Vol-2/Issue-6/Nov-Dec 2013
PhTechMed
ISSN: 2278-1099
Formulation and Evaluation of Pulsatile Drug Delivery System of Salbutamol Sulphate Using
pH Dependent Systems
Talasila Eswara Gopala Krishna Murthy*1, Kommineni Veditha2, Phanihassanth3
*1Bapatla College of Pharmacy, Bapatla, Guntur
2
Vignan Pharmacy College, Vadlamudi, Guntur
3
Dr.Reddy's Labs, Hyderabad
Abstract
Asthma is a chronopharmacological disease prone to occur during early morning hours that is around 4am to 6am. The objective of the
present study is to formulate and evaluate a pH dependent pulsatile drug delivery system to achieve the onset of action between 4am to
6am. The core tablets were prepared by direct compression method using different diluents such as Flow lac 100, Tablet tose-70,
DCL-21, Spray dried lactose, Avicel, Di calcium phosphate, Microlac 100. The pH dependent coating tablets were prepared by
compressing the core tablet with pH in sensitive polymer HPMC and pH sensitive polymer Eudragit L 100 of different ratios. The
duration of the lag phase during dissolution can be controlled by the thickness of the HPMC layer. The prepared tablets were
evaluated for weight variation, hardness, friability, content of active ingredient and content of uniformity and in vitro drug release
studies. The drug release from the core tablet is dependent on the diluent employed in the preparation of core tablet. The influence of
pH dependent polymer was found to be more compared to pH independent polymer. A lag time of five hours is observed from
compressed coated tablet containing Eudragit L 100 only.
Key Words: Enteric coated tablets, pulsatile drug delivey system, core, film coated
Introduction
Asthma is a chronic disease of the respiratory system in which
the airway occasionally constricts and lined with excessive
amounts of mucus. These acute episodes may be due to
exposure to cold air, emotional stress, environmental
stimulant, exercise, viral respiratory tract infections, food
additives and medications. During asthma attacks the smooth
muscle cells in the bronchi constrict the airways become
inflamed and swollen and breathing becomes difficult. This is
often referred to as a tight chest and is a sign to immediately
take medication. The treatment of asthma generally includes
conventional oral dosage forms like tablet, capsules, oral
liquids and inhalers, but oral administration is the most widely
accepted route of delivery due to its ease of administration,
convenience, compatibility and patient compliance [Bradley et.
al., 2001; Peter et. al., 1995].
Salbutamol sulphate is a short acting β2 adrenergic receptor
agonist has t1/2 of 2.8 hours used for the relief of bronchospasm
in conditions such as asthma and it is well absorbed through
out GIT. As Asthma is a chronopharmacological disease prone
to occur during early morning hours that is around 4am to 6am
[Martin et. al., 1998; Stroms et. al., 1994; Pincus et. al.,
1995]. To show action at that time, patient has to administer
the drug at 3am which may not be convenient to the patient.
Hence to increase patient compliance pulsatile drug delivery
system of Salbutamol sulphate is developed which delivers the
right drug, at right time, right amount, to the right patient
[Yoshida et. al., 1993; Lin et. al., 1996]. Hence the
objective of present study was to formulate an enteric coated
tablet to increase the onset of action of broncho dilator for the
treatment of asthma.
Materials and Methods
Salbutamol sulphate, Flow Lac 100, Tablet Tose-70, DCL-21,
Spray Dried Lactose, Avicel, Di Basic Calcium Phosphate,
Microlac 100, Cross Caramullose Sodium, HPMC (3000-5600
Address for Correspondence
Email ID: gopalakrishnatalasila@yahoo.com
Tel No.: +918643-223202
Received: 12/08/2013
Accepted: 01/10/2013
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cps) and Eudragit L 100 were obtained as gift samples from
M/S Natco pharma Ltd. Hyderabad and other chemicals like
Magnesium Stearate, Talc, and Ethanol were purchased
locally.
8 Stage Dissolution test apparatus (DISSO-2000)-Labinda
instrument Pvt Ltd, Weighing machine-Essae-Teraoka Ltd,
Digital pH meter-Systronics Pvt Ltd, UV- Vis SpectrometerElico Ltd, Digital balance(AX-200)-Schimazu corporation,
Disintegration Apparatus-Campbell Electronics, CMD 3-16
Station Rotary Tableting Machine-CMC Machinery, Cadmach
Single Stroke Tablet Machine (Hoko-25Type)-CMC
Machinery, Friability Apparatus-Campbell Electronics,
Monsanto Hardness Tester Shreeji Chemicals were also
employed in this investigation.
Pre Formulation Studies
The following Micromeritics properties of the selected diluents
were conducted.
Evaluation of Micromeritics Properties of Direct
Compression Diluents
Bulk density
5gms of blend was weighed and it was transferred to a
measuring cylinder. It was subjected to 3 tappings, the bulk
volume was noted8. The bulk density was calculated by the
formula:
Bulk weight
Bulk Density =
Bulk volume
Carr’s index (%)
5gms of blend was weighed and it was transferred to a
measuring cylinder and then it was subjected to 100 tappings.
The tapped density and poured density were noted8. Carr's
index was calculated by the following formula:
Carr’s Index (%) =
Tapped Density-Poured Density
Tapped Density
X100
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Hausner’s ratio
5gms of blend was weighed and it was transferred to a
measuring cylinder and then it was subjected to 100 tappings.
The tapped density and poured density were noted 8. Hauser's
ratio was calculated by the following formulae:
Tapped Density
Hausner’s Ratio =
Poured Density
Murthy et al.,
formed were noted down [Indian pharmacopeia, 2007].The
angle of repose (θ) was calculated by the formulae:
h
Angle of repose = Tan-1
r
Preparation of Core Tablet
The core tablets were prepared by direct compression
technique. The composition of the tablets was showed in the
table I. All the excipients were passed through sieve No. 60.
The required ingredients were weighed accurately and mixed
Angle of repose
5gms of blend was taken and it was poured into a hollow
thoroughly for 5 min. Then the resulting mixture was
cylinder which was placed on a graph sheet. Then the cylinder
compressed to form a tablet using 5mm compression tool with
was slowly lifted. Then height and diameter of the heap
Cadmach single stroke tablet machine (Hoko-25 Type).
Table I: Composition of Core Tablet
Quantity(mg per tablet)
Ingredient
F1
F2
F3
F4
F5
F6
F7
Salbutamol sulphate
4
4
4
4
4
4
4
Flow lac 100
65
-
-
-
-
-
-
Tablet tose-70
-
65
-
-
-
-
-
DCL-21
-
-
65
-
-
-
-
Spray dried lactose
-
-
-
65
-
-
-
Avicel
-
-
-
-
65
-
-
Di calcium phosphate
-
-
-
-
-
65
-
Microlac 100
-
-
-
-
-
-
65
Cross caramallose sodium
5
5
5
5
5
5
5
Magnesium stearate
1
1
1
1
1
1
1
Total Weight
75
75
75
75
75
75
75
Evaluation of core tablets
Weight variation
Twenty tablets were collected at random and were weighed
collectively and individually. From the collective weight,
average weight was calculated9. The percent weight variation
was calculated using the formula:
Average weight – Individual weight
%Weight Variation=
Average weight
Hardness
Hardness of the tablet was determined using the Monsanto
hardness tester. The lower plunger was placed in contact with
the tablet and a zero reading was taken. The plunger was then
forced against a spring by tuning threaded bolts until the tablet
fractured. Then the final reading was recorded [Leon et. al.,
1987]. The hardness was computed by deducting the initial
pressure from the final pressure.
Content of active ingredient
Ten tablets of Salbutamol Sulphate containing the equivalent
of 40mg of Salbutamol were collected randomly, powdered
and shaken with 60ml of water for 1hr. The resulting solution
was diluted to 100ml and then filtered. The filtrate was
suitably diluted and analyzed for Salbutamol at 276nm9.
Content uniformity
Ten tablets, each containing equivalent to 4mg Salbutamol
were collected randomly and analyzed for the content of
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Salbutamol separately in each case according to the procedure
described in content of active ingredient [Michael, 2006].
Friability
The Roche friability test apparatus was used to determine the
friability of the
tablets. 10 tablets were selected, dedusted
and weighed. Then they were placed in a drum and rotated for
100 times. Then tablets were dedusted to remove loose dust
and were reweighed9. The percentage friability was calculated
by formula:
Initial weight – Final Weight
%Friability=
Initial Weight
Disintegration
Six tablets were collected randomly and introduced one tablet
into each tube separately, added a disc to each tube. Suspended
the assembly in the beaker containing water and operated the
apparatus for 15min [Michael, 2006].
Dissolution studies on core tablet
Dissolution studies were performed for different core tablets
which were formulated using different diluents are by
employing paddle method. The
temperature was maintained
at 37±0.5ºc and paddle was set at 50 rpm. The dissolution
medium used was 7.4 pH phosphate buffer and about 5ml of
sample was withdrawn at a sample interval of 5min up to
30min and sample was replenished with fresh dissolution
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medium. The collected samples were analyzed at 276nm. The
dissolution studies were carried out in triplicate [United States
pharmacopeia, 2004].
Formulation of Compression Coated Tablets
Pulsatile drug delivery systems for Salbutamol sulphate were
prepared with compression coating technique by employing
the core tablet prepared with the diluents DCP and
combination of pH sensitive polymer Eudragit L 100 and
hydrophilic polymer HPMC as matrix forming material. The
composition of the prepared compression coated tablets was
showed in Table II. Accurately weighed (150mg) amount of
the polymer mixture was placed in 12mm die. The selected
core tablet F6 was placed at the centre with the help of forceps.
Then another portion of Eudragit L 100: HPMC mixture
equivalent to 150mg was accurately transferred into the die
cavity. The resulting blend was subjected to compression by
employing CMD 3-16 Station Rotary Tableting Machine.
Evaluation of compression coated tablets
The prepared compression coated tablets were evaluated for
the weight variation, hardness, friability, content of active
ingredient and content of uniformity as per the procedures
mentioned earlier.
Dissolution Studies
The dissolution studies on the coated tablets were performed
up to 7 hrs with different dissolution media viz 0.1N HCl (0-2
hrs), 6.8 pH Phosphate buffer (2-5 hrs) and 7.4 pH Phosphate
buffer (5-7 hrs).The dissolution studies were conducted at 37.0
± 0.5°c using paddle type apparatus (50 rpm).5ml of aliquot
were withdrawn at 30min time interval and replenished with
fresh dissolution media. The samples were analyzed at 276nm
for the estimation of Salbutamol sulphate.
Results and Discussion
Pulsatile drug delivery systems for Salbutamol sulphate were
prepared with a view to release the Salbutamol at 4am from
the administered dosage form for effective treatment of
noctural asthma. Pulsatile drug delivery systems were
designed with compression coating technique and the results
are reported here. Salbutamol sulphate core tablets were
formulated with direct compression technique by employing
different commercially available direct compressible diluents.
The blends containing the Salbutamol and the direct
compressible diluents were subjected to micromeritics
Murthy et al.,
evaluation and the results are shown in table III. These blends
exhibited good flow property and hence compressed to form
tablet. The prepared tablets were evaluated for various quality
control tests and the results were depicted in table IV. All the
tablets complied weight variation, friability, content of active
ingredient and content uniformity test. The tablets formulated
with the diluents DCL failed to disintegrate within the
specified 15 min disintegration time, however the remaining
tablets passed the disintegration test. The formulations were
further subjected to dissolution studies in 7.4 pH phosphate
buffer. The dissolution profiles were showed in fig 1. The
dissolution rate followed first order kinetics. The dissolution
kinetics parameters were presented in table V. The dissolution
rate was found to be influenced by the diluents employed in
the formulation of tablets. Based on the release rate of
Salbutamol sulphate, the diluents can be ranked as
DCP>Microlac 100>Tablet Tose 70>Avicel>Spray dried
lactose>Flow Lac 100> DCL-21. The formulations containing
DCP showed relatively better dissolution rate, hence the core
tablet containing DCP (F6) was selected for further studies.
Studies on compression coated tablets
Compression coated tablets of Salbutamol sulphate were
formulated with compression coating technique by employing
different proportions of pH sensitive polymer Eudragit L 100
and the hydrophilic swellable polymer HPMC as coating
material and the tablet formulated with DCP(F6) as core
material. All the formulated tablets were subjected to various
quality control tests and the obtained data was showed in table
VI. All the formulations complied the pharmacopoeial
requirements. The dissolution studies on these formulations
were conducted in 0.1N HCl for 0-2hours, 6.8 pH phosphate
buffer (2-5) and 7.4 pH phosphate buffer (5-7 hours). The
dissolution data was showed fig 2. The formulation containing
only Eudragit maintained a lag time of 5 hours and the drug
was released after 5 hours. The lag time was found to be
increased with the concentration of Eudragit L 100 and the
release rate was found to be increased with the reduction of
HPMC content. Thus pulsatile drug delivery systems
formulated with only Eudragit L 100 is more suitable for
pulsatile drug delivery systems to maintain a lag time of 5
hours.
Table II: Composition of Compression Coated Tablets Containing Salbutamol Sulphate Core Tablet
Quantity(mg per tablet)
Ingredients
CCT1 CCT2 CCT3 CCT4 CCT5
UPPER LAYER
HPMC
150
100
75
50
EUDRAGIT L 1OO
50
75
100
150
CENTRAL CORE(F5)
LOWER LAYER
HPMC
150
100
75
50
EUDRAGIT L 100
50
75
100
150
375
375
375
375
375
Total Weight
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Murthy et al.,
Table III: Micromeritics Properties of Blends Containing Salbutamol Sulphate and Direct Compressible Diluents
S. No Diluents
Bulk density (g/ml) Angle of repose(ϴ) Carr’s Index (%) Hausner's ratio
1.
Spray dried lactose
0.595
25.64
14.26
1.166
2.
Micro lac-100
0.465
18.72
18.56
1.22
3.
Avicel
0.333
30.96
24.48
1.324
4.
Flow lac-100
0.543
28.76
19.5
1.243
5.
DCL-21
0.531
37.66
25.63
1.344
6.
Di Calcium phosphate 0.416
47.46
15.75
1.37
7.
Tablet tose-100
29.50
16.2
1.194
0.510
Table IV: Quality Control Test Report of Salbutamol Sulphate Core Tablets
Formulation
Average weight Hardness (kg/meter) Friability %Drug Content Content uniformity Disintegration time (min)
F1
74.5±1.7
4.2
0.53
98.56
97.54±1.7
6
F2
74.7±1.8
4.3
0.55
98.34
98.35±1.9
5
F3
75.2±1.9
4.0
0.57
98.86
99.36±2.0
>15
F4
75.1±2.1
4.1
0.62
99.34
98.48±2.1
6
F5
74.9±2.0
4.7
0.66
98.29
99.23±1.8
5
F6
74.7±1.7
4.4
0.62
98.44
98.79±1.5
3
F7
74.8±2.2
4.8
0.59
99.67
97.86±1.6
4
Table V: Dissolution Kinetic Data of Salbutamol Sulphate Core Tablet
S. No
Formulation
T50 (F) (min)
T90 (F) (min)
DE20 (%)
K (Min-1)
1.
F1
4.442
14.762
58.9
0.156
2.
F2
2.21
7.35
73.6
0.313
3.
F3
55.8
185.0
11.4
0.0124
4.
F4
3.22
10.71
43.04
0.215
5.
F5
2.47
8.22
79.6
0.280
6.
F6
1.711
5.688
82.9
0.405
7.
F7
1.828
6.076
82.8
0.379
120
120
100
100
80
F1
F2
F3
60
F4
F5
F6
F7
40
20
%DRUG DISSOLVED
%DRUG DISSOLVED
Table VI: Quality Control Test Report of Compression Coated Tablets Containing Salbutamol Sulphate
Formulation Average Weight (mg) Hardness (Kg/Meter) Friability %Drug Content Content Uniformity
374.5±2.1
6.7
0.33
97.58
96.64±1.6
CCT1
374.6±2.3
6.2
0.35
98.54
97.45±1.8
CCT2
374.8±2.0
6.4
0.37
98.23
99.46±1.9
CCT3
374.3±1.9
6.5
0.46
99.68
98.58±1.9
CCT3
374.7±2.4
6.6
0.37
99.43
99.33±2.0
CCT4
80
CCT1
CCT2
60
CCT3
CCT4
CCT5
40
20
0
0
0
5
10
15
20
25
30
35
TIM E(M in)
Fig 1: Dissolution Profile of Salbutamol Sulphate Tablets
Formulated With Different Diluents
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0
1
2
3
4
5
6
7
8
TIM E(Hrs )
Fig 2: Dissolution Profile of Compression Coated
Salbutamol Sulphate Tablets
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Conclusion
All the selected diluents exhibited the required flow and
compressibility. All the formulated core tablets satisfied
weight variation, friability, drug content and content
uniformity requirements. The disintegration time and
dissolution rate was found to be influenced by the diluents
employed in the preparation. The dissolution rate from all the
core tablets followed first order kinetics. The lag time from the
compression coated tablets was found to be influenced by the
concentration of pH sensitive polymer. The lag time up to 5
hours can be achieved with compression coating technique by
employing Eudragit L 100 as coating polymer.
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