IAJPS 2016, 3 (8), 916--925
M.Naga Ganesh and Y.Madhusudan Rao
CODEN (USA): IAJPBB
ISSN 2349-7750
ISSN: 2349-7750
INDO AMERICAN JOURNAL OF
PHARMACEUTICAL SCIENCES
Available online at: http://www.iajps.com
Research Article
FORMULATION AND EVALUATION OF ELEMENTARY
OSMOTIC PUMP DOXOFYLLINE
M. Naga Ganesh*1,2 , Y. Madhusudan Rao3
1
Research Scholar, JNT University Anatapuramu, Anantapur, Andhra Pradesh, India-515002.
2
Department of Pharmaceutics,Geethanjali College of Pharmacy, Cheeryal, Hyderabad,Telagana,
India-501301.
3
Department of Pharmaceutics, Vaagdevi Group of Pharmacy Colleges,
Bollikunta,Warangal,Telagana, India-506003
Abstract:
In the present study elementary osmotic pumps (EOP) of Doxofylline were formulated and evaluated. The target
release profile was selected and different variables were optimized to achieve the same. Formulation variables like
nature and concentration of plasticizer (0-20% w/w of polymer) osmogens comparission and role of osmogen
concentration, aperture diameter and coat thickness were found to affect the drug release from the developed
formulations. Doxofylline release was directly proportional to the level of plasticizer and osmotic pressure
generated by an osmotic agent. Drug release from developed formulations was independent of pH and agitation
intensities of release media. Burst strength of the exhausted shells increased with increase in coat thickness but
decreased with increase in level of hydrophilic plasticizer.
Keywords: Elementary osmotic pumps, Doxofylline, plasticizer.
Corresponding Author:
M. Naga Ganesh,
Department of Pharmaceutics,
Geethanjali College of Pharmacy,
Cheeryal, Hyderabad,Telagana,
India-501301.
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Please cite this article in press as M.Naga Ganesh and Y.Madhusudan Rao, Formulation and Evaluation of
Elementary Osmotic Pump Doxofylline, Indo Am. J. P. Sci, 2016; 3(8).
www.iajps.com
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IAJPS 2016, 3 (8), 916--925
M.Naga Ganesh and Y.Madhusudan Rao
INTRODUCTION:
Osmotic pumps are controlled drug delivery devices
worked on the principle of osmosis. Wide range of
osmotic devices are avaliable, out of them osmotic
pumps are unique, dynamic and widely employed in
clinical practice. Osmotic pumps shows many
advantages like they (i) are easy to formulate and
simple in operation, (ii) improve patient acceptence
by decresing frequency of dosing (iii) shows good in
vitro in vivo correlation. However wide variety of
oral osmotic systems have been reported in literature,
but most important osmotic drug delivery system is
Theeuwes elementary osmotic pump (EOP). Due to
of its simple structure and high efficiency, EOPs are
the most important osmotic devices and more than
540 patents have been devoted. Procardia XL and
Adalat
CR
(nifedipine),
Acutrium
(phenylpropanolamine), Minipress XL (prazocine)
and Volmax (salbutamol) are examples of EOPs
currently available in the market [1-3]. In this drug
delivery system, the osmotic core is surrounded by a
semipermeable membrane drilled with a drug
delivery orifice. Once this system comes in contact
with the gastrointestinal fluids, the osmotically driven
water enters the system through the semipermeable
membrane, dissolves the soluble agents, and exits
through the delivery orifice. Because these systems
use osmotic pressure for the controlled delivery of
the active compound(s), delivery rates are expected
to be independent of gastrointestinal condition [4].
The rate of drug release from osmotic pumps is
dependent on the total solubility and the osmotic
pressure of the core. The highly dihydrogenmonoxide
(H2O) - soluble drugs may create considerable
osmotic pressures and may release the active drug at
desirable rates.
Asthma and COPD (Chronic Obstructive Pulmonary
Disease) are the most common life threatening
pulmonary disease that requires constant monitoring.
Doxofylline, a methyl xanthine derivative that works
by inhibition of phosphodiesterase IV activities, has
recently drawn attention because of its better safety
profile and similar efficacy over the most widely
prescribed analogue, theophylline, indicated for
asthma and chronic obstructive pulmonary disease
due to decreased affinities towards adenosine A1 and
A2 receptors. Doxofylline is chemically designated
as 7-(1, 3 dioxolone-2-yl methyl) theophylline.
Presence of a dioxolane group in position C-7
differentiates it from theophylline. Doxofylline is an
anti-tussive and bronchodilator used for maintenance
therapy in patients suffering with asthma and chronic
obstructive pulmonary disease (COPD) and is
extensively metabolized in the liver by demethylation
and oxidation to an extent of 80-90% and 48%
plasma protein bound. Elimination half life (t) is
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ISSN 2349-7750
around 6-7 h and<4% of an administered dose of
Doxofylline is excreted unchanged in the urine. The
daily dose is 200-400 mg two to three times in a day.
Doxofylline is coming under class III of BCS
classification and oral absorption is 62.2%. It is
having solubility of 12 mg/ml in water and having
PKa 9.87 [5].
The present study was aimed towards the
development of EOP of Doxofylline. A theoretically
designed zero-order delivery pattern was deigned to
produce plasma level within the desired range. The
manufacturing procedure was standardized.
MATERIALS AND METHODS:
Materials
Doxofylline(99.9% purity) was a gift sample from
Smruthi Organics Pvt. Ltd., New Delhi, India.
Hydroxypropyl methyl cellulose, ethyl cellulose and
dibutylpthalate was gifted from Dr. Reddys Labs
Ltd., Hyderabad, India. cellulose acetate (39.8%
acetylation), polyvinyl pyrrolidone (PVP K-30),
microcrystalline cellulose (MCC pH 101),
magnesium stearate, talc and sodium chloride from
CDH Delhi, India. Acetone (HPLC grade), isopropyl
alcohol, poly ethylene glycol-400, sodium hydroxide,
hydrochloric acid, mannitol and potassium
dihydrogen ortho-phosphate from S.D. Fine
Chemicals, Mumbai, India.
Methods
Preparation of Core Tablets
Before starting formulation, compatibility of
Doxofylline with different excipients were tested
using the techniques of Differential scanning
calorimetry (DSC) (METTLER, Toledo, UK) and
Fourier transforms infrared spectroscopy (FT-IR)
(PERKIN ELMER BX 1, USA). Excipients used in
the final formulation were found to be compatible
with Doxofylline.
Core tablets of Doxofylline were prepared by wet
granulation method and batch size was kept as 50
tablets. Formulae of different core formulations of
Doxofylline are listed in Table 1&2. Required
amounts of Doxofylline and other excipients were
weighed and passed through # 40 mesh. Osmotic
agents Sodium chloride and mannitol were passed
through #100 mesh. The blend was mixed for 10min
and PVP K-30 was added. The mixture was
granulated with water and the resulting wet mass
passed through #18 mesh. The granules were dried at
700C. Then the dried granules were passed through
#25 mesh. These granules were then blended with
Magnesium stearate and Talc. Finally granules were
compressed into tablets having an average weight of
700mg using 16 station rotary tablet compression
machine (Riddhi, Ahmedabad, India) fitted with
12mm round standard concave punches. The
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M.Naga Ganesh and Y.Madhusudan Rao
compression was adjusted to tablet with
approximately 7-8 kg cm2 hardness. [6] The purity
and drug content of the tablets was found to be within
the limit of 98.24-99.65%.
Table 1: Formula for different batches of
core formulation (manitol as osmogen)
Ingredients
Batch Number
(mg/tablet)
F1
F2
F3
F4
F5
Doxofylline
Manitol
MCC
PVP-K30
Talc
Magnesium
stearate
Total weight
400
120
145
25
5
5
700
400
125
140
25
5
5
700
400
130
135
25
5
5
700
400
135
130
25
5
5
700
400
140
125
25
5
5
400
120
400
125
400
130
400
135
400
140
145
25
5
5
140
25
5
5
135
25
5
5
130
25
5
5
125
25
5
5
700
700
700
700
700
Coating and Drilling
Core tablets of Doxofylline containing different
osmogens were coated in a conventional pan coater
(VJ instruments, New Delhi, India) fitted with three
baffles placed at angle of 120[7]. The composition of
coating solutions used for coating of core tablets is
given in Table 3. Cellulose acetate was dissolved in
acetone and homogenized, plasticizer was added at
various proportions and sprayed onto core tablets in
pan coater. Ethyle cellulose was dissolved in
isopropyl alcohol and quantities of plasticizers were
added, mixed thoroughly and was used for coating.
Pan speed was maintained at 23-27 rpm and hot air
inlet temperature was kept at 50-550C. The manual
coating procedure based on intermittent spraying and
coating procedure was used with spray rate of 2-3
ml/min. Coat weight and thickness were controlled
by the volume of coating solution consumed in
coating process [8]. An appropriate size orifice (480700 m) is made on one side of all coated tablets
using microdrill (Kamlesh Engineers, Udaipur,
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India). In all the cases active coated tablets were
dried at room temperature for 24hrs before further
evaluation. [9, 10].
Table 3: Composition of coating solutions
Ingredients
Coat code
Cellulose acetate
(gm)
Ethyl
cellulose
(mg)
PEG-400 (gm)
DBP(gm)
HPMC(gm)
Acetone(ml)
IPA(ml)
0.6
2
0.3
90
0.6
90
0.3
90
0.6
90
90
-
700
Table 2: Formula for different batches of core
formulation (sodium chloride as osmogen)
Batch Number
Ingredients
(mg/tablet)
F6
F7
F8
F9
F10
Doxofylline
Sodium
Chloride
MCC
PVP-K30
Talc
Magnesium
stearate
Total weight
ISSN 2349-7750
Evaluation of developed formulation
Evaluation of powder blend
The bulk and tap density of the powdered blend was
determined using USP method I and Compressibility
index and hausner ratio were calculated [11] .The
results were presented in Table 4.
Evaluation of core and coated tablets
The core and coated tablets were evaluated for
weight variation. Thickness and diameter of core and
coated tablets were measured using digital screw
gauze (Mitutoyo, Japan). Hardness of randomly
selected tablets was tested using hardness tester
(Pfizer hardness tester, Cadmach,Ahmedabad, India).
Friability of core tablets was carried out on Roche
friability tester (Roche, Mumbai, India) using 20
accurately weighed tablets.
Drug content uniformity
Accurately weighed 20 tablets (of all batches) were
dissolved in 500 ml of distilled water. The samples
were sonicated for 30 min. and filtered through
0.45m nylon membrane filter. The filtered samples,
after appropriate dilution with mobile phase, were
analyzed
at
274
nm
using
UV-Visible
spectrophotometer (Elico, SD-159, India).
In vitro drug release study [12]
The developed formulations (n=3) of Doxofylline
were subjected to in vitro release studies using USPII dissolution apparatus (Electro lab, India) at 50 rpm.
0.1N HCL dissolution media was used for 2hrs
followed by pH 6.8 phosphate buffer ( 900ml)
maintained at 37 0.5 0C which was found to provide
sink condition (solubility of Doxofylline was
determined to be >1gm/ml) [12]. The samples (5 ml)
were withdrawn at different time intervals and
replaced with equivalent pre warmed (37 0.5 0C)
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IAJPS 2016, 3 (8), 916--925
M.Naga Ganesh and Y.Madhusudan Rao
volume of fresh medium. The withdrawn samples,
after filtration through 0.45 m nylon membrane
filters,
were
analyzed
using
UV-Visible
spectrophotometer (Elico, SD-159, India) at 274
nm.The cumulative percentage release and standard
deviation were calculated. After analyzing the drug
content in the dissolution samples, correction was
made for the volume replacement and the graph of
cumulative percent of drug release versus time was
plotted.
Release kinetics
In order to understand the mechanism and kinetics of
drug release, the results of the in-vitro
drug release study were fitted to various kinetics
equations like zero order (% of cumulative drug
release vs. time), first order (log %cumulative drug
remaining vs. time), Higuchi matrix (%
cumulative drug release vs. square root of time). In
order to define a model which will represent a better
fit for the formulation, drug release data were further
ISSN 2349-7750
analyzed by Peppas equation, Mt/M = ktn, where
Mt is the amount of drug released at time t and M is
the amount released at , Mt/M is the fraction of
drug released at time t, k is the kinetic constant and n
is the diffusional exponent, a measure of the primary
mechanism of drug release. R2 values were
calculated for the linear curves obtained by
regression analysis of the above plots.
RESULTS AND DISCUSSION:
The compatibility of the drugs and polymer was
studied by FTIR. The IR spectra of drugs and
polymer mixture shows the major characteristic
absorption bands of the polymer PVP-K30 with
negligible difference of absorption band values. So,
FTIR spectra show there is no change in the nature
and position of absorption bands which proves that
there is no chemical reaction between Doxofylline
and PVP-K30.
Fig 1: FT-IR spectra of Doxofylline
Fig 2: FT-IR spectra of Doxofylline +Manitol
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M.Naga Ganesh and Y.Madhusudan Rao
ISSN 2349-7750
Fig 3: FT-IR spectra of Doxofylline +NaCl
Table 4: Properties of the Powdered Blend, Core Tablets, and Final Coated Tablets of the Optimized
Formulation (Batch-VE)
Parameters
a
Mean value S.D
510
560
10.71
0.90
Bulk density (mg/cm )
Tap densitya (mg/cm3)
Compressibility indexa (%)
Hausnerratioa
Tablet weight (mg, n=10)
Core tablet
705.221.21
Coated tablet
718.331.45
Thickness (mm, n=10)
Core tablet
6.860.03
Coated Tablet
7.050.03
Hardness (Kg/cm)
Core tablet
8.200.5
Coated tablet
12.500.5
Friabilityb (%)
0.096
c
Content uniformity (%, n=5)
99.232
a
properties of powder blend; b property of the core tablet; c property of final coated tablet
The results of the dissolution studies indicate that the
influence of osmotic agent as well as the polymer
shows the controlled release of drugs from the
tablets. The results suggest that the ratio of drug to
polymer has greater influence on the release pattern
of Doxofylline. The drug release pattern showed a lag
time of 1hour for all the formulations which is the
basic character of the osmotic drug delivery systems.
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It is observed that the all formulations are able to
control the drug release up to 24 hours. The
cumulative percentage drug release from the
formulations met the standard criteria of drug release
from extended release formulations as specified by
the US-FDA which is around 20% within the first 4
hrs, 50 70 % at 12 hrs and > 85% after 24 hrs.
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M.Naga Ganesh and Y.Madhusudan Rao
ISSN 2349-7750
Table 5: Comparative In- vitro drug release data of formulations containing Manitol as osmogen (F1 to F5)
Cumulative % drug release*
F1 F2 F3 F4 F5
Time
(Hrs)
F1
F2
F3
F4
F5
0.00
0.00
0.00
0.00
0.00
0.60.173
0.830.115
0.460.208
0.530.230
1.160.251
2.960.152
4.730.642
3.360.450
3.660.450
5.060.556
11.360.152
11.160.251
10.20.400
11.030.351
12.730.503
16.010.300
17.030.251
15.930.251
15.360.305
19.860.305
22.030.251
22.80.600
21.330.351
21.90.458
26.330.472
38.090.500
29.630.493
26.660.750
27.830.404
31.930.251
34.130.404
36.00.655
340.360
350.300
40.020.558
38.930.416
41.630.750
40.330.351
41.090.264
47.960.378
45.060.305
47.00.721
44.660.709
49.250.503
55.030.650
10
52.160.667
55.430.832
51.630.702
55.060.251
62.030.321
12
59.860.378
60.040.818
57.040.360
61.930.321
70.760.602
14
67.460.832
67.010.700
64.040.321
70.80.400
78.560.288
16
72.560.611
76.230.450
71.160.971
76.090.458
83.860.493
20
82.081.153
82.960.611
76.660.776
81.730.589
89.040.360
24
87.030.458
91.050.700
82.630.665
90.030.793
96.060.360
* Mean SD, n=3.
Table 6: Kinetic data of formulations containing Manitol as osmogen (F1 to F5)
Zero
First
Higuchis
Korsemeyer-
order plot
order plot
Plot
Peppas plot
R2
R2
R2
R2
F1
0.976
0.989
0.982
0.987
0.947
Non-Fickian release
F2
0.980
0.976
0.903
0.977
0.948
Non-Fickian release
F3
0.968
0.986
0.977
0.966
0.934
Non-Fickian release
F4
0.990
0.981
0.987
0.996
0.964
Non-Fickian release
F5
0.980
0.961
0.972
0.914
0.957
Non-Fickian release
F.Code
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Mechanism of drug
release
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M.Naga Ganesh and Y.Madhusudan Rao
ISSN 2349-7750
Fig 4: Comparative In- vitro drug release of formulations (F1-F5)
Effect of formulation variables on in vitro drug
release [13, 14]
Effect of nature and type of semi-permeable
membrane forming polymer
The choice of rate controlling membrane is an
important aspect in the formulation development of
oral osmotic systems. The delivery of drug from oral
osmotic systems is controlled by the influx of solvent
across the SPM, which in turn carries the agent to the
outside environment. To study the effect of nature of
semi-permeable membrane forming polymer on in
vitro drug release, the core tablets were coated with
cellulose acetate and ethyl cellulose and the
dissolution data were compared.
A 5% ethyl cellulose (18-22 cps) dissolved in
Isopropyl alcohol was used as a coating solution with
dibutylphthlate (15% w/w of ethyl cellulose) as
plasticizer. The results showed that coating with ethyl
cellulose showed dose dumping after 4 hrs of
dissolution because of the detachment of the coating.
The reason may be attributed to the extreme
hydrophobic surface of ethyl cellulose unable to
attach to the smooth surface of Doxofylline core
tablet. Thus, to increase the roughness of the surface
and thus the adherence of ethyl cellulose, the core
tablets of Doxofylline were coated with 3% aqueous
solution of HPMC (15 cps) until 2% increase in
weight of tablet was obtained. The coating remained
for a period of 6 hrs, and then got detached resulting
in dose dumping at the end of 6th hour. The bust
strength of the ethyl cellulose coating was not
sufficient to withstand the hydrodynamic pressure of
the dissolution medium, due to formation of porous
structure.
Cellulose acetate (CA) films are insoluble, yet semipermeable to allow water to pass through the tablet
coating. The water permeability of CA is relatively
high and can be easily adjusted by varying the degree
of acetylation. The permeability of CA film can be
further increased by the addition of hydrophilic flux
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enhancer (necessary in case of poorly water soluble
drugs). Incorporation of a plasticizer in CA coating
formulation generally lowers the glass transition
temperature, increases the polymer chain mobility,
enhances the flexibility, and affects the permeability
of the film. The semipermeable membrane formed
from CA possesses sufficient wet strength and wet
modulus so as to retain its dimensional integrity
during the operation and the reflection coefficient,
leakiness of the membrane (i.e., leakage of solute
through the membrane) is near to 1 which is desired.
The polymer is also biocompatible.
Cellulose acetate coating remained intact even after
24 hrs of dissolution. The 4% w/w of CA in acetone
had excellent spray properties. CA coating improved
the elegance of osmotic pump along with controlling
the release of the drug from the core formulation.
Effect of nature and concentration of plasticizer
To study the effect of nature and concentration of
plasticizer, hydrophilic plasticizer such as PEG-400
and hydrophobic plasticizer dibutylphthlate were
included in the coating formulation at varying
concentrations and their influence in controlling the
drug release.
Core formulation of batch-F5 were coated with
coating formulation B and C containing 10% and
20% w/w (of cellulose ace-tate) of PEG-400
respectively coded as batch VB and batch VC. It is
clearly evident that level of plasticizer (PEG-400) has
direct effect on the drug release. As the level of PEG400 increases the membrane become more porous
due to solubilization of water soluble PEG-400 in
dissolution media resulting in higher drug release
[15]. Another parameter affected by the level of
plasticizer was burst strength of the exhausted shells.
With the increase in level of PEG-400, the membrane
became more porous after exposure to water, leading
to a decrease in its strength.
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IAJPS 2016, 3 (8), 916--925
M.Naga Ganesh and Y.Madhusudan Rao
In contrast core formulation of batch-F5 were coated
with coating formulation D and E containing 10%
and 20% w/w (of cellulose acetate) of
Dibutylphthlate (DBP) respectively coded as batch
VD and batch VE. As DBP is insoluble in water, it is
difficult to leach. Because of its hydrophobic
character, the residual DBP would resist water
diffusion and, as a consequence the drug release was
controlled. The more DBP incorporated into the
membrane, the more difficult it was to leach, and in
turn, the lower permeability of the membrane, the
lower the drug release rate obtained. DBP in the
concentration of 10% of cellulose acetate in the
coating solution formed coating which was found to
be brittle with low burst strength. DBP at a
concentration of 20% w/w of the polymer was found
to form a film with good flexibility, elegant
appearance, controlling the imbibitions of water from
the dissolution media and thus the drug release.
ISSN 2349-7750
chloride and manitol) were compared how the
concentration of osmogen will effect the drug release
from the dosage form.
Mannitol with an osmotic pressure of 38 (nearly ten
times less than that of sodium chloride) was chosen
as an osmogen. Formulations containing mannitol as
osmogenat higher concentrations was found to
release drug in zero-order for a period of 24hrs .
Effect of percentage increase in weight of coating
Formulations with percentage increase in weight
from 1.9% to 8.05% were subjected to dissolution
and the results are presented in the Table 7. It is
evident from the results that the drug was released in
less than 6hrs from formulations with % increase in
weight from 1.90% to 4.86%. The reason may be
attributed to non-uniform formation of coating with
the resultant weak points at some places in coating
through which drug might have leached. The coating
with % increase in weight of 6.50% and 8.05%
showed controlled release of drug over a period of 24
hrs. Among all the formulations, formulations with
6.50% increase in weight showed zero-order drug
release.
Effect of type and amount of osmogen
In osmotic drug delivery system osmotic pressure is
the basic principle. To create osmotic pressure in
dosage form, in formulation generally will use the
osmogen.In the present study two osmogens( sodium
Table 7: Effect of percentage increase in weight upon coating on in vitro drug release profile.
Percentage increase in weight upon coating
Time (hrs)
1.90 %
2.61 %
3.45 %
4.86 %
6.50 %
8.05 %
Cumulative %
release SD
Cumulative %
release
Cumulative %
release
Cumulative
% release
Cumulative %
release
Cumulative
% release
30.85
41.75
17.24
19.56
0.430.152
1.160.251
40.30
50.56
24.96
25.37
2.230.321
5.060.556
60.249
65.98
29.78
29.85
10.20.500
12.730.503
70.37
71.29
40.12
33.77
15.260.450
19.860.305
82.34
85.89
60.69
35.91
19.80.800
26.330.472
98.24
90.82
71.54
45.91
26.70.458
31.930.251
82.57
65.01
30.960.802
40.020.558
97.68
78.26
36.60.793
47.960.378
--
--
99.87
--
--
--
--
89.3
43.760.776
55.030.650
10
--
--
--
49.150.650
62.030.321
12
14
16
20
24
-------
------
------
98.56
------
55.731.002
62.010.755
67.040.400
75.30.500
83.030.404
70.760.602
78.560.288
83.860.493
89.040.360
96.060.360
Values are expressed as mean cumulative percentage release SD = 3
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M.Naga Ganesh and Y.Madhusudan Rao
ISSN 2349-7750
Fig 5: Effect of weight gain on release rate
Effect of pH
Formulation batch I was subjected to dissolution. The
release media used were 900 ml of distilled water
(pH = 7.0) and 900 ml of 0.1 N HCl (pH = 1.2) for
the first 2hrs followed by 900 ml of phosphate buffer
(pH 6.8) for the remaining time. The samples (5 ml)
were withdrawn at predetermined intervals and
analyzed using UV-visible spectrophotometer (Elico,
India) at 274 nm. From the results it was evident that
there was no significant difference in the cumulative
percentage drug release form osmotic systems,
proving that the osmotic systems release drug in
zero-order which is independent of pH. The
cumulative percentage of drug released in a
dissolution medium of pH 7.0 and 0.1 N HCl ans pH
6.8 are 96.29% and 98.90%respectively. The reason
could be attributed to the effective isolation of the
core form the dissolution media by the semipermeable membrane.
CONCLUSION:
The developed of elementary osmotic tablet shows a
controlled drug release of Doxofylline. The results
demonstrate that release profile is strongly dependent
on the concentration of the polymer and osmogent.
The results also indicate that the osmotic drug
delivery system may be successfully utilized for the
controlled delivery of Doxofylline up to 24hours.
Drug release from the developed formulations was
independent of pH and agitation intensity of the
release media, assuring the release to be fairly
independent of pH and hydrodynamic conditions of
the absorption site. Doxofylline release from
developed EOP was directly related to the level of
plasticizer. Drug release data from Doxofylline
formulations fitted well into zero-order kinetics. It
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can be conclusively stated that an elementary osmotic
tablet of Doxofylline is a promising approach to
alternate the conventional dosage forms.
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IAJPS 2016, 3 (8), 916--925
M.Naga Ganesh and Y.Madhusudan Rao
ISSN 2349-7750
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