RESEARCH ARTICLE Formulation development and evaluation of

controlled porosity osmotic pump delivery

system for oral delivery of atenolol
Garvendra S Rathore, RN Gupta1
Department of Pharmaceutics, Lal Bahadur Shastri College of Pharmacy, Tilak Nagar, Jaipur, Rajasthan, 1Department of
Pharmaceutical Sciences, Birla Institute of Technology, (Deemed University) Mesra, Ranchi, Jharkhand, India

I n the present study, we developed and evaluated the controlled porosity osmotic pump (CPOP) based drug delivery
system of sparingly water soluble drug atenolol (ATL).We selected target release profile and optimized different variables
to help us achieve this. Formulation variables, such as, the levels of solubility enhancer (0-15% w/w of drug), ratio of the
drug to the osmogents, coat thickness of the semipermeable membrane (SPM) and level of pore former (0-20% w/w of
polymer) were found to effect the drug release from the developed formulations. Cellulose acetate (CA 398-10) was used as
the semipermeable membrane containing polyethylene glycol 400 as the Cplasticizer. ATL release was directly proportional
to the level of the solubility enhancer, osmotic pressure generated by osmotic agent and level of pore former; however, was
inversely proportional to the coat thickness of SPM. Drug release from developed formulations was independent of the pH
and agitation intensities of release media. Burst strength of the exhausted shells decreased with increase in the level of pore
former. The optimized formulations were subjected to stability studies as per International Conference on Harmonisation
(ICH) guidelines, and formulations were found to be stable after 3 months study. Steady-state plasma levels of drug were
predicted by the method of superposition.

Key words: Atenolol, controlled porosity osmotic pump, osmogents, semipermeable membrane

INTRODUCTION concentration of drug for absorption and allows for

maintenance of therapeutic plasma concentrations
Oral ingestion is one of the oldest and most extensively within a therapeutic window to avoid side effects and/
used routes of drug administration. It is also a or reduced frequency of administration. Despite these
convenient mean of effectively achieving both the advantages, drug release from oral controlled-release
local and systemic effects. Until recently, the drugs dosage forms may be affected by pH, gastrointestinal
were almost always administered orally in conventional tract (GIT) motility, and the presence of food. [4]
dosages. In the past few years, pharmaceutical research One method with the potential to overcome these
has developed innovative methods for drug delivery via disadvantages is the osmotic drug delivery system.
the oral route.[1-3] Conventional preparation is usually
in the form of two or three daily doses, which can lead Osmotic pumps are controlled drug delivery devices
to large fluctuations in the drug plasma concentration based on the principle of osmosis. Wide spectrums
and cause side effects on the human body. Ideal oral of osmotic devices are in exifstence. Amongst them,
drug delivery systems are those that progressively the osmotic pumps are unique, dynamic and widely
deliver a measurable, reproducible amount of drug employed in clinical practice.[5,6] Osmotic pumps offer
over a prolonged period. Delivery systems capable of many advantages, such as, (i) Easy to formulate and
this are controlled-release dosage forms, which attempt simple in operation, (ii) improve patient compliance by
to provide drug for absorption at a zero-order rate.
Drug delivery at a zero-order rate provides a uniform Access this article online
Quick Response Code:
Website:
www.asiapharmaceutics.info
Address for correspondence:
Dr. Garvendra S Rathore,
Lal Bahadur Shastri College of Pharmacy,
DOI:
Udai Marg, Tilak Nagar, Jaipur - 302 004, Rajasthan, India
10.4103/0973-8398.102941
E-mail: garvendra@gmail.com

Asian Journal of Pharmaceutics - April-June 2012 151

 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

reducing dosing frequency (iii) provide good in vitro in vivo 2+

correlation[7] (iv) and, their industrial adaptability vis-a- vis
production scale up is easy.[5,7] These drug delivery devices +
also prevent sudden increase and decrease in the plasma 2 1
&+
concentration of the drugs that may produce side effects or
lower a drug’s effectiveness, respectively.[8] 2
+
The first osmotic pump for delivery of active ingredients was
invented by Rose Nelson in the 1950s.[9] The first commercial &+
osmotic device was introduced by Theeuwes in the 1970s and +1
was known as the elementary osmotic pump (EOP).[10] The EOP
Figure 1: Atenolol
was in the form of a core tablet coated by a semipermeable
membrane with a micro-orifice drilled on the surface. The EOP
was very simple in preparation and could deliver water-soluble atenolol solid dispersion to improve the solubility. Although
drugs at an approximately constant rate up to 24 hours. this method slightly improved the solubility of atenolol,
However, it was not feasible for the delivery of low solubility large amounts of carrier were consumed. In addition, the
drugs and for the drugs that dissolved insufficiently and solid dispersion method had some problems, such as the
settled in the bottom of the tablet. Therefore, research was difficulty of scale-up, the physical stability of dispersion, and
done in the fields of enhancing the solubility of the drugs,[11,12] the reproducibility of physicochemical properties, [26] all which
and modifying the performance of the semipermeable the limited its commercial application. For some alkaline drugs,
membrane;[13,14] however, these methods again were applicable it was feasible to convert them into salt by reacting them
only for a few drugs. One attempt in improving the delivery with acid. Ayer and Theeuwes[27] used citric acid, maleic acid,
of the low solubility drugs was the development of controlled malic acid and succinic acid as solubility promoters, and to
porosity solubility modulated osmotic pump. In majority of increase the solubility of haloperidol substantially. Atenolol is
the cases, osmotic systems have a pre-formed passageway in an alkaline drug with an imide group. Appropriate solubility
the membrane from where the drug release takes place. Oral in tartaric acid made it a suitable candidate for modulating
osmotic systems in which the delivery passage way is formed solubility of alkaline drugs.
in situ are described in US patent no. 5,736,159. [15] Controlled
porosity osmotic pumps (CPOP) contain water-soluble The objective of the present study was to develop controlled
additives in the coating membrane, which after coming in porosity-based osmotically controlled release tablets of
contact with water, dissolve, resulting in an in situ formation Atenolol. Tartaric acid was used as solubility modifier.
of a microporous membrane. The resulting membrane is Sodium chloride and Mannitol were used as osmogents. The
substantially permeable to both water and dissolved solutes, tablets were coated with cellulose acetate (CA 398-10) as
and the mechanism of drug release from these systems is the semipermeable membrane, also containing sorbitol as a
found to be primarily osmotic, with simple diffusion playing pore forming / channelling agent. The influences of tartaric
a minor role.[16-18] Controlled porosity solubility modulated acid, sodium chloride, level of pore former and membrane
osmotic pumps for delivery of drugs having low water thickness on drug release profile were investigated. The
solubility are described in US patent nos. 4,946,686 and influences of release media and agitation rate on in vitro
4,994,273.[19,20] In the examples, tablet cores of two different release profile were also evaluated.
drugs, namely, simvastatin and lovastatin, along with the
solubility modulating agents were prepared and coated with a MATERIALS AND METHODS
microporous membrane. The release of drug from the systems
was controlled for an extended period of 4–24 hours. Materials
Atenolol was obtained as a gift sample from Cadila Healthcare
Atenolol, also known as 4-[2-hydroxy-3-[(1-methylethyl) Ltd. Ahmedabad, India. Sodium chloride, tartaric acid, mannitol,
amino] propoxy] benzeneacetamide [Figure 1], is a cardio and starch were purchased from Qualigens Fine Chemicals,
selective β 1-blocking agent, and can effectively reduce systolic Mumbai, India. PVP K30 and colloidal silicon dioxide were
and diastolic blood pressures, and it is widely used alone or purchased from Signet chemical cooperation, Mumbai, India.
in combination to treat hypertension.[21] Atenolol is slightly Cellulose Acetate (CA 398-10) was obtained as a gift sample
soluble in water, as reported in the Italian Pharmacopoeia,[22] from Signet chemical cooperation Pvt. Ltd., Mumbai, India.
and is characterized by a low oral bioavailability.[23] Atenolol is PEG-400, PEG-4000, sorbitol, and glycerin were purchased
a sparingly soluble drug (27 mg/ml at 37 °C). Some methods from S.D. Fine Chem Limited, Mumbai, India. Isopropyl alcohol,
had been attempted to improve its solubility. Ficarra et al. [24] Methanol and Acetone were purchased from Merck Limited,
prepared β-cyclodextrin inclusion complex. However, it was Mumbai, India. High performance liquid chromatography
proved that atenolol solubility could not be significantly (HPLC) grade water was used for the HPLC analysis. All the other
enhanced in this method. Moneghini et al.[25] prepared an reagents used were of the analytical grade.
152 Asian Journal of Pharmaceutics - April-June 2012
 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

Methods coating solutions used for coating of core tablets is given in

Drug-excipient interaction studies Table 2. Various components of coating solution were added
Assessment of possible incompatibilities between an active to the solvent mixture in sequential manner. Coating solution
drug substance and different excipients forms an important was prepared by dissolving accurately weighed quantities of
part of the preformulation stage during the development of polymer, pore formers and plasticizer in the solvent (ethanol
a solid dosage form. Differential scanning calorimeter (DSC) and acetone 1:9 mixture) using a stirrer. The component added
allows the fast evaluation of possible incompatibilities, first was allowed to dissolve before next component was
because it shows changes in the appearance, shift or added. Coating process was done on a batch of 250 tablets.
disappearance of melting endotherms and exotherms, and/ Pan speed was set at 22 revolutions per minute (rpm) and
or variations in the corresponding enthalpies of reaction. The inlet hot air temperature was set at 45°C. The manual coating
DSC thermograms of pure drug, core tablets, placebo of core procedure based on intermittent spraying and coating was
tablets, and coated tablets were recorded. The samples were used with a spray rate of 2ml/minute followed by 4 ml/ minute.
separately sealed in aluminium cells and set in DSC (Universal Coat weight and thickness were controlled by the volume
V4.2E TA Instruments). The thermal analysis was performed of coating solution consumed in coating process.[28] After
in a nitrogen atmosphere at a heating rate of 10°C/minute attaining the desired coat thickness, the tablets were dried in
over a temperature range of 50°C to 300°C. an oven at 60°C for 3 to 4 hours, followed by drying at room
temperature for 8 to 10 hours. The prepared osmotic pump
Preparation of core tablets of atenolol tablets were kept in a desiccator for future experiments.
All formulations were prepared by the wet granulation
method. All raw materials were sifted through 60 mesh. Evaluation of developed formulation
Atenolol powder was mixed with tartaric acid, sodium Evaluation of core and coated tablets
chloride, mannitol and starch in a mixer granulator for The core and coated tablets were evaluated for weight
10 minutes. The above mixture was passed through variation. Thickness and diameter of core and coated tablets
30 mesh sieve. The dry blend was granulated with PVP were measured using screw gauze (Campbell Electronics
K-30, and dissolved in Isopropyl Alcohol (IPA). The wet Mumbai, India). Hardness of randomly selected tablets was
blend was granulated and dried at 40-50°C and sized tested using hardness tester (Monsanto hardness tester,
through 20 mesh. Colloidal silicon dioxide was added to Campbell Electronics Mumbai, India). Friability of core tablets
this mixture, and granules were lubricated with magnesium was tested on the Electrolab friability tester (Electrolab,
stearate for 10 more minutes. The resultant granules were Mumbai, India) using 20 accurately weighed tablets.
then compressed into core tablets on 8 station single rotary
compression machine (KMP-8, Cadmach Engg., Ahmedabad, Drug content uniformity
India) with 8 mm round standard concave punches. The Accurately weighed 20 tablets (of all batches) were dissolved
weight of each tablet was maintained within the range of in 500 ml of distilled water. The samples were sonicated for
200 ± 5 mg and the drug loading was 50 mg/tablet. The 30 minutes and filtered through a 0.45µm nylon membrane
composition of tablets is shown in Table 1. filter. The filtered samples, after appropriate dilution
were analyzed at 225 nm using ultraviolet (UV) Visible
Coating spectrophotometer (Shimadzu, 1601 and 1800, Japan).
Core tablets of ATL were coated in a conventional laboratory
coating pan (Sehgal Industries Ltd., New Delhi) fitted with In vitro drug release study
three baffles placed at angle of 120° each. The composition of The developed formulations (n=3) of ATL were subjected
to release studies using USP dissolution apparatus type I
(Electrolab, TDT 06T, Mumbai, India) at 75 rpm. Dissolution
Table 1: Composition of core atenolol tablets in the
media used was simulated intestinal fluid (SIF without
study
enzymes, pH 6.8, 900ml) maintained at 37±0.5°C. The
Ingredients (mg/tablet) Formulation code
samples (5 ml) were withdrawn at different time intervals
I II III IV V
Atenolol 50 50 50 50 50 Table 2: Composition of coating solutions in the study
Tartaric acid 2.5 5.0 7.5 7.5 7.5
Ingredients† Coating code
Sodium chloride 15 15 15 20 25
A B C D
Mannitol 50 50 50 50 50
Cellulose Acetate (gm) 3.4 gm 3.1 gm 2.8 gm 2.6 gm
Starch 70 67.5 65 60 55
PEG-400 (gm) 0.6 gm 0.6 gm 0.6 gm 0.6 gm
Polyvinyl pyrrolidone 10 10 10 10 10
K-30 Sorbitol (gm) – 0.3 gm 0.6 gm 0.8 gm
Magnesium stearate 1.5 1.5 1.5 1.5 1.5 Ethanol (ml) 10 ml 10 ml 10 ml 10 ml
Acetone (ml) 90 ml 90 ml 90 ml 90 ml
Colloidal silicon dioxide 1 1 1 1 1 †
Composition based on percentage wt/wt of cellulose acetate. Total solids in the coating
Total 200 200 200 200 200 composition are 4% wt/vol

Asian Journal of Pharmaceutics - April-June 2012 153

 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

and replaced with equivalent prewarmed (37± 0.5°C) volume Effect of pH

of fresh medium. The withdrawn samples, after filtration To study the effect of pH and to assure a reliable performance
through 0.45 µm nylon membrane filters, were analyzed using of the developed formulations independent of pH, in vitro
UV/Visible spectrophotometer at 225 nm. After analyzing release studies were conducted in media of different pH.
the drug content in the dissolution samples, correction was The release media were simulated gastric fluid (SGF) (pH 1.2),
made for the volume replacement and a graph of cumulative acetate buffer (pH 4.5), and simulated intestinal fluid (pH 6.8).
percentage of drug release versus the time was plotted. Samples were analyzed by UV/Visible spectrophotometer.

High-performance liquid chromatography analysis Effect of agitational intensity

Chromatographic separation of atenolol was performed In order to study the effect of agitational intensity of the
on a Shimadzu SDP-10 HPLC system using Kromasil C 18 release media, release studies were performed in dissolution
column (30 cm × 4.0 mm × 5μm particle size; Shimadzu, apparatus at various rotational speeds. USP-I (rotating basket)
Kyoto, Japan). Mobile phase used was filtered mixture of type dissolution apparatus with rotational speeds of 75, 100,
buffer solution (1.1 gm of sodium 1-heptanesulfonatea and and 150 rpm was used. Degassed SIF (without enzymes) was
0.71 gm of anhydrous disodium hydrogen phosphate was used as dissolution media (pre-equilibrated to 37°C ± 1°C).
dissolved in 700 ml HPLC water and 2.0 ml of dibutylamine Samples were analyzed spectrophotometrically after filtration
was added) and methanol prepared in the ratio of 70:30, through 0.45 µm nylon membrane filters.
with pH 3.5. Temperature of the column was maintained
at 30°C. Injected volume was 20 µl and standard solution Effect of osmotic pressure
and dissolution samples were analyzed at 226 nm using a To confirm the major mechanism of drug release, release
UV detector. studies of the optimized formulation were conducted in
media of different osmotic pressure.[30] To increase the osmotic
Statistical analysis pressure of the release media (pre-equilibrated to 37°C ± 1°C),
Experimental results were expressed as mean ± Standard sodium chloride (osmotically effective solute) was added in
Deviation (S.D.) values. Release profiles of various batches SIF (without enzymes). Release studies were performed in
were compared using model independent pair wise approach, 900 mL of media using USP-I dissolution apparatus (75 rpm).
which included the calculation of ‘difference factor’ f1 and Samples were analyzed spectrophotometrically after filtration
‘similarity factor’ f2. The two release profiles were considered through 0.45 µm nylon membrane filters.
to be similar if f1 value was lower than 15 (between 0 to15),
and f2 value was more than 50 (between 50 to100). Release Burst strength
profiles were also compared using mean dissolution time Burst strength of the exhausted shells, after 8 hour of
(MDT) which was calculated using following equation:[29] dissolution, was determined to assure that the tablets
would maintain their integrity in the GIT. Burst strength
n was determined as the force required to break/rupture the
∑ t∆Mj
j =1
j shells after dissolution studies. The texture analyzer (TAX
MDT = n
(1) T2i, Stable Micro systems, England) with a 5 kg load cell
∑ ∆Mj and 25 mm aluminium cylindrical probe was utilized for this
j =1 purpose. Test speed of 0.8 mm/sec was selected and the
distance moved was set at 2 mm.
where, j is the sample number, n is the number of dissolution
sample times, tj is the time at midpoint between tj and t(j=1), Kinetics and mechanism of drug release
and DMj is the additional amount of drug dissolve between Dissolution data of the optimized formulation was fitted to
tj and t(j=1). One way analysis of variance test (ANOVA) was various mathematical models (zero-order, first-order, and
performed to check whether there is significant difference Higuchi) in order to describe the kinetics of drug release.
among the different formulations. Difference was considered Smallest value of sum of squared residuals (SSR) and best
statistically significant at P<0.05. In this study, mean goodness-of-fit test (R2) were taken as criteria for selecting
dissolution time for 50% drug release (MDT50%) was used for the most appropriate model.
comparison of release profiles from different batches.
Accelerated stability studies
Scanning electron microscopy Optimized formulations of ATL were packed in blisters
Coating membranes of formulation obtained before and after (10 tablets in one strip) of 0.25mm amber Polyvinyl chloride (PVC)
complete dissolution of core contents were examined for with 0.05mm lidding aluminum foil. The packed formulations
their porous morphology by scanning electron microscope were stored in ICH certified stability chambers (NSW-175,
(JSM-6390 LV SEM, Jeol Japan). Membranes were dried at Narang Scientific work, New Delhi, India) maintained at
45°C for 12 hours and stored between sheets of wax paper 40°C and 75% relative humidity (RH) for 3 months. The
in dessicator until examination. samples were withdrawn periodically and evaluated for drug
154 Asian Journal of Pharmaceutics - April-June 2012
 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

content, hardness, burst strength and release studies. The of water-soluble additive(s) in the membrane. Cellulose
withdrawn samples, after filtration through 0.45 µm nylon acetate and sorbitol were used as water-insoluble polymer
membrane filters, were analyzed using the HPLC method and water-soluble additive, respectively. Polyethylene glycol
400 (PEG-400) was used as plasticizer.
Prediction of in vivo performance
Using the known pharmacokinetic properties of ATL [Table 3] Drug-excipient interaction studies
and various drug release parameters (R0 and tDel), which Figure 2 depicts the DSC thermograms of atenolol and the
were calculated from in vitro release data, steady-state formulation. Some broadening of peaks leading to changes in
plasma levels of drug were predicted by the method of area, onset of peak, and changes in peak temperature occur
superposition.[31] It was assumed that after the administration simply due to mixing of the components without indicating
of a test dose of formulation, the drug would be released any significant interaction. If all the thermal features more
at a release rate (R0) for a period of time (tDel), shorter than or less remain the same, compatibility can be expressed.
the selected dosing interval (τ). Time of delivery, tDel, is the No changes in the endotherms were observed as the drug
time taken to deliver 90% of the total drug within a selected exhibited a sharp melting endotherm in the core and coated
dosing interval (τ = 12 hr). The predicted plasma levels of formulation. From the DSC thermograms it was clear that no
developed CPOP were compared with those of desired level specific interaction between the drug and excipients was used
by calculating the percent-predicted error (% PD) in Cmax and in the present formulation.
AUC 0-τ.  Bioequivalence was anticipated if the average % PD
was less than 15% for Cmax and AUC 0-τ.[32,33] The % PD was Desired release profile
calculated using the following equation: The purpose of this study was to select a release profile
that could be used as a target for developed CPOP of
Predicted value - Reference value ATL. The therapeutic range of ATL is between 100-1000 ng/
% PD= ×100 (2)
Reference value ml,[34] and therefore, the desired maximum steady-state
concentration, Css max desired of ATL for 50 mg dose was
selected as 400 ng/ ml. In order to provide good therapeutic
RESULTS AND DISCUSSION effect ATL plasma level should not fall below 150 ng/ml.
Keeping this point in consideration desired minimum steady
The dosage form developed was designed as a tablet state concentration was kept at 250 ng/ml. Taking different
core coated with a rate-controlling membrane. Tablet pharmacokinetic parameters of ATL into consideration
core consisted of drug along with osmogent, and other [Table 3] a zero-order based delivery strategy was designed
conventional excipients to form the core compartment. The to produce the desired plasma levels of ATL.[35] Series of
core compartment is surrounded by a membrane consisting of simulations (using Sigma plot-10) were performed and it
a semipermeable membrane-forming polymer, water-soluble was found that a delivery rate of 4.46 mg/hour for a period
pore-forming additives, and at least one plasticizer capable of 8.0 hours was found to meet the above requirements.
of improving film forming properties of the polymers. The The simulated plasma concentration- time profile using
semipermeable membrane-forming polymer is permeable to this approach and the corresponding in vitro drug release
aqueous fluids; however, substantially impermeable to the profile are shown in Figure 3. Since, this delivery pattern
components of the core. In operation, the core compartment was expected to maintain plasma levels of ATL within desired
imbibes aqueous fluids from the surrounding environment range, it was selected as target release profile.
across the membrane and dissolves the drug. The dissolved
drug is released through the pores created after leaching

Table 3: Various pharmacokinetic parameters of atenolol

Pharmacokinetic Value Reference (s)
parameters
Bioavailability (f) 56% [35]

Elimination half life (t1/2) 6 h [34]

Terminal deposition 0.11 h-1 [36]

rate constant (Kel)

Apparent volume of 0.95 l/kg [34]

distribution (Vd)
Maximum safe 1 µg/ml [34]

conc. (Cmax)
Minimum effective 0.1 µg/ml [34]

conc. (Cmin)
Figure 2: Differential Scanning Calorimetry thermograms of drug,
Clearance total (ClT) 2.0 ml/min/kg [34]
placebo blend, coated formulation and core blend of atenolol

Asian Journal of Pharmaceutics - April-June 2012 155

 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

Drug content and physical evaluation 

3UHGLFWHGSODVPDFRQFHQWUDWLRQ—JPO
The content of drug as seen in various formulations varied 
between 98.6% and 101.5% (mean 100.05%). Core tablet
weights varied between 195 mg and 207 mg (mean 200 mg 

and thickness of the core tablets was found to be in the 

range of 3.79 and 3.84 mm (mean 3.80 mm). The hardness 

of core tablets was found to be between 5.1 and 7.2 kg cm2
(mean 6.2 kg cm2); while the friability of prepared core tablets 

ranged between 0.12% and 0.26% (mean 0.17%). Thus, all 

the physical parameters of the compressed matrices were 

practically within limits.


Concentration of atenolol in tartaric acid aqueous Solutions 

       
The concentration of atenolol in various concentrations
7LP HKUV
of tartaric acid aqueous solution is shown in Figure 4.
The solubility of atenolol (37°C) in deionized water was Figure 3: Predicted steady-state plasma levels of ATL using
21 mg/ml. It was clear that the concentration of atenolol in theoretically designed zero-order delivery approach
tartaric acid aqueous solution increased with the increase
of original tartaric acid concentration. A more than 10-fold

increase in atenolol concentration was achieved at original
tartaric acid concentration of 100 mg/ml. This could be 

explained by its molecular structure. Atenolol had an imide &RQFHQWUDWLRQRI$WHQROROPJPO

group exhibiting alkalinity. When atenolol came in contact 

with the tartaric acid aqueous solution, it reacted and


changed to salt. As a consequence, atenolol became freely
soluble, and the concentration was increased markedly. It 

could be concluded that this method should be much more

suited for the solubilisation of atenolol and the preparation of 

CPOP tablet compared with technologies of solid dispersion


and cyclodextrin inclusion.


Effect of ratio of drug to osmogent and tartaric acid       

& RQ FHQ WUDWLR QRIWD UWDULFD FLGP JP O
To optimize the amount and type of osmogent to be used
in the formulation and to study the effect of drug-to- Figure 4: Concentration of atenolol in tartaric acid aqueous solution
osmogent ratio, core formulations were prepared as shown
in Table 1. The ratios of drug (ATL) to osmogents (drug:

sodium chloride: mannitol) studied were 1:0.3:1, 1:0.4:1,
% D WF K ,
and 1:0.5:1 (formulation code III, IV and V respectively). 
% D WF K ,,
The ratios of drug (ATL) to tartaric acid (drug: tartaric acid)  % D WF K ,,,
% D WF K ,9
studied were 1:0.05, 1:0.1, and 1:0.3 (formulation code I, II  % D WF K 9
and III respectively). All the core formulations were coated 
GUXJUHOHDVH

with similar coating composition, C containing 15% w/w 

(of CA) of sorbitol. Release profile from these formulations

is shown in Figure 5. It is clear from Figure 5 that osmogent

and tartaric acid enhances the release of drug and thus
had a direct effect on drug release. The drug release after 

8 hours for formulation code I, II, III, IV, and V was 27.36, 

39.37, 51.29, 69.49, and 71.52 % respectively. From the 

         
comparative release profiles it was found that release of ATL
7 LP H + UV 
from formulation code IV is more controlled with highest
zero-order coefficient of determination value (R2 = 0.991) Figure 5: Effect of osmogent and tartaric acid on in vitro percent release
of ATL CPOP tablets. Bars represent ± Standard Deviation (n = 3)
than other batches. Hence, formulation IV was chosen for
further experimental studies.
release, core formulation of batch IV was coated with
Effect of coat thickness coating composition C so as to give different coat thickness
To study the effect of coat thickness of SPM on drug (50  µm, 150 µm, 200 µm). Release profiles of ATL from
156 Asian Journal of Pharmaceutics - April-June 2012
 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

these formulations are shown in Figure 6. Drug release 

% D WFK ,9   — P 
was decreased with increase in coat thickness of SPM. The % D WFK ,9    — P 
% D WFK ,9    — P 
increase of SPM thickness resulted in an increased resistance 

&XPXODWLYHSHUFHQWUHOHDVH
of SPM to water imbibition, causing a rate of decreased
water imbibition, consequently causing a decrease in rate

of liquefaction/ dissolution of drug in core, and ultimately
resulting in a decline in the ATL release. MDT50% value
between different batches (2 hour 2 minutes., 3 hour 

6 minutes. and 3 hour 44 minutes for formulation with coat

thickness of 50 µm, 150 µm, 200 µm, respectively) w found 
to be statistically significant (P < 0.05). No bursting of the
systems was observed during the dissolution run in any of
the formulations. 
    
7 LP H  K UV
Effect of pore forming level
Figure 6: In vitro release profile of ATL CPOP tablets showing the
To study the effect of pore forming agent, core formulations effect of coat thickness. Bars represent ± Standard Deviation (n = 3)
of atenolol of batch IV were coated with varying coating
compositions of pore forming agent containing 0%, 7.5%,
B a tc h IV (d e v o id o f p o re fo rm e r)
15%, and 20% wt/wt (of total solids) of sorbitol. Release B a tc h IV (7 .5 % w /w o f p o re fo rm e r)
profile from these formulations is shown in Figure 7. It is B a tc h IV (1 5 % w /w o f p o re fo rm e r)
80 B a tc h IV (2 0 % w /w o f p o re fo rm e r)
clearly evident that the level of sorbitol had a direct effect
on drug release. As the level of pore former increases, Cumulative percent release (%)
the membrane becomes more porous after coming into 60

contact with the aqueous environment, resulting in faster

drug release. The level of pore former also affects the burst
40
strength of exhausted shells. Exhausted tablets (after 8 hours
of dissolution studies) were evaluated for burst strength to
assure that the tablets maintain their integrity in GIT and do 20

not lead to dose dumping. Figure 8 shows the dependency

of burst strength of the exhausted shells on the level of pore
0
former. The burst strength was inversely related to the initial 0 2 4 6 8

level of pore former in the membrane. With the increase in T im e (h rs .)

the level of sorbitol, the membrane became more porous Figure 7: In vitro release profile of ATL CPOP tablets showing the effect of
after exposure to water, leading to a decrease in its strength. concentration of pore former. Bars represent ± Standard Deviation  (n = 3)
Since, satisfactory drug release and adequate burst strength
were obtained in case of formulations with 15% pore level, 700
this was selected as the “optimized” formulation and used Batch IV (devoid of pore former)
Batch IV (7.5% w/w of pore former)
for further evaluation. 600
Batch IV (15% w/w of pore former)
Batch IV (20% w/w of pore former)
Performance evaluation of optimized formulation 500
Burst Strength (gm)

Scanning electron microscopy

400
Cellulose acetate (CA) membranes of optimized formulation,
IV (coat C), obtained before and after dissolution were 300
studied by SEM. Membranes obtained before dissolution
clearly showed nonporous region. After 8 hour dissolution, 200

the membrane clearly showed pores in range of 1 to 10 μm

100
[Figure 9] owing to dissolution of sorbitol. The leaching of
sorbitol from the membrane leads to formation of pores, and 0
thus releasing the drug. -5 0 5 10 15 20 25
Level of pore former-Sorbitol (%w/w of cellulose acetate)

Effect of pH Figure 8: Bar diagram showing the effect of concentration of pore

The optimized formulation, IV (coat C), was subjected to former on burst strength of SPM membrane. Bars represent ± Standard
in vitro release studies in buffers with different pH. As can Deviation (n = 3)
be seen from Figure 10, there is no significant difference
in the release profile, demonstrating that the developed Effect of agitation intensity
formulation shows a pH-independent release. The release profile of atenolol from the optimized
Asian Journal of Pharmaceutics - April-June 2012 157
 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

formulation IV (coat C) was independent of the agitational Kinetics and mechanism of drug release
intensity of the release media [Figure 11]. The difference Dissolution data of the optimized formulation was assessed
factor (f1) and similarity factor (f2) values were found to be with various mathematical models (zero-order, first-order,
3.03 and 91.33 (for 75 and 100 rpm), 2.74 and 93.63 (for and Higuchi) in order to describe the kinetics of drug
100 and 150 rpm), and 4.11 and 90.73 (for 75 and 150 rpm). release. Smallest value of sum of squared residuals (SSR), best
Therefore, the formulations can be expected to show a goodness-of-fit test (R2) and higher correlation coefficient were
release profile, fairly independent of the hydrodynamic taken as criteria for selecting the most appropriate model.
conditions of the body. Drug release from optimized formulations (batch- IV, coat C)
fitted well into zero-order kinetics [Table 5] confirming that
Effect of osmotic pressure the release from formulation is close to the desired release.
The effect of osmotic pressure on the optimized formulation
was studied in media of different osmotic pressures, and the Table 4: Dissolution parameters of optimized formulation
dissolution parameters with varying osmotic pressures are with varying osmotic pressure in the study
depicted in Table 4. The drug release rate decreased with Osmotic Lag time Average Average
increase in osmotic pressure in the media; however, the lag pressure (hrs.) release rate release
time was prolonged. The drug release profiles with varying atm.) (cumulative rate (mg/hr)
osmotic pressure are shown in Figure 12, and it is evident percent)
that the drug release from the formulation decreased as 15 2.967±0.021 7.802±0.361 4.015±0.122
the osmotic pressure of the media increased. This finding 45 3.464±0.014 6.924±0.327 3.551± 0.157
confirms that the mechanism of drug release is by the osmotic 60 5.207±0.016 6.421±0.882 3.158±0.241
pressure. 90 6.341±0.011 5.735±0.692 2.853±0.116

Figure 9: Scanning electron microphotographs of membrane structure of optimized formulation before and after dissolution studies

 

6,)S+ USP
 
S+FKDQJHHIIHFW USP
USP
&XPXODWLYHSHUFHQWUHOHDVH
&XPXODWLYHSHUFHQWUHOHDVH

 

 

 

 

 

 

 
     
7LPHKUV 7 LP HKUV

Figure 10: Release profiles showing the effect of pH on ATL Figure 11: Release profiles showing the effect of agitation intensity
release from optimized formulation. Bars represent ± Standard on ATL release from optimized formulation. Bars represent ± Standard
Deviation  (n = 3) Deviation (n = 3)

158 Asian Journal of Pharmaceutics - April-June 2012

 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

Accelerated stability study performance prediction, the developed formulations can be

The stored formulations of batch-IV, coat C were found to expected to perform similarly in vivo.
be stable in terms of drug content and dissolution stability
[Table 6]. In all the cases, the burst strength was higher than Table 5: Fitting drug release data of the optimized
the reported values of mechanical destructive forces in the formulation (Batch-IV, Coat C) according to various
GIT, ensuring that the formulations remained intact in GIT mathematical models in the study
without any incidence of dose dumping, even after storage. Models R2 r Intercept k SSR
(%)
In vivo prediction Zero order 0.998 0.999 -0.559 4.328 4.217
Method of superposition was used to predict the steady First order 0.976 0.988 2.043 -0.0625 123.628
state plasma levels of ATL after administration of a test dose Higuchi model 0.973 0.986 -23.563 30.739 151.363
(50 mg) of optimized formulation (Batch-IV C). Since osmotic R2: Goodness of fit; r: Correlation coefficient, SSR: Sum of squares of residuals, k: Release
rate constant for respective models (k0 in mg/h, k1 in h-1 and kh in % h1/2 for zero-order, first
pumps are reported to exhibit a significant in vitro/in vivo order, and Higuchi rate equations respectively)
correlation, predicted data of steady-state plasma levels from
drug release studies can be used for comparison with the
desired plasma levels. The desired steady-state plasma levels Table 6: Evaluation of batch IV, coat C formulation for
of ATL were predicted from a theoretically designed zero 3 months of storage at 40°C and 75% Relative humidity
(RH) in the study
order delivery system. Prediction of steady-state levels of ATL
after administration of a test dose of optimized formulation Parameter Initial 1 month 2 month 3 month
showed that the plasma levels are between 250 ng/ml to Drug content (%) 98.72± 98.34± 98.57± 98.11±
400 ng/ml. Figure 13 shows the predicted values of the steady- 1.04 1.11 1.21 1.18
state plasma levels of the drug, after the administration of Hardness (kg/cm2) 6 7 8 8
a test dose of Batch-IV C formulation, as compared to the Burst strength (kg) 358±21 372±16 379±11 385±17
desired steady state plasma levels. It is clearly evident from f1 – 2.6 2.9 3.1
the figure that the predicted steady state plasma levels are f2 – 95.2 94.2 93.6
MDT 50% (hrs.) 3.102 3.074 3.063 3.011
very close to the desired levels. The predicted Css max and
AUC0–t values after administration of optimized formulations
of ATL, in comparison with the desired ones is listed in Table 7: Predicted In vivo performance of the developed
Table 7. The % PD of the steady-state parameters of the controlled porosity osmotic pump of atenolol in the study
optimized formulations was calculated taking the data of the Product Predicted % PD Predicted % PD
desired profile as the reference. The absolute % PD was found Css max AUC0-t
to be less than 15%, ensuring that the optimized formulations (ng/ml) (ng hr/ml)
will produce plasma levels close to the desired ones. Thus, it Desireda 372.6 – 716 –
can be concluded that the developed optimized formulation Batch IV coat 343.4 -7.83 704 -1.68
(batch-IV C) will produce plasma levels well within the Cb
% PD= Percent predicted error. aPredicted from desired zero-order delivery profile
therapeutic range. Since osmotic pumps are reported to (Dose = 50mg, R0= 4.46mg/hr, and tDel 7.73hr). bPredicted from drug release study
exhibit a good in vitro/in vivo correlation, based on in vivo (Dose = 50mg, R0= 4.32mg/hr, and tDel 8.00hr)

 
2SWLPL]HGIRUPXODWLRQ%DWFK,9FRDW&
DWP  
'HVLUHG
 DWP 
3UHGLFWHGSODVPDFRQFHQWUDWLRQ—JPO

DWP  
&XPXODWLYHSHUFHQWUHOHDVH

 DWP 














 
            
7LP HKUV 7LPHKUV

Figure 12: Profiles showing the effect of osmotic pressure of the release Figure 13: Predicted steady-state plasma levels of ATL following
media on ATL release from optimized formulation. Bars represent ± administration of test dose of optimized formulation (batch IV coat C)
Standard Deviation (n = 3) in completion with the desired profile

Asian Journal of Pharmaceutics - April-June 2012 159

 Rathore and Gupta: Formulation and evaluation of CPOP delivery system for oral delivery of atenolol

CONCLUSION 15. Chen C, Lee D, Xie J. Controlled release formulation for water insoluble
drugs in which a passageway is formed in situ. US patent 5736159, 1998.
16. Zentner GM, Rork GS, Himmelstein KJ. The controlled porosity osmotic
In the present study, CPOP of sparingly water soluble drug
pump. J Control Release 1985a;1:269-82.
ATL was developed and evaluated. Target release profile was 17. Zentner GM, Rork GS, Himmelstein KJ. Osmotic flow through controlled
selected and different formulation variables were optimized porosity films: An approach to delivery of water soluble compounds.
to achieve the result. Drug release from the developed J Control Release 1985b;2:217-29.
formulations was independent of pH and agitation intensity of 18. Zentner GM, Rork GS, Himmelstein KJ. Controlled porosity osmotic
pump. US Patent 4968507, 1990.
the release media, assuring the release to be fairly independent 19. McClelland GA, Zentner GM. Solubility modulated drug delivery system.
of pH and hydrodynamic conditions of the absorption site. US patent 4946686, 1990.
ATL release from developed CPOP was directly related to the 20. Zentner GM, McClelland GA. Solubility modulated drug delivery device.
level of osmogent and pore former; however, was inversely US patent 4994273, 1991.
proportional to the level of coat thickness of SPM. Drug 21. Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic
and diastolic left ventricular function of nebivolol versus atenolol in
release data from ATL formulations fitted well into zero- patients with uncomplicated essential hypertension. Am J Cardiol
order kinetics. From drug release studies, steady-state plasma 2003;92:344-8.
levels were predicted using the method of superposition. The 22. Italian Pharmacopoeia. 10th ed. Rome, Italy: Istituto Poligrafico e Zecca
predicted steady-state plasma levels were within the desired dello Stato; 1998. p. 610-1.
range (250-400 ng/ml) to show a safe therapeutic effect. Since 23. Caplar V, Mikotic-Mihun Z, Hoffman H, Kuffinec J, Kajfez F. Atenolol,
in Analytical Profiles of Drug Substances. In: Florey K, editor. Vol. 13.
osmotic pumps are reported to exhibit a good in vitro/in vivo New York: Academic Press; 1984. p. 1-25.
correlation, based on in vivo performance prediction, the 24. Ficarra R, Ficarra P, DiBella MR, Raneri D, Tommasini S, Calabro ML,
developed formulations can be expected to perform similarly et al. Study of the inclusion complex of atenolol with β-cyclodextrins.
in vivo. Developed formulations were found to be stable during J Pharm Biomed Anal 2000;23:231-6.
three months of storage at accelerated stability condition. 25. Moneghini M, Carcano A, Zingone G, Perissutti B. Studies in dissolution
enhancement of atenolol. Int J Pharm 1998;175:177-83.
26. Serajuddin AT. Solid dispersion of poorly water-soluble drugs: Early
REFERENCES promises, subsequent problems, and recent breakthroughs. J Pharm
Sci 1999;88:1058-66.
1. Khan MA, Bolton S, Kislalioglu MS. Optimization of process variables 27. Ayer AD, Theeuwes F. Osmotic system with distribution zone for
for the preparation of ibuprofen coprecipitates with Eudragit S100. Int dispensing beneficial agent. US Patent 4200098, 1980.
J Pharm 1994;102:185-91. 28. Ramakrishna N, Mishra B. Plastizer effects and comparative evaluation
2. Khan MA, Karnachi AA, Singh SK, Sastry SV, Kislalioglu SM, of cellulose acetate and ethyl cellulose-HPMC combination coating as
BoRon S. Controlled release coprecipitates: Formulation considerations. semi-permeable membrane for oral osmotic pump of naproixen sodium.
J Control Release 1995;37:132-41. Drug Dev Ind Pharm 2002;28:403-12.
3. Singh SK, Dodge J, Durrani MJ, Khan MA. Optimization and 29. Costa P, Lobo JM. Modeling and comparison of dissolution profiles. Eur
characterization of controlled release pellets coated with an J Pharm Sci 2001;13:123-33.
experimental latex: I. Anionic drug. Int J Pharm 1995;125:243-55. 30. Verma RK, Kaushal AM, Garg S. Development and evaluation of extended
4. Jonkman JH. Food Interactions with Sustained-Release Theophylline release formulations of isosorbide mononitrate based on osmotic
Preparations 1: A Review. Clin Pharmacokinet 1989;16:162-79. technology. Int J Pharm 2003;263:9-24.
5. Santus G, Baker WR. Osmotic drug delivery: A review of the patent 31. Ritschel WA. Biopharmaceutic and pharmacokinetic aspects in the
literature. J Control Release 1995;35:1-21. design of controlled release per-oral drug delivery systems. Drug Dev
6. Verma RK, Garg S. Current status of drug delivery technologies and Ind Pharm 1989;15:1073-103.
future direction. Pharm Tech 2001;25:1-14. 32. Sheskey P, Sackett G, Maher L, Lentz K, Tolle S, Polli J. Roll compaction
7. Verma RK, Mishra B, Garg S. Osmotically controlled oral drug delivery. granulation of a controlled-release matrix tablet formulation containing
Drug Dev lnd Pharm 2000;26:695-708. HPMC: Effect of Process Scale-up on Robustness of Tablets and Predicted
8. Chao ST, Prather D, Pinson D, Coen P, Pruitt B, Knowles M, et al. Effect in Vivo Performance. Pharm Technol Tabletting and Granulation Year
of food on bioavailability of pseudoephedrine and brompheniramine book 1999. p. 6-21.
administered from a gastrointestinal therapeutic system. J Pharm Sci 33. Sheskey P, Pacholke K, Sackett G, Maher L, Polli J. Roll compaction
2000;80:432-5. granulation of a controlled release matrix tablet formulation
9. Rose S, Nelson JF. A continuous long-term injector. Aust J Exp Biol containing HPMC: Effect of process scale-up on robustness of tablets,
1955;33:415-20.
tablet stability and predicted in vivo performance. Part II. Pharm
10. Theeuwes F. Elementary osmotic pump. J Pharm Sci 1975;64:1987-91.
Technol 2000;24:30-52.
11. Okimoto K, Miyake M, Ohnishi N, Rajewski RA, Uekama K,
34. Wadworth AN, Murdoch D, Brogden RN. Atenolol: A reappraisal of
Stella VJ. Design and evaluation of an osmotic pump tablet
its pharmacological properties and therapeutic use in cardiovascular
(OPT) for prednisolone, a poorly water soluble drug, utilizing
disorders. Drugs 1991;42:468-510.
(SBE) 7M - β - CD. Pharm Res 1998;15:1562-8.
35. Jeffers TA, Webster J, Petrie JC, Baker NP. Atenolol once-daily in
12. Rao VM, Haslam JL, Stella VJ. Controlled and complete release of a
hypertension. Br J Pharmacol 1977;4:523-7.
model poorly water-soluble drug, prednisolone, from hydroxypropyl
36. Mehvar R, Gross ME, Kreamer RN. Pharmacokinetics of atenolol
methycellulose matrix tablets using (SBE) 7M -β-cyclodextrin as a
enantiomers in humans and rats. J Pharm Sci 1990;79:881-5.
solubilizing agent. J Pharm Sci 2001;90:807-16.
13. Herbig SM, Cardinal JR, Korsmeyer RW, Smith KL. Asymmetric-
membrane tablet coatings for osmotic drug delivery. J Control Release
1995;35:127-36. How to cite this article: Rathore GS, Gupta RN. Formulation
development and evaluation of controlled porosity osmotic pump delivery
14. Thombre AG, DeNoto AR, Gibbes DC. Delivery of glipizide from
system for oral delivery of atenolol. Asian J Pharm 2012;6:151-60.
asymmetric membrane capsules using encapsulated excipients.
J Control Release 1999;60:333-41. Source of Support: Nil. Conflict of Interest: None declared.

160 Asian Journal of Pharmaceutics - April-June 2012