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V.Felix Joe et al. / Journal of Pharmacy Research 2011,4(2),507-508
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Formulation and evaluation of Pseudoephedrine hydrochloride and Loratadine extended
release tablet.
V. Felix Joe *1, Prasanth V. V2, B. A. Viswanath 1, Rinku Mathappan2, Kamalakkannan Vairappan3, Sam .T.Mathew4
Department of Pharmaceutics, Aditya Bangalore Institute for Pharmacy Education and Research, Bangalore – 560064, India
2
Department of Pharmaceutics, Gautham College of Pharmacy, Bangalore 560032, India
3
Caplin Point Laboratories Limited, Puducherry - 605 502, India
4
Accenture Pharmaceutical services, Bangalore, 560072, India
*1
Received on: 10-09-2010; Revised on: 17-10-2010; Accepted on:13-01-2011
ABSTRACT
The present study was aimed to develop extended release tablets of pseudophedrine hydrochloride and loratadine using hydroxy propyl methyl cellulose and sodium
carboxymethylcellulose in different proportions a matrix material in core tablet and loratadine is used as immediate release for this a film coating formula was
developed, so as to provide immediate release from the zone of coating. The results of the dissolution study indicated the formulations FC – VI and FC – VII showed
maximum drug release up to 12 hr, the release of the drug was found to be dependent on the relative proportions of hydroxypropylmethylcellulose and
sodiumcarboxymethylcellulose used in core tablet. Mathematical treatment of the in vitro drug release data suggests that, all the formulations best fitted into first
order release kinetics. Drug release from the matrix occurred by combination of two mechanisms, diffusion of drug from tablet matrix and erosion of tablet surface.
Key words:Pseudoephedrine hydrochloride, loratadine, extended release and film coating
INTRODUCTION
Pseudoephedrine Hydrochloride a sympathomimetic drug effective for treating
nasal congestion. Loratadine, a non-sedating Antihistaminic agent is also known
to be useful as an anti-allergy agent for the treatment of seasonal allergic rhinitis
symptoms such as sneezing and itching. Therefore an oral dosage composition
containing both loratadine and pseudoephedrine is used for treating patients
showing the sign and symptoms associated with upper respiratory diseases and
allergic rhinitis [1, 2].
Biological half-life of Pseudoephedrine Hcl is only about 6.3hours, while loratadine
which combines with plasma proteins after being absorbed through the gastrointestinal tract has a much longer biological half-life of 12-15hrs. Further
loratadine has poor water solubility and exhibits a very low dissolution rate.
Therefore a conventional formulation prepared by simply mixing loratadine
and pseudophedrine is not capable of maintain therapeutically effective blood
concentrations of both ingredients at the same time for a prescribed period. A
film coated tablet comprising an extended release matrix core containing Pseudoephedrine Hydrochloride and a hydrophilic gel, a coating layer containing
loratadine being formed when this formulation is ingested, loratadine having a
longer biological half-life is released from the coating layer before the dissolution of Pseudoephedrine Hydrochloride having a shorter biological half-life
from the extended release matrix core [1, 2].
The selection of release regarding excipients is necessary to achieve a constant
in vivo input rate of the drug. The matrix tablets composed of drug and the
release retarding material (polymer) offers the simplest approach in designing
an extended release system [3]. Number of studies shows the use of hydrophilic
matrices to formulate the controlled release dosage forms of different drugs.
Because of their simplicity and cost effectiveness, matrix tablets are widely used
for oral controlled release dosage forms. Hydrophilic polymers from a gel like
structure around the tablet core, which controls the drug release. The Hydrophilic polymer hydroxy propyl methylcellulose and sodium carboxymethylcellulose was selected in the present study is a pH- independent material, which has
been widely used to prepare extended release dosage forms [4].
*Corresponding author.
V.Felix Joe
Lecturer
Department of Pharmaceutics
Aditya Bangalore Institute of Pharmacy Education and Research
Bangalore – 560064, India
Hence in the present work, an attempt has been made to develop extendedrelease matrix tablets of Pseudoephedrine Hydrochloride and loratadine and to
study the in vivo release characteristics and kinetics of the prepared formulations.
MATERIALS AND METHODS
Pseudoephedrine Hcl, Loratadine, as gift sample were obtained from Medo Pharm,
Chennai, India. Hydroxy propyl methylcellulose, Carboxy methylcellulose were
obtained as gift samples from Colorcon Asia Pvt.Ltd (Goa, India). Dicalcium
Phosphate and polyvinylpyrrolidine (pvp-k30). Materials and excipients used
in preparing tablets were of IP grade. All the other ingredients used throughout
the study were of Analytical grade.
Preparation of core matrix tablets:
Different tablet formulations (Batch size of 300 tablets) were prepared by wet
granulation technique i.e. F-I to F-VII (Table 1). Accurately weighed quantities
of pre-sieved drug, Pseudoephedrine Hydrochloride, Hydroxy propyl methyl
cellulose, sodium carboxy methyl cellulose, Dicalcium phosphate and Polyethylene glycol 6000 were mixed uniformly and wetted with solution of PVP in IPA
as granulating fluid, the cohesive mass this obtained was screened through a sieve
NO:12. The granules were dried at 40°c for 15 minutes. The coarse granules so
obtained were once again screened using the same sieve. Stearic Acid, Microcrystalline cellulose and silicon dioxide were finally added as antifrictional agents to
the uniform sized granules and the granules were compressed (11.11mm diameter, biconvex punches) in a rotary tablet machine [3]. Each tablet contained
400mg of Pseudoephedrine hydrochloride and other excipients as listed in Table.1
Evaluation of Granules:
Both loose bulk density (LBD) and tapped bulk density (TBD) were determined.
A quantity of 2g of granules from each formulation. Previously lightly shaken to
break any agglomerates, was introduced a 10ml measuring cylinder. After the
initial volume was observed, the cylinder was allowed to fall under its own weight
onto a hard surface from the height of 2.5cm at 2sec intervals. After 300 taps,
the tapped volume of packing was noted. LBD and TBD were calculated using
the formulae; LBD = weight of the powder / volume of the packing. TBD =
weight of the powder / tapped volume of the packing.
The compressibility index of the granules was determined by Carr’s compressibility index, Carr’s index (%) = [(TBD – LBD) x 100] / TBD. The angle of
repose of granules was determined by the funnel method. The accurately weighed
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
507-508
V.Felix Joe et al. / Journal of Pharmacy Research 2011,4(2),507-508
granules were taken in a funnel, which was maintained at 4 inches from the
surface. The granules were allowed to flow through the funnel freely onto the
surface. The diameter of the powder cone was measured and angle of repose was
calculated using the equation tanθ = h/r, θ = tan-1 h/r, where θ is the angle of
repose, ‘h’ is the height in cm of the powder cone and r the radius in cm of the
powder cone. Moisture content of granules was determined using Karl Fisher
instrument [3]
Evaluation of matrix tablets:
Hardness test:
For the determination of the hardness, Pfizer hardness tester was used. For each
formulation 10 tablets were determined [5, 6].
Weight variation test:
Twenty tablets were randomly selected and weighed to determine the average
weight and were compared with individual tablet weight. The percentage weight
variation was calculated [5, 6].
Thickness and diameter test:
The thickness and diameter was determined for 10 tablets with the help of a
digital vernier caliper.
Friability test:
Weighed amount of 20 dedusted tablets were subjected to rotating drum of
friability test apparatus. The drum was rotated at a speed of 25 rpm for 4
minutes and reweighed the tablets [5, 6].
Drug content:
Drug content of the matrix tablets was determined by weighing and finely
grinding 10 tablets of each batch. Aliquot of this powder equivalent to 25mg of
Pseudoephedrine Hydrochloride and dilute to 100ml with water to get a solution
of 25mcg/ml. To 5ml each of standard and sample solutions added 1ml of sodium
carbonate solution and 2ml of sodium Meta periodate solution mix. Allow
standing for 10 minutes. Add 20ml of n-hexane and shake for 30 seconds.
Measure the absorbance of both standard and sample solutions at the maximum
at about 242nm using uv/vis spectrophotometer.
In vitro release studies
The in vitro release rate studies were carried out in USP dissolution test apparatus Type I in distilled water from 3-12 hr. rotation speed of 50 rpm at temperature of 37 ± 0.5° the dissolution medium of 900ml was maintained throughout
the experiment. At predetermined time intervals, 10ml of sample was with
drawn and replaced with the same volume fresh dissolution medium. The samples
withdrawn were filtered through 0.45µ membrance filters, and drug content in
each sample was analyzed after suitable dilution by uv/vis spectrophotometer at
242nm. All dissolution studies were carried out in duplicate and repeated at least
thrice [3].
Preparation of coating solution
With the objective to develop Pseudoephedrine (ER) and Loratadine (IR) combination a coating formula was developed so as to provide immediate release of
loratadine from the zone of coating. Loratadine was deposited in the form of a
thin and uniform film. Loratadine is dissolved in IPA coating solution is prepared by the mixture of titanium dioxide, HPMC, castor oil and methylene
chloride. To the above mixture drug solution is added and stirred well. Tablets are
transferred to a coating pan and the coating solution sprayed on the core tablet.
During coating, the temperature is maintained at 40°c. The formula for coating
solution is given in Table II. The coated tablets were evaluated for drug dissolution, assay and other parameters.
Evaluation of coated tablets
Drug content of the coated tablets was determined by weighing and finely
grinding 10 tablets weigh accurately about 10mg loratadine equivalent sample
powder in 20ml volumetric flask. Add 10ml methanol and shake for 10 minutes
make up with mobile phase. Filter through 0.45 µ filter paper and inject the
filtrate by high performance liquid chromatography and the content was compared from a calibration curve prepared with standard loratadine in the same
medium.
Table 1. Tablet formulations with combined matrix material
Sl.No
Ingredients (mg / tablet)
F-I
F-II
F-III
F-IV F-V
F-VI
F-VII
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pseudoephedine Hydrochloride
Dicalcium Phosphate
Hydroxy Propyl Methyl Cellulose
Poly Vinyl Pyrolidone
Silicon dioxide
Magnesium Sterate
Stearic Acid
Talc
Isopropyl Alcohol
Methylene Chloride
Microcrystalline Cellulose
Ethyl Cellulose
Sodium Carboxymethyl Cellulose
Polyethylene Glycol 6000
120
200
25
6
10
3
3
3
Q.S
Q.S
-
120
120
10
6
3
6
Q.S
Q.S
60
60
-
120
123
26
6.6
6.6
6.6
Q.S
Q.S
50
50
-
120
147
20
13
3
13
Q.S
Q.S
30
147
16
-
120
90
80
40
8
13
Q.S
Q.S
13
100
8
120
100
80
90
8
13
Q.S
Q.S
13
100
8
120
180
40
6.6
6.6
6.6
Q.S
Q.S
30
60
-
Table 2. Film Coating Solution
Sl.No
Ingredients
Qty / Batch (gm)
1
2
3
4
5
6
Loratadine
Hydroxy Propyl Methyl Cellulose
Titanium dioxide
Castor Oil
Isopropyl Alcohol
Methylene Chloride
8.25
10.200
9.800
0.006
0.120
0.300
RESULTS AND DISCUSSION
Formulation of granules is the key factor in the production of tablet dosage
from involving extended release of drug from matrix type particle. Physical
parameters such as area, hardness, surface characteristics and size can significantly affect the rate of dissolution of drugs contained in a complex system.
The selection of wet granulation technique for matrix tablet preparation was
based on previously reported study which suggested that wet granulation results
in harder tablets with lower matrix porosity that give very slow release rates
when compared to direct compression.
The granules of different formulations were evaluated for LBD, TBD, compressibility index, angle of repose and moisture content. The LBD and TBD of
granules ranged from 0.19 ± 0.6g/ml and 0.26 g/ml respectively. Compressibility index values up to 15% result in good to excellent flow properties, but
readings above 25% indicates poor flowability. Angle of repose values form
27.53 ± 0.12° to 38.32 ± 0.25°. Generally values of angle of repose are rarely
less than 20° and values up to 40° indicate reasonable flow properties. All these
results indicate that the formulated granules possessed satisfactory flow properties and compressibility. The moisture content of all the formulations was found
to be satisfactory. The results of hardness and friability of the prepared matrix
tablets ranged from 5.5 ± 0.22 to 8 ± 0.12 kg/cm2. All the batches of fabricated
tablets were of good quality with regard to hardness, friability and drug content.
The results of thickness and diameter of tablets ranged from 4.0 ± 0.05 to 5.4
± 0.02 and 10.4 ± 0.3 to 11.3 ± 0.2 mm, respectively. Thus all formulations
showed uniform variation results of the matrix tables ranged from 395 ± 1 to
406 ± 1 mg. For weight variation test, the pharmacopocial limit for the percentage deviation for tablets of more than 250mg is ± 5%. The average percentage deviation of all tablet formulations was found to be within the above
limit in compliance with official standards.
Defined bulk weight per tablet is 400mg-containing 120mg of Pseudoephedine
Hydrochloride; F-I to F-VII represents the various formulations of
Pseudoephedine Hydrochloride. In which F-VI Dissolution profile was satisfactory and complies with the limit of 12hr. By using this F-VI formula a stability
batch F-VII was taken and their dissolution was also satisfactory.
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Source of support: Nil, Conflict of interest: None Declared
Journal of Pharmacy Research Vol.4.Issue 2. February 2011
507-508