CHAPTER 6: FORMULATION AND EVALUATION OF ATENOLOL...

Ph.D Thesis Atenolol Press Coated (HE) Tablet

Rajesh A. Keraliya 129

CHAPTER 6: FORMULATION AND EVALUATION OF

ATENOLOL PULSATILE PRESS COATED TABLETS USING

RUPTURABLE AND ERODIBLE POLYMERS

6.1. INTRODUCTION AND AIM OF THE STUDY

In order to achieve the chronopharmaceutical design for the time controlled pulsatile type

of colon targeted preparations, formulation design to control the lag time is prior to the

immediate release of drug. These systems have a peculiar mechanism of delivering the

drug rapidly and completely after a lag time (a period of no drug release). Though most

delivery systems are designed for constant drug release over a prolong period of time,

pulsatile delivery systems are characterized by a programmed drug release, as constant

blood levels of a drug may not always be desirable. Pulsatile time release systems are

designed in a manner that the drug is available at the site of action at the right time in the

right amount. These systems are beneficial for drugs having high first pass effect, drugs

administered for diseases that follow chronological behavior, drugs having specific

absorption site in GIT, targeting to colon, where night time dosing is required (Sadaphal

et al., 2011).

Atenolol, a β-blocker, is prescribed widely in diverse cardiovascular diseases like;

Hypertension, angina pectoris, arrhythmias, and myocardial infarction. In case of

cardiovascular diseases, several functions (e.g. BP, heart rate, stroke volume, cardiac

output, blood flow) of the cardiovascular system are subject to circadian rhythms. It has

been reported that more shocks and heart attacks occur during morning hours (Shweta et

al., 2008). The level of cortisol is higher in the morning hours, and its release is reported

to decline gradually during the day. Blood pressure is also reported to be high in the

morning till late afternoon, and then drops off during night (Lemmer, 1999). On oral

administration of colon targeted pulsatile drug delivery system at bed time, releases

atenolol after a desired lag time of about 6 – 6.5 hr which corresponds with peak levels of

cortisol, capillary resistance, platelet agreeability and vascular reactivity in the morning

hours, which leads to hypertension in the early hours of the morning.



After oral administration, press coated tablets undergo transit from the stomach to the

cecum or colon. Despite widespread use of pH dependent systems for colon targeted

delivery of drugs, there has always been a controversy about their usefulness for the

intended purpose, mainly because of high pH variability of the gastrointestinal tract

between and within individuals and lack of proper coating materials that would dissolve

at the desired pH of the colon. It is affected by diet and disease. During acute stage of

inflammatory bowel disease colonic pH has been found to be significantly lower than

normal. In ulcerative colitis pH values 2.3—4.7 have been measured in the proximal parts

of the colon (Ashish et al., 2009). This disadvantage was overcome by developing time

dependent rupturable and erodible type press coated pulsatile colon targeted drug

delivery using combination of hydrophilic and hydrophobic polymer.

Hydroxypropylmethylcellulose (HPMC) is a well known water-soluble polymer that has

long been used as a rate-controlling membrane in medication dosage forms to regulate

drug release. HPMC has an ability to swell upon gellification once in contact with water.

The gel becomes a viscous layer around a core, acting as a protective barrier to both the

influx of water and the efflux of the drug in solution (Kiil and Dam, 2003). HPMC K4M

has a swelling, viscous property of gelation and an erosion property which might delay

the drug release because of lengthening of the drug diffusion pathway and drug release

rate. This hydrophilic polymer is responsible for rupturing the outer coat (Andrea et al.,

2008). Hydrophilic polymer (HPMC K4M) alone for controlling the drug release of

highly water soluble drugs like atenolol is restricted due to rapid diffusion of the

dissolved drug through the hydrophilic gel layer (Lin et al., 2004). Use of hydrophobic

polymers such as Ethyl cellulose with HPMC K4M will retard the drug release. So, in the

present investigation, an attempt has been to formulate time controlled pulsatile release

tablets of atenolol using hydrophilic polymer (HPMC K4M) in combination with

hydrophobic polymer (EC). Ethylcellulose (EC) is a semipermeable in nature, although it

is naturally insoluble in water, has been used as a rate-controlling membrane to regulate

drug release. EC has been directly compressed to form compact film in which plastic

deformation is the predominant consolidation mechanism (Liberman et al., 1990). Ethyl

cellulose exhibiting a porous structure, it controls the diffusion of the water inside the

coating layer of HPMC K4M, kept integrity of sweallbale layer of HPMC K4M and the



retard the drug release. When the barrier layer containing HPMC K4M along with ethyl

cellulose was exposed to dissolution media, the HPMC K4M particles swell and erode

which is responsible for breakdown of outer coating, a process which was retarded to

varying degrees depending upon the quantity of EC present, demonstrating that

manipulation of both components controls the erosion rate (Rubinstein et al., 1997).

The purpose of this study was to develop press coated tablets for pulsatile drug delivery

of atenolol by achieving the pH independent time-controlled disintegrating or rupturing

function with a distinct predetermined lag time. The rapidly disintegrating inner core

tablets containing atenolol and other excipients were compression coated by a barrier

layer consisting of mixture of different weight ratios of hydrophobic polymer

(ethylcellulose) and hydrophilic polymers (HPMC K4M) to avoid drug release in gastric

and intestinal fluids. Ethyl cellulose was chosen because of its rupturable behavior and

HPMC K4M was chosen because of its swelling and erodible behavior.

6.2. PREPARATION OF ATENOLOL CORE (AT2) TABLETS

The core tablets of atenolol (AT2) were prepared by direct compression method. An

optimized core tablet was formulated using various concentrations of dry binder and

super disintegrant as describe in table 21. An accurately weighed quantity of atenolol,

microcrystalline cellulose, polyvinyl pyrroloide (PVP K30) and sodium starch glycolate

pass through 40# and mix in double cone blender for 15 min. Add talc (2% w/w) (40#)

into blend and mix in double cone blender for 10 min. Add magnesium stearate (1% w/w)

(40#) into blend and mix in double cone blender for 5 min. The resultant powder

mixtures were compressed into tablets (average tablet weight = 80 mg) by 6 mm standard

concave plain punches using rotary tabletting machine (Hardik Engineering Works,

Ahmedabad, India). The prepared atenolol core tablets were tested for weight variation,

hardness, thickness, drug content, disintegration time, friability and in vitro dissolution

study (Sawada et al., 2003, Mayur et al., 2009, Gang et al., 2004).

6.3. PREPARATION OF ATENOLOL PRESS COATED (HE) TABLETS

The core tablets were compression coated with 150 mg of coating material containing

different weight ratios of HPMC K4M and EC. The weight ratios of HPMC K4M and EC



were used for the compression coating shown in table 22. Weigh accurately 150 mg of

coating material, add talc (2% w/w) (40#) into it and mix in double cone blender for 10

min. Add magnesium stearate (1% w/w) (40#) into blend and mix in double cone blender

for 5 min. 43 % of (64.5 mg) weight of coating material was first placed into die cavity

(diameter 9 mm). Then, the core tablet was carefully placed on it manually at the centre

of the die. The remaining 57 % of (85.5 mg) of the coating materiel was added into the

die and the coating material was then compressed around the core tablet by 9 mm

standard concave plain punches using rotary tabletting machine (Cadmach Machinery,

Ahmedabad, India). The prepared compression coated atenolol tablets were tested for

weight variation, hardness, thickness, drug content, friability and in vitro dissolution

study (Chickpetty et al., 2010, Soad et al., 2009, Krishnaiah et al., 2003).

Table 21: Composition of atenolol core (AT2) tablet

Ingredients Quantity for each tablet (mg)

Atenolol (API) 45 mg

Sodium Starch Glycolate (SSG) (5%) 4 mg

Polyvinyl pyrollidone K30 (PVP K30) (5%) 4 mg

Microcrystalline Cellulose (MCC) 24.6 mg

Talc (2%) 1.6 mg

Mg Stearate (1%) 0.8 mg

Total Weight 80 mg

Table 22: Formulations of atenolol press coated (HE) tablets

Formulation code Core tablet HPMC K4M : EC ratio (mg)

HE1 A2 150 : 00

HE2 A2 125 : 25

HE3 A2 100 : 50

HE4 A2 75 : 75

HE5 A2 50 : 100

HE6 A2 25 : 125

HE7 A2 00 : 150



6.4. EVALUATION OF ATENOLOL CORE (AT2) AND PRESS COATED (HE)

TABLETS

6.4.1. Spectrophotometric estimation of atenolol

Atenolol was estimated by UV visible spectroscopy. Spectrophotometric estimation of

atenolol was carried out in methanol, 0.1 N HCl, phosphate buffer pH 6.8 and phosphate

buffer pH 7.4. Detail procedures and results of spectrophotometric estimation of atenolol

in methanol and phosphate buffer pH 7.4 were discussed in chapter 5 on page no. 110 and

114-117. The study was carried out in triplicates.

Preparation of standard stock solution in 0.1 N HCl and phosphate buffer pH 6.8

Accurately weighed 100 mg of atenolol was placed in 100 ml volumetric flask and

dissolved in 100 ml of 0.1 N HCl and phosphate buffer pH 6.8. From this solution, 10 ml

solution was withdrawn and further diluted to 100 ml with 0.1 N HCl and phosphate

buffer pH 6.8 to yield the standard stock solution of atenolol (100 µg/ml).

Construction of calibration curve in 0.1 N HCl and phosphate buffer pH 6.8

From the stock solution, 5, 10, 15, 20, 25 and 30 ml were withdrawn and diluted to 100

ml with 0.1 N HCl to yield concentration of 5, 10, 15, 20, 25 and 30 g/ml respectively.

For phosphate buffer pH 6.8, 2.5, 5, 10, 15, 20, 25, 30 and 35 ml of stock solution were

withdrawn and dilute to 100 ml with phosphate buffer pH 6.8 to yield concentration of 5,

10, 15, 20, 25 and 30 g/ml respectively. Absorbance of each solution was measured at

225 nm using UV visible spectrophotometer (Thermo Scientific Evolution 201). Samples

were analyzed in triplicate and the average values were used for plotting the graph of

absorbance versus concentration (g/ml). Regression analysis was done on each beer’s

plot using Microsoft excel.

6.4.2. Drug-Excipient compatibility study

The compatibility of drug with polymeric excipients of press coated tablets was

performed using Fourier transform infrared spectroscopy and Differential Scanning

Calorimetry (DSC). Procedure followed to obtain FTIR spectra and DSC thermographs

of pure sample powder of atenolol and powder of atenolol core tablet is discussed in

chapter 5 on page no. 110-111.



6.4.3. Evaluation of flow property of powder blends

Powder blends used for preparation of atenolol core tablets and compression coated

tablets were evaluated for flow property by measuring bulk density, tapped density, carr’s

index, hausner’s ratio and angle of repose. Detailed procedure adopted for evaluation of

flow property was discussed in chapter 5 on page no. 111-112.

6.4.4. Post compression evaluation of atenolol core (AT2) and press coated (HE)

tablets

Weight Variation

Twenty tablets from each batch were individually weighed using electronic digital

balance (Shimadzu BL – 220 H) and average weight was calculated. Individual weights

of the tablets were compared with the average weight according to the official method in

Indian Pharmacopoeia, 2007 (Fukui et al., 2000, Gazzaniga et al., 1994).

Hardness

Six tablets from each batch were selected and tested for tablet hardness using Monsanto

hardness tester. The tablet was placed in contact between the plungers and the handle

was pressed, the force of the fracture that causes the tablet to break was recorded.

Thickness

The thickness of ten tablets from each batch was determined using vernier calipers as per

Indian Pharmacopoeia, 2007 (Madhusudan and Vishal, 2001).

Friability

The friability of the twenty tablets from each batch was determined using Roche

friabilator (Indosati Scientific Lab. Equipments) (Mastiholimath et al., 2007, Matsuo et

al., 1995). This device subjects the tablets to the combined effect of abrasions and shock

in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches

in each revolution. A pre-weighed sample (20 tablets) was placed in the friabilator and is

subjected to 100 revolutions. Tablets were dedusted and reweighed. The % friability (F)

was calculated using following formula:

F = (W1-W2 / W1) × 100 ………………………….. (10)



Where, W1 is the initial weight of the sample of twenty tablets before the test

W2 is the weight of the tablet after the test

Drug content

For determination of drug content, ten tablets were crushed into powder and powder

equivalent to 45 mg of atenolol was weighed and dissolved in methanol then filtered

through syringe filter (Axiva SFCA25X, 0.45µm). Solution was analyzed for Atenolol

content by spectrophotometrically by UV spectrophotometer (Thermo Scientific

Evolution 201) at wavelength of 225 nm using methanol as blank (Swati et al., 2010).

Swelling studies

One tablet from each press coated formulation was randomly selected, weighed

individually (W1) and placed separately in petridishes containing 20 ml of phosphate

buffer pH 7.4. After 6 h, the tablets were carefully removed from petridishes and excess

water was removed using filter paper. The swollen tablets were reweighed (W2) and

swelling index of each tablet was calculated using the equation 11 and expressed in

percentage (Yeole et al., 2006, Prabhakara et al., 2010).

Swelling index = (W2 – W1)/ W1 *100 …………………………… (11)

Position of Core Tablet

Compression coated tablet is cut vertically and cross sectional photographs were taken to

evaluate the position of core tablet in the compression coated tablet (Reddy et al., 2010).

In vitro drug release study of atenolol press-coated tablets

In vitro drug release studies were carried out using USP Type II dissolution apparatus

(Electrolab, TDT-08L) in a 900 ml of dissolution media at a temperature of 37±10C at

100 rpm. In order to simulate the pH changes along the GI tract, multimedia dissolution

studies were performed. Three dissolution media with pH 1.2, 6.8 and 7.4 were

sequentially used. Initially dissolution study was performed using 0.1 N HCl (pH 1.2) as

dissolution medium for 2 hrs (since the average gastric emptying time is 2 hrs), than

dissolution medium was discarded and replaced with phosphate buffer pH 6.8 and

dissolution study was continued for next 3 hrs (average small intestinal transit time is 3



hrs). After 3 hrs, the dissolution medium was removed and replaced with phosphate

buffer pH 7.4 for subsequent hours. At regular time intervals, 10 ml of sample was

withdrawn and same amount replaced by fresh medium. Samples were suitably diluted

and filtered through syringe filter (Axiva SFCA25X, 0.45µm). Drug amount released was

analyzed spectrophotometrically by UV spectrophotometer (Thermo Scientific Evolution

201) at wavelength of 225 nm. All studies were carried out in triplicates (Swati et al.,

2010, Sungthongjeen et al., 2004). The time for which the tablet does not show any

release of the drug is known as its lag time. The lag time can be estimated through the

dissolution profile of the tablet. The study was carried out in triplicates.

6.4.5. Stability study

The optimized formulations of atenolol press coated tablets were subjected for

accelerated stability studies according to ICH guidelines (40 ± 2 0C and 75 ± 5% RH) for

a period of 6 months in a stability chamber. The optimized formulations of atenolol press

coated tablets were placed in vials and hermetically closed with bromobutyl rubber plugs,

sealed with aluminum caps and placed in stability chamber. The samples were withdrawn

at initial, 1 month, 2 months, 3 months and 6 months to evaluate for the drug content,

hardness, and in vitro dissolution. The study was carried out in triplicates.

6.5. RESULT AND DISCUSSION

6.5.1. Spectrophotometric estimation of atenolol

Spectrophotometric estimation of Atenolol in 0.1 N HCl

Table 23: Spectrophotometric analysis of atenolol in 0.1 N HCl

Conc.

(µg/ml)

Absorbance Average

Absorbance

Standard

Deviation Set 1 Set 2 Set 3

5 0.149 0.152 0.149 0.150 0.002

10 0.346 0.35 0.348 0.348 0.002

15 0.441 0.44 0.441 0.441 0.001

20 0.612 0.615 0.61 0.612 0.003

25 0.73 0.733 0.729 0.731 0.002

30 0.859 0.861 0.857 0.859 0.002



Atenolol exhibited its maximum absorption at 225 nm and obeyed Beer’s law in the

range of 5-30 μg/ml. Linear regression of absorbance on concentration gave equation

y = 0.027x + 0.037 with a correlation coefficient of 0.992. So, calibration curve of

atenolol in methanol showed in figure 39 was linear in concentration range of 5-30 μg/ml.

Figure 39: Calibration curve of atenolol in 0.1 N HCl

Figure 40: Spectrophotometric images showing λmax of atenolol in 0.1 N HCl

y = 0.0278x + 0.0374R² = 0.9929

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30 35

Ave

rage

Ab

s.

Conc. (µg/ml)

Calibration curve of atenolol in 0.1 N HCl



Spectrophotometric estimation of Atenolol in phosphate buffer pH 6.8

Table 24: Spectrophotometric analysis of atenolol in phosphate buffer pH 6.8

Conc.

(µg/ml)

Absorbance Average

Absorbance

Standard

Deviation Set 1 Set 2 Set 3

5 0.136 0.133 0.135 0.135 0.002

10 0.312 0.314 0.310 0.312 0.002

15 0.480 0.477 0.482 0.480 0.003

20 0.629 0.628 0.631 0.629 0.002

25 0.773 0.771 0.775 0.773 0.002

30 0.880 0.879 0.881 0.880 0.001

Figure 41: Calibration curve of atenolol in phosphate buffer pH 6.8

Atenolol exhibited its maximum absorption at 225 nm and obeyed Beer’s law in the

range of 5-30 μg/ml. Linear regression of absorbance on concentration gave equation

y = 0.03x + 0.009 with a correlation coefficient of 0.993. So, calibration curve of atenolol

in methanol showed in figure 41 was linear in concentration range of 5-30 μg/ml.

y = 0.03x + 0.0091R² = 0.9938

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 5 10 15 20 25 30 35

Ave

rage

Ab

s.

Conc. (µg/ml)

Calibration curve of atenolol in Phosphate Buffer pH 6.8



Figure 42: Spectrophotometric images showing λmax and overlay spectra of atenolol in

phosphate buffer pH 6.8

6.5.2. Drug-Excipient compatibility study

Fourier transform infrared spectroscopy

Fourier transform infrared spectroscopy was used to analyze of pure sample powder of

atenolol and powder of atenolol press coated tablet (HE). Figure 43 showed that FTIR

spectras of all samples were identical and the main absorption bands of atenolol appeared

in all the spectra. Absorption band for N-H stretching of CO-NH2 group of atenolol

appeared around 3340 and 3160 cm−1 in the both spectra. The absorption band for -C=O

(amide I) and –N-C=O (amide II) stretching of atenolol located at 1625 cm− 1 and 1500

cm− 1 in spectra of pure atenolol drug powder, and these were also appear and not shifted

in the FTIR spectra of powder of atenolol press coated tablet (HE). All spectra showed

=C-H stretching of alkane group of atenolol around 2940 cm− 1. Similarly, the –H2N-C=O

stretching of atenolol located at 1400 cm− 1 was appeared both in both spectra. Isopropyl

group of atenolol showed a sharp peak in all spectra around 1385 cm− 1 and 1170 cm− 1.

Arylether of atenolol structure give the peak at 1390 cm− 1 and 1235 cm− 1 in spectra of

pure atenolol drug powder, and these were also appear in the FTIR spectra of powder of

atenolol press coated tablet (HE) (Klaus et al., 2005). The FTIR spectra of the tested



samples showed the prominent characterizing peaks of pure atenolol which confirmed

that no chemical modification of the drug had been taken place and indicated that there is

no chemical interaction occurred between drug and excipients at the molecular level.

Figure 43: FTIR spectra of: pure sample powder of atenolol (A) and powder of atenolol

press coated (HE) tablet (B)

Differential Scanning Calorimetry (DSC)

The DSC results of pure sample powder of atenolol and powder of atenolol press coated

tablet showed in figure 44. DSC thermographs of pure sample powder of atenolol and

powder of atenolol press coated tablet showed a sharp exothermic peak (Tm) at 156.110C

and 155.520C respectively, which corresponding to melting point of atenolol (154°C to

156°C) (Klaus et al., 2005, Gurpreet et al., 2009). Melting exotherm not appreciably

change in powder of atenolol press coated tablet as compared to atenolol pure sample.

This observation confirmed the absence of chemical interaction of drug with excipients of

press coated tablet, further supporting the results of IR spectroscopy.



Figure 44: DSC thermographs of: pure sample powder of atenolol (A) and powder of

atenolol press coated (HE) tablet (B)

6.5.3. Flow property study of powder blend

The bulk density, tapped density, angle of repose, hausner’s ratio and carr’s index of

powder blend for atenolol core tablets are 0.280 ± 0.03, 0.33 ± 0.04, 29.74O ± 0.40, 1.178

± 0.12 and 15.15 ± 0.65 respectively as shown in table 25. The results of indicated that

powder blend has good flow property with good compressibility and suitable for direct

compression method.

The angle of repose, hausner’s ratio and carr’s index of powder blend used for coating of

core tablets were ranged from 27.15O ± 0.95 to 29.92O ± 0.5, 1.163 ± 0.05 to 1.189 ±

0.08, and 14.00 ± 0.69 % to15.89 ± 0.44% respectively as shown in table 25. The values

of pre-compression parameters evaluated were within prescribed limit and indicated a

good free flowing property and suitable for direct compression method.



Table 25: Flow property study for powder blend of atenolol core (AT2) and press coated

(HE) tablets

Formulation

Code

Bulk Density

(g/cm3)

(Avg. ± SD)

Tapped Density

(g/cm3)

(Avg. ± SD)

Carr’s

Index (%)

(Avg. ± SD)

Hausner’s

Ratio (HR)

(Avg. ± SD)

Angle of

Repose (Ɵ)

(Avg. ± SD)

A2 0.280 ± 0.03 0.33 ± 0.04 15.15 ± 0.65 1.178 ± 0.12 29.74O ± 0.40

HE1 0.365 ± 0.04 0.434 ± 0.03 15.89 ± 0.44 1.189 ± 0.08 29.92O ± 0.5

HE2 0.368 ± 0.02 0.437 ± 0.05 15.78 ± 0.74 1.188 ± 0.13 29.60O ± 0.75

HE3 0.374 ± 0.05 0.443 ± 0.02 15.57 ± 0.55 1.184 ± 0.16 29.49O ± 1.05

HE4 0.380 ± 0.02 0.45 ± 0.04 15.55 ± 0.49 1.184 ± 0.07 29.05O ± 0.45

HE5 0.388 ± 0.03 0.458 ± 0.02 15.28 ± 0.52 1.180 ± 0.13 28.79O ± 0.60

HE6 0.402 ± 0.05 0.47 ± 0.03 14.46 ± 0.81 1.169 ± 0.11 28.10O ± 0.85

HE7 0.43 ± 0.04 0.5 ± 0.05 14.00 ± 0.69 1.163 ± 0.05 27.15O ± 0.95

6.5.4. Post compression study of core tablets and press coated tablets

The data obtained from post-compression study of core and press coated tablets such as

weight variation, hardness, friability, and drug content are shown in table 26. The

hardness of core tablets of atenolol was 3.25 ± 0.15, indicated that core tablets had good

crushing strength. The friability, drug content, weight variation and thickness of atenolol

core tablets were 0.12 ± 0.05 %, 99.97 ± 1.3 %, 79.57 ± 2.57 and 3.20 ± 0.05

respectively, which indicate that atenolol core tablets passed the post compression study.

In all press coated formulations, the hardness test indicated good mechanical strength.

Hardness was ranged from 6.0 to 7.5 Kg/cm2. Friability was ranged from 0.08 ± 0.08 to

0.15 ± 0.05. Friability is less than 1% which indicated that tablets had good mechanical

resistance. Drug content was found to be high (>99.45 %). It was ranged from 99.32 ±1.3

to 100.1 ± 1.4 % and uniform in all tablet formulations. In weight variation test, 20

tablets were selected random and average weight variation was calculated. Then

individual tablet were weighed and weight was compared with average weight. It was

varied from 229.45 ± 1.90 to 231.0 ± 2.30 mg. None of tablets showed more than 7.5 %

weight variation from average weight. So, all formulations pass the weight variation test

as per IP. Tablet thickness varied from 4.9 to 5.1 mm.



Table 26: Post-compression parameters of atenolol core (AT2) and press coated (HE)

tablets

Formulation

Code

Hardness

(Kg/cm2)

(Avg. ± SD)

Friability

(%)

(Avg. ± SD)

Drug

content (%)

(Avg. ± SD)

Weight

variation (mg)

(Avg. ± SD)

Tablet

Thickness (mm)

(Avg. ± SD)

AT2 3.25 ± 0.15 0.12 ± 0.05 99.97 ± 1.3 79.57 ± 2.57 3.20 ± 0.05

HE1 7.5 ± 0.45 0.09 ± 0.04 99.89 ± 1.0 230.57 ± 1.55 4.9 ± 0.05

HE2 7.0 ± 0.5 0.08 ± 0.08 99.45 ± 1.9 229.45 ± 1.90 5.0 ± 0.02

HE3 6.5 ± 0.15 0.11 ± 0.05 99.32 ±1.3 229.18 ± 2.6 4.9 ± 0.05

HE4 6.5 ± 0.2 0.10 ± 0.06 100.1 ± 1.4 231.0 ± 2.30 4.9 ± 0.02

HE5 6.0 ± 0.6 0.13 ± 0.1 99.66 ± 1.5 229.50 ± 2.91 4.9 ± 0.02

HE6 6.0 ± 0.3 0.15 ± 0.05 99.98 ± 1.1 231.26 ± 2.75 5.0 ± 0.05

HE7 6.0 ± 0.4 0.14 ± 0.06 99.70 ± 1.6 229.5 ± 3.10 5.1 ± 0.05

Position of Core Tablet

Cross sectional photograph in figure 45 of atenolol compression coated tablet showed

that atenolol core tablet centrally placed into compression coated tablet.

Figure 45: Cross sectional photographs of atenolol press coated (HE) tablet

% Swelling study

Swelling study of press coated tablets indicated that, combination of EC and HPMC

K4M, when used have better capacity to protect the drug from being released in the upper

parts of the GIT than HPMC K4M alone compression coated tablets. This may be due to



HPMC K4M is being more hydrophilic as the swelling index is better for HPMC K4M.

Table 27 describes the % swelling ratio of different batches of HE1 to HE7. As the

amount of HPMC K4M increases swelling of tablet increases. HE1 batch having high

amount of HPMC K4M (having HPMC K4M alone) was showed high 172.72 ± 6.40

percentage of swelling. HPMC K4M alone released the drug relatively at a faster rate

than combination of EC and HPMC K4M because it formed weak sweallable layer,

which could rupture easily upon exposure to the dissolution medium. While HE7 batch

having EC alone could not maintain the integrity, it divided into two equal halves and no

sign of swelling. Batches HE2 to HE6 showed that as amount of EC is increased in the

mixture of HPMC K4M and EC, % swelling of tablet decreases because of EC retard the

swelling of HPMC K4M. It was also observed that throughout drug release study;

combination of EC and HPMC K4M compression coated tablets (Formulation HE2 to

HE6) released the drug at slower pace compared to HPMC K4M alone compression

coated tablets (Formulation HE1), EC retard the retards hydration of HPMC K4M and

maintain the integrity of swellable layer of HPMC K4M (Prabhakara et al., 2010). EC

acts as a semipermeable membrane, controls the passage of water inside the core, core

swells and ruptures the EC coat.

In vitro dissolution study of atenolol press coated tablets

In time controlled press coated tablets, drug containing core compressed with the outer

barrier layer, being outer barrier layer present, it prevents the rapid drug release from core

tablets. The drug will not be released unless the coat is broken. When the dissolution

medium reaches the core after eroding or rupturing the outer barrier layer rapid drug

release was observed. The release profile of compression coated tablet exhibited lag time

followed by burst release, in which outer shell break into two halves (Carla et al., 2007,

Janugade et al., 2009). Release of drugs from the compression coated tablet follows three

consecutive steps:

1. Penetration of dissolution media into the compressed coated tablet

2. Swelling or erosion of hydrophilic polymer

3. Breakdown of outer coating into two halves due to swelling or erosion of

hydrophilic polymer used in coating



Dissolution profile showed in figure 46 produce a lag time prior to drug release due to

incorporation of core tablet into press coated tablet. Press coated tablets (HE1 to HE7

formulations) showed distinct lag time as given table 27. When, HPMC K4M alone

(HE1), showed lag time of only 04 hr. This is probably because of mechanism of

producing a lag time of this formulation was based upon the hydration and swelling of

outer barrier layer or water penetration through outer barrier layer (Ghimire et al., 2007).

When HPMC K4M was used alone, it formed a mechanically weak sweallable layer,

which could rupture easily upon exposure to the dissolution medium and resulting

development of internal pressure within tablet core and drug release was initiated

(Prashant et al., 2011). With Ethylcellulose alone (HE7), showed lowest lag time of two

hours as compared to any weight ratio of mixture of HPMC K4M and EC. The porosity is

proportional to the proportion of EC. Increase amount of EC leads to higher penetration

of dissolution media in press coated tablet. EC is semipermeable in nature, although it is

naturally insoluble in water. Water penetrates faster the coating layer of the core tablet

when used alone. After hydration of core, the drug was released (Janugade et al., 2009).

Table 27: Lag time and % swelling index of atenolol press coated (HE) tablets

Formulation Code Lag Time (hr) % Swelling Index

HE1 04 172.72 ± 6.40

HE2 5.5 137.6 ± 6.60

HE3 7.5 113.50 ± 7.50

HE4 6.5 101.86 ± 6.78

HE5 6 66.38 ± 5.07

HE6 7 37.19 ± 3.95

HE7 2 Divide into two equal halves

When ethylcellulose was used in combination with HPMC K4M, it causes

synchronization between swelling and erosion of the polymer in maintaining a constant

stable gel layer for a long period of time (Prajapati et al., 2010). Upon contact with

dissolution medium HPMC K4M hydrated and formed compact with ethylcellulose. The

hydrophobicity of ethylcellulose retards the hydration of HPMC K4M. Therefore

dissolution medium did not penetrate the outer coating layer, but the coating eroded



slowly. The active erosion rate of outer barrier layer depends upon the composition of the

formulation which determines the lag time of press coated tablets (Prashant et al., 2011).

Press coated tablets HE2-HE6 formulations showed distinct lag time as given in table 27.

Obviously, the period of lag time was different and dependent on the weight ratio of

mixture of HPMC K4M and EC. The combination of HPMC K4M and EC showed the

synergistic effect on lag time. The finding indicates that the lag time of a press coated

tablet can be modulated from 5.5 to 7.5 hrs by combining EC with HPMC K4M in

different weight ratio. The system was found to be satisfactory in terms of release of the

drug after a predetermined lag time of 6-7 hr and thus the dosage forms can be taken at

bedtime, so, that the content will be released in the morning hours, i.e., at the time of

symptoms. The release of drug was rapid and complete after the lag time. Lag time can

be controlled by adjusting the mixture containing different weight ratio of HPMC K4M

and EC. Results of drug release study of atenolol press coated tablets shown in table 28

stated that formulations HE4 and HE5 compression coated tablets achieve a burst release

after 6.5 hr and 6 hr lag time respectively, which is applicable pulsatile drug delivery of

atenolol for hypertension.

Figure 46: Dissolution profile of atenolol press coated (HE) tablets

0

20

40

60

80

100

120

0 2 4 6 8 10 12

% C

um

ula

tiv

e D

rug R

elea

se

Time (hrs)

Dissolution profile of Atenolol Press Coated (HE) tablets

HE1

HE2

HE3

HE4

HE5

HE6

HE7



Table 28: % Cumulative drug release study of atenolol press coated (HE) tablets

Time

(hrs)

% Cumulative Drug Release

HE1 HE2 HE3 HE4 HE5 HE6 HE7

1 0 0 0 0 0 0 0

2 0 0 0 0 0 0 0

3 0 0 0 0 0 0 72.31±4.5

4 0 0 0 0 0 0 98.84±3.0

5 46.43±5.6 0 0 0 0 0

5.5 77.53±4.8 0 0 0 0 69.56±2.7

6 97.84±3.7 60.84±3.5 0 0 0 93.09±1.5

6.5 99.69±4.5 76.34±7.0 0 0 68.53±3.2 99.61±2.5

7 98.43±3.7 0 28.42±6.0 98.94±5.5

7.5 0 98.46±5.2

8 14.64±5.2 100.34±5.3

8.5 16.60±4.7

9 20.63±5.2

9.5 35.93±2.5

10 97.26±2.7

6.5.5. Stability study

Table 29: Stability study of optimized atenolol press coated (HE5) tablets

Tests Initial 1 month 2 months 3 months 6 months

Drug content (%)

(Avg. ± SD)

99.66 ± 1.5 99.60 ± 1.2 99.54 ± 1.4 99.46 ± 1.8 99.38 ± 1.7

Hardness (kg/cm2) 6.0 ± 0.6 6.0 ± 0.5 6.0 ± 0.75 6.0 ± 0.25 5.75 ± 0.75

Lag time (hr) 6 6 6 6 6

The optimized HE5 batch of atenolol press coated tablets was subjected for accelerated

stability studies according to ICH guidelines (40 ± 20C and 75 ± 5% RH) for a period of 6

months in a stability chamber. Formulations did not show any significant changes in the

drug content, hardness and in vitro dissolution during stability study as shown in table 29.



Hence, the HE5 atenolol press coated tablets were sufficiently stable as per regulatory

requirements.

CONCLUSION

The promising colon targeted pulsatile type release of atenolol is successfully achieved

by press coating technique using combination of time dependent rupturable and erodible

polymers. Ethyl cellulose was chosen because of its rupturable behavior and HPMC K4M

was chosen because of its swelling and erodible behavior. Atenolol press coated tablets

were prepared using different weight ratios of HPMC K4M and EC. The formulations

HE4 and HE5 were achieve a burst release after 6.5 hr and 6 hr lag time respectively,

which is applicable pulsatile drug delivery of atenolol for treating early morning

hypertension.

CHAPTER 6: FORMULATION AND EVALUATION OF ATENOLOL...

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