Formulation and Evaluation
of Taste Masked Fast Dissolving/ Disintegrating Tablets of Hydroxyzine
Hydrochloride
Pawar P.B.1, Dr. M.P. Wagh2,
S.N. Bhandare1
1Department of Pharmaceutics, P.R.E.S’s College of Pharmacy, Chincholi, Nasik-422101, Maharashtra, India.
2Department of Pharmaceutics, N.D.M.V.P’s College of Pharmacy,
Nasik-422002, Maharashtra, India.
*Corresponding
Author E-mail: poonampawarcpn@gmail.com
ABSTRACT:
Hydroxyzine hydrochloride is histamine H1 antagonist, antipruritic and anxiolytic,
sedative and hypnotic agent. It helps in suppression of histaminic edema, flare
and pruritus, but it has poor patient compliance due
to its bitterness. So its taste should be masked to formulate it in a palatable
dosage form. So in the present work undertaken , an attempt was made to mask the
taste of Hydroxyzine hydrochloride by complexation technique using Ion exchange resin (IER), Indion- 234 (Polyacrylic hydrogen
with carboxylic functionality), and to formulate mouth dissolving tablet(MDT).
The drug –IER complex (resinate) was evaluated for
taste masking and characterized by DSC, IR. MDTs were formulated using resinate by direct compression method using solid drug:
resin complex of Hydroxyzine HCl
with indion-234 (equivalent to dose of drug, 1:3 ratios). Super disintegrating
agents like Croscarmellose Sodium, sodium starch glycolate, crospovidone, L-HPC, Pregelatinised Starch and combination of sodium bicarbonate
and citric acid (1.5:1). Formulations were coded as formulation F1, F2, F3, F4,
F5 and F6 respectively. Tablets are
evaluated for hardness, friability, Disintegration time, Thickness, weight
variation and drug content and In vitro release study. The tablets
disintegrated in vitro within 10-50 sec. Cros povidone shows lesser disintegration time from all the
formulation. The result showed that Hydroxyzine HCl was successfully taste masked and formulated into MDT
as an alternative to conventional tablets.
KEYWORDS: Mouth
dissolving tablet, Hydroxyzine hydrochloride,
Indion-234, Taste masking.
INTRODUCTION:
An inability or unwillingness to swallow solid oral dosage forms such as
tablets and poor taste of medicine are some of the important reasons for
consumers dissatisfaction (1,5). IER are
water insoluble, crosslinked polymers containing salt
forming groups in a repetitive position on a polymer chain. The unique
advantage of IER for complexation is due to the fixed
positively or negatively charged functional groups attached to water insoluble
polymer backbones. These groups have affinity for oppositely charger counter
ions, thus absorbing the ion into the polymer matrix. Since most of the drug
possesses ionic site in their molecule, the resin charge provides means to
loosely bind such drugs. The binding is generally an equilibrium process,
resulting in continuous desorption or elution of drug from the resin as drug is
absorbed into the body(6,7).
IER are water insoluble high molecular weight polymers
and so are not absorbed by the body and therefore inert and safe for oral use.
The complex of cationic drug and weak ion exchange
resin does not break at pH of saliva i.e. 6-7 with cation
concentration of 40 meq./lit.
but at high ionic concentration in stomach and pH 1.2,
free drug is immediately released. This implies that while passing through
mouth, the drug remain in a complex form, thereby imparting no bitter taste in
the mouth. This property was exploited to formulate the consumer friendly
dosage form i.e. Mouth dissolving tablets(4,8).
MDT are dosage form, which disintegrates in patients mouth within a few
seconds without the need of water, or
chewing, providing best remedy for the patient suffering from dysphagia. Some drugs are absorbed from the mouth, pharynx
and esophagus as the saliva passes down the stomach.
In such case, the bioavailability is greater than those observed for
conventional dosage form.
MATERIAL AND METHODS:
Hydroxyzine hydrochloride, Croscarmellose Sodium, sodium starch glycolate,
crospovidone, L-HPC, Pregelatinised
Starch obtained as a gift sample from Glenmark
Pharmaceuticals (Sinnar, India) Indion-234 obtained
from Ion exchange India Ltd, (Mumbai) All other
reagents used in present work were of analytical grade.
Figure No: 1. FTIR spectrum of
A)Indion-234 Resin B) Drug: Resin Complex C)Hydroxyzine hydrochloride
Preparation of resinate(9)
Resinate were prepared
using batch method. Ion exchange resins were weighed accurately. Then were swelled by stirring in 20 ml of water for 30 min using a
magnetic stirrer. After 30 min, the accurately weighed quantity of drug
was added in slurry of resin during stirring. The resultant mixture of drug and
ion exchange resin was stirred for 1 hour. The slurry was filtered off and the
filtrate was analyzed for drug complexed with each of
the ion exchange resin. The residue was washed with 10ml water and air-dried.
Solid complexes of each of the ion exchange resin with drug were prepared in
various ratios, keeping the quantity of drug constant,
The percent drug complexed with each of the ion
exchange resin was determined by analyzing the filtrate, after appropriate
dilution with distilled water. The filtrate was analyzed by Shimadzu UV-250 1PC
double beam spectrophotometer at λ max 229.8 nm.
Table No: 1 Percent drug complexed in various
ratios of cation exchange resins
|
Ratio Drug:
Resin (% w/w) |
Percent
drug complexed |
|
Indion-234 |
|
|
1:1 |
83.181±1.124 |
|
1:2 |
91.001±0.656 |
|
1:3 |
91.780±0.4 |
Optimization of concentration of resin for drug
loading
The ratio of resin which shows the highest amount of
drug loading was then optimized for various drug: resin concentration varying
from 1:1 to1:3. Accurately weighed Hydroxyzine HCl (100 mg) was added to the 100, 200, 300 mg of
indion-234 respectively. The best ratio showing maximum adsorption of drug was
then optimized.
Characterization of resinate
FT-IR Spectroscopy:
Drug was characterized by FTIR spectroscopy. The
spectrum was recorded using FTIR spectrophotometer (Shimadzu FTIR-8400 S).
Samples were prepared in Chloroform. The scanning range was 400-3500 cm -1.
Then the spectra were comparatively analyzed for drug interaction.
Figure No: 2 DSC Curves of A) Hydroxyzine
hydrochloride, B) Indion
-234, C) Drug-resin complex
Figure No: 3 X-Ray
Diffraction pattern of A) Drug- resin complex B) Indion-234 C) Hydroxyzine hydrochloride
Differential Scanning Calorimetery (DSC):
Shimadzu DSC-60 Differential Scanning Calorimeter
using aluminium pans equipped with an intracooler and
a refrigerated cooling system was used to analyze the thermal behavior of Hydroxyzine
Hydrochloride, Indion-234 and drug: resin complex of Hydroxyzine
Hydrochloride: Indion-234. Indium standard was used to calibrate the DSC
temperature. The thermal behavior of hermetically
sealed samples (5-10 mg) heated at 20°C/min.
X ray diffractometry
X-ray powder diffractometry was carried out to
investigate the effect of complexation process on crystallinility of drug. Powder X-ray diffractometry
were carried out using a Philips-PW-1050 scanner with filter Ni, CuKa
radiation, voltage 40kV and a current of 20 mA. The
scanning rate employed was 10/min over the 50to 500
diffraction angle (2θ) range. The X-RD patterns of drug powder, resin
(Indion-234), and drug-resin complex were recorded.
Determination of drug content:
A complex equivalent to 10 mg was accurately weighed
and in that 10 ml of 1N HCl was added to break the
drug: resin complex. This was stirred on magnetic stirrer for 2 hours. Solution
was filtered and dilutions were made, and absorbance was measured at 232.2nm using UV-Spectrophotometer.
Table No. 2: Assay of drug: resin complex
|
Ratio of Drug: Resin (% w/w) |
Percent drug content |
|
Indion-234 |
|
|
1:1 |
99.242±0.928 |
|
1:2 |
98.793±0.529 |
|
1:3 |
98.282±1.136 |
Taste evaluation:
The sample of each drug
resin complex was subjected to sensory evaluation by a panel of nine members
with respect to bitter taste. Bitterness was measured by consensus of panel
which contain three group, each group contain three subjects The evaluation was
performed by classifying bitter taste into following five classes.
Level 5: Very strongly bitter
taste is sensed.
Level 4: Strongly bitter taste is sensed.
Level 3: Moderately bitter taste is sensed.
Level 2: Slightly bitter taste
is sensed.
Level 1: No bitter taste is sensed.
The pure drug without complexation with ion exchange resin was used as a control
having an average bitterness value of 5.
A written consent of the
members of the panel was taken and were explained the procedure involved in
testing the taste of complexes. Each of the members was given the control that
is the pure drug and was asked to compare the bitterness of each of the ratio
of complex with that of the control and indicate the level of bitterness
perceived by them. The members of the panel were asked to gargle for complete
removal of taste sense of previous samples and then the next sample was given
for taste analysis. The average bitterness value of each of the ratio was
worked out based upon the level of bitterness perceived by individual member of
the panel.
Table No. 3: Design for sensory analysis of drug: resin complexes
|
Subjects group |
Samples of drug: resin complexes |
|||
|
Group I |
Pure Drug |
A |
B |
C |
|
Group II |
Pure Drug |
B |
C |
A |
|
Group III |
Pure Drug |
C |
A |
B |
A-
1:1, B- 1:2, C- 1:3 Drug: Resin
complexes (%w/w)
Table No: 4 Average
bitterness values of drug: resin complexes
|
Ratio of Drug: Resin Complex |
Average bitterness value |
|
Pure drug |
5 |
|
Indion 234 |
|
|
1:1 (A) |
2.444 |
|
1:2 (B) |
1.444 |
|
1:3 (C) |
1.111 |
Table 5: Percent cumulative
release from Hydroxyzine HCl:
Indion 234 complexes in simulated gastric fluid
|
Time (min) |
Percent cumulative release from Hydroxyzine HCl: Indion- 234 |
||
|
1:1 |
1:2 |
1:3 |
|
|
5 |
32.625±0.323 |
30.75±0.462 |
27.375±0.348 |
|
10 |
52.612±0.391 |
51.341±0.371 |
47.554±0.445 |
|
15 |
72.579±0.451 |
68.408±0.410 |
65.704±0.254 |
|
20 |
85.375±0.392 |
81.158±0.127 |
79.925±0.240 |
|
25 |
93.054±0.533 |
90.666±0.556 |
88.670±0.216 |
|
30 |
97.433±0.267 |
95.395±0.553 |
93.004±0.695 |
In vitro dissolution:
Solid drug: resin complex equivalent to 10 mg of drug
was weighed accurately and subjected to release rate study using USP
dissolution test apparatus II (Model: Disso 2000 Apparatus: Labindia)
and 900 ml of simulated gastric fluid. 10 ml of the aliquot were withdrawn at 5
min. time interval as per requirement and replacement was made each time with
10 ml of fresh dissolution medium. Each of the 10 ml sample was filtered
through whatman filter paper. The drug concentration
in the sample was determined at 231nm.
Formulation development:
Oral fast disintegrating tablets were prepared by
using solid drug: resin complex (1:3 ratio) of Hydroxyzine Hydrochloride with Indion-234, by direct
compression method. The complex was taken equivalent to dose of drug. Six
different types of oral fast disintegrating tablets were formed using different
type of super disintegrating agents. These super disintegrating agents are croscarmellose sodium, sodium starch glycolate,
crospovidone, L-HPC, pregelatinised
starch and combination of sodium bicarbonate and citric acid (1.5:1).
Formulations were coded as formulation F1, F2, F3, F4, F5 and F6 respectively
(Along with these super-disintegrating agents, diluents, sweeteners and flavor were also used in different concentrations as per
requirement.)
Figure: 4 Cumulative percent drug release from Hydroxyzine
HCl: Indion 234 at SGF
Table:6 Scheme for oral fast disintegrating
tablet formulations using different ingredients
|
Ingredients |
Quantity
of Ingredients |
|||||
|
Formulations |
||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
Hydroxyzine HCl:
Indion-234 complex
(1:3 Ratio) |
Equivalent
to 10 mg (37mg) |
Equivalent
to 10 mg (37mg) |
Equivalent
to 10 mg (37mg) |
Equivalent
to 10 mg (37mg) |
Equivalent
to 10 mg (37mg) |
Equivalent
to 10 mg (37mg) |
|
Cros carmellose Sodium |
10mg |
- |
- |
- |
- |
- |
|
Sodium
starch Glycolate |
- |
10mg |
- |
- |
- |
- |
|
Cros povidone |
- |
- |
10mg |
- |
- |
- |
|
L- HPC |
- |
- |
- |
10mg |
- |
- |
|
Pregelatinised Starch |
- |
- |
- |
- |
10mg |
- |
|
NaHCO3 |
- |
- |
- |
- |
- |
6mg |
|
Citric
acid |
- |
- |
- |
- |
- |
4mg |
|
Mannitol |
24mg |
24mg |
24mg |
24mg |
24mg |
24mg |
|
Avicel |
24mg |
24mg |
24mg |
24mg |
24mg |
24mg |
|
Talc |
3mg |
3mg |
3mg |
3mg |
3mg |
3mg |
|
Magnesium
stearate |
2mg |
2mg |
2mg |
2mg |
2mg |
2mg |
|
Flavor |
Qs |
Qs |
Qs |
Qs |
Qs |
Qs |
In each formulation tablet weight is 100 mg
|
Evaluation Parameter |
Formulations |
|||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
|
Hardness (Kg) |
2.51±0.1 |
2.52±0.2 |
2.5±0.12 |
2.54±0.1 |
2.51±0.2 |
2.51±0.2 |
|
Disintegration time (Sec.) |
18±0.51 |
17±0.84 |
10±0.56 |
45±0.75 |
30±0.64 |
12±1.4 |
|
Wetting time (Sec.) |
34 |
40 |
30 |
56 |
48 |
35 |
|
Thickness
(MM) |
1.5±0.32 |
1.5±0.42 |
1.51±0.2 |
1.49±0.3 |
1.5±0.42 |
1.52±0.2 |
|
Friability
(%W/W) |
0.68 |
0.87 |
0.74 |
0.94 |
0.42 |
0.85 |
|
Drug
content (%W/W) |
98.42 |
99.14 |
98.62 |
97.24 |
98.31 |
98.36 |
|
%
Weight variation |
100±0.83 |
99.5±0.6 |
101±1.2 |
100±0.84 |
99±1.1 |
100±0.64 |
Evaluation of Tablets:
The prepared tablets were evaluated for various
official and non-official specifications
Weight variation:
Twenty tablets
were selected at random and average weight was calculated. Then individual
tablets were weighed and the individual weight was compared with an average
weight.
Hardness and friability:
Tablets were evaluated for hardness and friability
testing using Monsanto hardness tester and Roche friabilator
respectively
Table8: Cumulative % drug release from Formulation F3
|
Time (min) |
Cumulative
percent drug release |
|
5 |
27.2750.348 |
|
10 |
48.5540.445 |
|
15 |
65.7040.254 |
|
20 |
80.5650.240 |
|
25 |
87.6700.216 |
|
30 |
94.1240.695 |
In-vitro disintegration time:
Tablets were put into 100 ml distilled water at
37+2oc. Time required for complete disintegration of a tablet was measured with
the help of tablet disintegration test apparatus
Fig:5 Cumulative percent drug release from
Formulation F3 at SGF
In vitro dissolution of optimized fast disintegrating tablet i.e.
formulation F3 of drug resin complex was carried out using USP type II (paddle)
apparatus. Dissolution was carried in simulated gastric fluid. Tablet of
formulation F3 was subjected to release rate study using USP dissolution rate
test apparatus Il (Model: Disso 2000, Lab India).
Ten ml of the aliquot were withdrawn at different time interval of 5, 10,
15, 20, 25 and 30 min. and replacement was made each time with 10 ml of fresh
dissolution medium. Each of the 10 ml sample was filtered through Whatman filter
paper. The absorbance was measured at 231nm.
The reported values of percent drug release are average values of three
readings.
RESULT AND DISCUSSION:
1. Complexation
and taste masking of drug with Ion Exchange resin
Resin indion-234 shows good complexation with hydroxyzine hydrochloride i.e.1:3 ratio of drug: resin
shows 91.78% drug loading which is evident from determination of drug content.
Percent complexation, taste evaluation,
characterization by FTIR, DSC and X-Ray Diffraction gives evidence of complex
formation. Drug release from complex in SGF shows 93% drug release within 30 min.
2. Characterization of drug: resin complex
DSC Thermogram of pure drug shows sharp
endothermic peak at 186C, indicating melting point of Hydroxyzine Hydrochloride. On the other hand, no peak over
the range 140oC - 220oC was found in the DSC curves of
the resin and drug: resin complex.
X-ray diffraction studies were performed to examine the crystallinity and provide further evidence of complex
formation. The analysis of the X-ray powder diffraction patterns is a powerful
and very well assessed method for the characterization of complexes in the
solid state. Significantly different X-ray diffraction pattern are to be
expected if a complex is formed, since crystal structure will change. The X-ray
diffraction pattern confirms the crystalline nature of Hydroxyzine Hydrochloride that is evident from the
number of sharp and intense diffraction peaks obtained for drug. The X-ray diffraction
pattern of resin showed diffused peaks. Only diffused peaks were observed in
the diffraction pattern for the complex regardless of presence of drug.
(fig.3). According to the data from The X-ray diffraction pattern, the
molecular state of pure drug was crystalline and that of the resin was
amorphous. The molecular state of the drug prepared as drug-resin complex was
changed from the crystalline to the amorphous. These results demonstrated that
the entrapped molecule of drug was dispersed monomolecularly
in the resin particles. The X-ray diffractometry
results show formation of complex of drug with the resin.
FTIR spectroscopy
was used to confirm these results.
The FTIR spectrum of complex exhibit significant
difference in the characteristic spectrum of the Hydroxyzine
Hydrochloride, revealing modification of the drug environment. As
shown in figure, characteristic intense band of aromatic NH2, and aliphatic OH of Hydroxyzine Hydrochloride can be observed at 1300cm-1,
3421cm-1, 3383cm-1 resp. In case of complex, the
characteristic intense band of aromatic NH2 get diminished results
in masking of amino group responsible for bitter taste.
3. Formulation development
The batches of rapidly disintegrating tablets were prepared by using solid
drug: resin complex of Hydroxyzine hydrochloride with
Indion -234 (equivalent to dose of drug, 1:3 ratios).
Six different types of formulations were formed by direct compression technique
using different type of superdisintegrating agents.
These superdisintegrating agents are Croscarmellose
Sodium, sodium starch glycolate, crospovidone,
Low substituted-HPC, Pregelatinised Starch and
combination of sodium bicarbonate and citric acid (1.5:1) and the formulations
were coded as formulation F1, F2, F3, F4, F5, F6 respectively. Along with these
superdisintegrating agents, Diluents, sweeteners and flavor were also used in different required concentrations
and evaluated for various official and non-official parameters. Tablets were
obtained of uniform weight due to uniform die fill, with acceptable variations
as per I.P. specifications, i.e. below 7.5%. The hardness, friability and
uniformity of content are given in table no:7. hardness of the tablets for each formulation was between
2.51-2.54kg/cm2. Friability below 1.0% was an indication of good
mechanical resistance of the tablets drug content was found to be 98%-99% which
was within acceptable limit. F3 formulation containing crospovidone
as superdisintegrant shows less disintegration time. i.e. 10 sec.
CONCLUSION:
Hydroxyzine Hydrochloride,
a bitter drug could be successfully taste masked using suitable ion exchange
resin. The taste masked complex was incorporated into patient compliant and
palatable mouth disintegrating tablets. Tablets formulated with crospovidone superdisintegrant
showed faster disintegration and drug release.
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Received on 03.06.2014 Accepted on 20.06.2014
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Press All Right Reserved
Asian J. Pharm.
Tech. 2014; Vol. 4: Issue 2, Pg 63-68