.39

82.53 ±0.33

83.74 ±0.39

46.38 ±0.41

47.09 ±0.34

55.88 ±0.80

37.54 ±0.43

37.84 ±0.49

43.16 ±0.82

6 91.09 ±0.24

93.19 ±0.66

94.19 ±0.49

58.90 ±0.41

59.63 ±0.26

70.09 ±0.62

47.26 ±0.26

49.15 ±0.59

51.12 ±0.64

8 98.87 ±0.70 - - 73.15

±0.4774.57 ±0.51

83.33 ±0.25

56.85 ±0.56

60.57 ±0.14

63.24 ±0.49

10 - - - 84.82 ±0.64

86.25 ±0.72

93.08 ±0.28

68.81 ±0.24

71.20 ±0.51

75.03 ±0.57

12 - - - 92.98 ±0.46

97.16 ±0.57 - 75.44

±0.52 78.31 ±0.32

85.14 ±0.49

All values are expressed as mean ± standard deviation, n=3

It was observed that drug release decreased with increased concentration of HPMC

K100M. Amongst 12 formulations only 5 batches sustained the drug effect of 12 hr

i.e. F4, F5, F7, F8 and F9. Formulation F7, F8 and F9 were too slow to release as they

released only 75 to 80% drug in 12 hr. From the result, it was concluded that

concentration of hydrophilic polymers HPMC K100M along with xanthan gum was

sufficient to retard the atenolol release up to 12 hr.

Figure 9.3: Dissolution profile of atenolol of factorial formulations

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cumulative Drug Re

lease (%

)

Time (h)

F1

F2

F3

F4

F5

F6

F7

F8

F9



9.7.4 Determination of dependent variables of factorial design formulations

In the present study, a 32 full factorial design was employed for optimization of

Atenol tablets. Optimization was carried out by studying effect of independent

variables, i.e. HPMC K-100M concentration (X1) and sodium bicarbonate

concentration (X2) on dependent variables. Three factorial levels coded for low,

medium, and high settings (−1, 0 and +1, respectively) were considered for three

independent variables. The selected dependent variables investigated were the time

required for 50% drug release (t50), release at 15 min (Q15), release at 360 min (Q360),

FLT, and time required for 75% drug release (t75). The response (Yi) in each trial was

measured by carrying out a multiple factorial regression analysis using the quadratic

model.

A statistical model incorporating interactive and polynomial terms was utilized to

evaluate the responses.

Y = b0 + b1X1+b2X2 + b12X1X2 + b11X12 +b22X2

2 [9.2]

Table 9.16: 32 full factorial design layout for sustained release tablet

Formulation

code

Response

X1 X2 X1

(%)

X2

(%)

FLT

(s)

Q15

(%)

Q360

(%)

T50

(min)

T75

(min)

F1 -1 -1 20 10 95 28.96 91.09 43 176

F2 -1 0 20 12.5 87 30.09 93.19 36 171

F3 -1 1 20 15 81 32.35 94.19 27 159

F4 0 -1 25 10 84 13.34 58.9 284 517

F5 0 0 25 12.5 79 14.70 59.63 276 485

F6 0 1 25 15 61 19.23 70.09 188 397

F7 1 -1 30 10 94 4.29 47.20 392 715

F8 1 0 30 12.5 85 7.01 49.15 373 676

F9 1 1 30 15 68 8.59 51.12 348 603

Check point batch (actual value)

- - 23 13 76 18.60 81.15 172 332

Check point batch (practical value

- - 23 13 74 19.10 83.65 168 341



Where, Y is the dependent variables, b0 is the arithmetic mean response of the nine

runs, and b1 is the estimated coefficient for the factor X1. The main effects (X1 and

X2) represent the average result of changing one factor at a time from its low to high

value. The interaction terms (X1X2) show how the response changes when two factors

are simultaneously changed. The polynomial terms (X12 and X2

2) are included to

investigate non-linearity. Formulation of desired characteristics can be obtained by

factorial design application. The fitted equations for full model relating the responses

of dependent variables were given below:

A. FLT = 76.78 – 2.67 X1 – 10.50 X2 – 3.00 X1X2 + 10.33 X12 – 3.17 X2

2 [9.3]

Time required for floating for batches F1-F9 varies from 68-95 sec and showed

correlation coefficient 0.9775. This showed best fit to model. From the P-value, it was

concluded that X2 has the prominent effect (P<0.05) on FLT than X1. Negative sign of

X1 and X2 in regression equation indicated the response value decreases as the amount

of factor increases.

B. Q15 =15.41 – 11.92 X1 + 2.26 X2 + 0.23 X1X2 + 2.79 X12 + 0.53 X2

2 [9.4]

The amount of drug release at 15 min from batches F1-F9 varies from 4.29%-30.09%

and showed correlation coefficient 0.9967. This showed best fit to model. From the P-

value, it was concluded that X1 has the prominent effect (P<0.05) on Q15 than X2.

Negative sing of X1 in regression equation indicates the response value decreases as

the amount of factor increases and positive sign of X2 indicates response value

increases as the amount of factor increases.

C. T50 = 259.11 + 167.83 X1 – 26.0 X2 – 7.0 X1X2 – 46.17 X12 – 14.67 X2

2 [9.5]

Time required for 50% drug release from batches F1-F9 varies from 27-392 min and

showed correlation coefficient 0.9884. This showed best fit to model. From the P-

value, it was concluded that X1 has the prominent effect (P<0.05) on T50 than X2.

Positive sign of X1 in regression equation indicates the response value increases as the

amount of factor increases and Negative sign of X2 indicates response value decreases

as the amount of factor increases.



D. T75 = 477.11 + 248.00 X1 – 41.56 X2 – 23.75 X1X2 – 49.67 X12 – 16.17 X2

2[9.6]

Time required for 75% drug release from batches F1-F9 varies from 159-715 min and

showed correlation coefficient 0.9968. This showed best fit to model. Positive sign of

X1 in regression equation indicates the response value increases as the amount of

factor increases and Negative sign of X2 indicates response value decreases as the

amount of factor increases.

E. Q360 = 61.91 – 21.82 X1 + 3.02 X2 + 0.19 X1X2 + 8.13 X12 + 1.45 X2

2 [9.7]

The amount of drug release at 360 min from batches F1-F9 varies from 47.20%-

94.19% and showed correlation coefficient 0.9897. This showed best fit to model.

From the P-value, it was concluded that X1 has the prominent effect (P<0.05) on

Q360 than X2. Negative sign of X1 in regression equation indicates the response value

decreases as the amount of factor increases and positive sign of X2 indicates response

value increases as the amount of factor increases.

Check point batch was prepared as shown in Table 9.16 using X1 = 23% (HPMC

K100M concentration) and X2 =13% (sodium bicarbonate concentration). The

observed responses were determined practically and results were compared with

values generated from full model polynomial equation. Comparison of these values

indicates good fit and validationof polynomial equation.

9.7.5 Analysis of variance

Table 9.17: Analysis of Variance for response FLT

Source Sum of Squares

Degrees of

Freedom

Mean Square

F Value

P Value

Model Significant/Non signifi-cant Relative to

Noise

R2

Model 973.78 5 194.76 26.03 0.0112 Significant

0.9775

X1 42.67 1 42.67 5.70 0.047 Significant

X2 661.50 1 661.50 88.42 0.002 Significant

Residual 22.44 3 7.48 - - - Core Total

996.22 8 - - - -



Table 9.18: Analysis of Variance for response Q15


Degrees of

Freedom

Mean Square

F Value

P Value Model Significant/Non

significant Relative to Noise

R2

Model 899.36 5 179.87 183.33 0.0006 Significant 0.9967

X1 852.28 1 852.28 868.6 <0.0001 Significant

X2 30.74 1 30.74 31.33 0.0113 Significant

Residual 2.94 3 0.98 - - - Core Total

902.31 8 - - - -

Table 9.19: Analysis of Variance for response T50


Degrees of

Freedom

Mean Square

F Value

P Value

Model Significant/Non

significant Relative to

Noise

R2

Model 177953.1 5 35590.6 50.96 0.0042 Significant

0.9884

X1 1.690E

+005 1 1.690E

+005 242.0 0.0005 Significant

X2 4056.00 1 4056.00 5.81 0.0350 Significant

Residual 2095.1 3 698.37 - - -

Core Total

180048.2 8 - - - -

Table 9.20: Analysis of Variance for response T75


Degrees of

Freedom

Mean Square

F Value

P Value



Noise

R2

Model 387070 5 77414.0 50.96 0.0006 Significant

0.9968

X1 3.690E

+005 1 3.690E

+005 242.0 0.005 Significant

X2 10333.5 1 10333.5 5.81 0.001 Significant

Residual 1227.6 3 409.18 - - - Core Total 388287.6 8 - - - -



Table 9.21: Analysis of Variance for response Q360

Source

Sum of Squares

Degrees of

Freedom

Mean Square

F Value

P Value



Noise

R2

Model 3048.90 5 609.78 57.92 0.0035 Significant 0.9897

X1 2857.55 1 2857.5 271.44 0.0005 Significant

X2 54.90 1 54.90 5.22 0.0066 Significant

Residual 31.58 3 10.53 - - - Core Total 3080.48 8 - - - -

9.7.6 Contour plot and response surface plot design

Figure 9.4: Contour plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on FLT



Figure 9.4: Contour plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on Q15

Figure 9.6: Contour plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on T50



Figure 9.7: Contour plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on T75

Figure 9.8: Contour plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on Q360



Figure 9.9: Response surface plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on FLT

Figure 9.10: Response surface plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on Q15



Figure 9.11: Response surface plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on T50

Figure 9.12: Response surface plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on T75



Figure 9.13: Response surface plot showing the effect of HPMC K100M (X1) and sodium bicarbonate (X2) on Q360

9.8 Fitting of atenolol sustain release tablet in mathematical kinetic models11-16

Table 9.22: Curve fitting analysis for atenolol sustain release layer

Batch Regression co efficient (R2 )

Zero

order

First

order

Highichi

plot

Korsemeyer plot Hixon Crowell

plot (R2 ) n-value

F1 0.8383 0.7940 0.9304 0.9729 0.250 0.8383

F2 0.7241 0.6914 0.8461 0.9261 0.214 0.7241 F3 0.7430 0.7204 0.8599 0.9377 0.195 0.7430 F4 0.9889 0.9096 0.9942 0.9968 0.597 0.9889 F5 0.9947 0.9293 0.9906 0.9957 0.584 0.9947 F6 0.9588 0.9136 0.9850 0.9865 0.456 0.9588 F7 0.9898 0.9116 0.9941 0.9975 0.651 0.9898 F8 0.9938 0.9379 0.9900 0.9897 0.601 0.9938 F9 0.9975 0.9621 0.9780 0.9828 0.500 0.9975



Dissolution profiles were fitted to various model and release data were analyzed on

the basis of Higuchi kinetics, Zero order, Korsmeyer Peppas equation, Hixon- crowel

and First order. From the Korsmeyer Peppas equation, the diffusion coefficient (n)

ranges from 0.195 to 0.651. Batches F4, F5, F7 and F8 were found to be value more

than 0.5 which indicated the drug release mechanism of anamolous type and rest of

the formulations followed fickian release. Regression Coefficients (R) were used to

evaluate the accuracy of the fit. The R2 values are given in Table 9.22. Drug release

mechanisms follow Zero order, Higuchi order and Korsemeyer kinetic rather than

First order.

9.9 Conclusion

Atenolol tablets were prepared by wet granulation technique using hydrophilic,

hydrophillic and natural polymers such as HPMC K4M, HPMCK100M, carbopol,

eudragit RSPO, guar gum and xanthan gum. All formulations were subjected to

various physical and pharmacotechnical evaluation parameters. From the preliminary

trials HPMC K100M was selected as one of the independent variables as release

retardant polymer because it was able to deliver sustained effect up to 12 hr. Sodium

bi carbonate was selected as other independent variable for better floating properties.

Final strength of tablets was fixed as 300mg incorporating 50mg of drug. A 32

factorial design was adopted to get 9 combinations in each formulation. It was found

that both the independent variables i.e. amount of polymer and amount of gas

generating agent had significant influence on the percentage drug release and

buoyancy time. The floating dual retard tablets were evaluated for various physical

and pharmacotechnical parameters like weight variation, hardness, friability, drug

content, in vitro buoyancy and dissolution studies. Batch F5 (25% HPMC K100M and

12.5% sodium bicarbonate) was considered as sustained release part to prepare dual

retard tablet as it was able to release the drug up to 12 hr with buoyancy. Batch F5

was followed by zero order drug release and diffusion mechanism of dissolution.

9.10 References

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