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’s College of Pharmacy, Nasik-422002 Maharashtra, India.
3Reasearch and Development
cell, Glenmark Pharmaceuticals Ltd., Sinnar, Nasik, Maharashtra, India.
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. Hence an
attempt was made to mask the taste of Hydroxyzine hydrochloride
with strong and weak cation exchange resins. The
complex formation of drug with different cation
exchange resins was carried out to block the functional group responsible for
causing bitter taste. DSC analysis, X-ray diffractometry,
FTIR spectra and decomplexation studies give evidences
of complex formation.Hydroxyzine hydrochloride shows good complexation and effective
taste masking with strong cation exchanger like
Tulsion-343, Tulsion-344 and weak cation exchanger
like Indion-234. But Tulsion-343 and Tulsion-344 resins affect the drug release
from complex at gastric pH due to their sustained release action. The complex
for formulation was selected considering the results obtained from release of
drug from complex at salivary pH as well as at gastric pH, sensory evaluation
of complex. Accelerated stability studies (at 400C ±
20C /75% RH±5% RH) on the selected resinate
indicate that there are no significant change in drug content and in vitro
dissolution profile (p < 0.05).
INTRODUCTION:
Hydroxyzine hydrochloride is histamine
H1 antagonist, Antipruritic and Anxiolytic, sedative and hypnotic agent. It competes with
histamine for binding at H1 receptor site on the effector
cell surface resulting in suppression of histaminic edema,
flare and pruritus but it has poor patient compliance
due to its bitterness1, 2. The most important class of ion-exchangers is the organic
ion-exchange resins. They consists of a framework, so called matrix, carrying a
functional component having a positive or negative electric fixed charge, which
is compensated by mobile counter ions of opposite sign3.
Framework
in pharmaceutical grade ion exchange resins (IER) consists mostly of polyacrylic acid or polystyrene cross linked with suitable
amount of cross linking agent such as divinyl
benzene, amount of which greatly affects swelling property and in turn rate of
ion exchange and capacity to absorb large molecules4.
Ion
exchange resins are water insoluble, cross-linked polymers containing salt
forming groups in repeating position on the polymer chain. Drug can be bound to
the ion exchange resin by either repeated exposure of the resin to the drug in
a chromatographic column (column method) or by prolonged contact of resin with
the drug solution(Batch method)5,6,7,8,9. The resins forms insoluble
adsorbates or resinates
through weak ionic bonding with oppositely charged drugs. The exchange of
counter ions from resin is competitive8.
A
drug: resin complex (Resinate) is made from the bitter
drugs and ion - exchange resins. The nature of the drug: resin
complex is such that the average pH of 6.7 and cation
concentration of about 40 meq/lit in saliva are not
able to break the drug: resin complex but it is weak enough to be broken down
by the hydrochloric acid present in the stomach. Thus the drug: resin complex
is absolutely tasteless and stable, with no after taste, but at the same time
its bioavailability is not affected10.
MATERIALS
AND METHODS:
Hydroxyzine hydrochloride was obtained as a gift sample from Glenmark
Pharmaceuticals (Sinnar, India). Amberlite
IRP-64, Amberlite IRP-88 were obtained from Rohm and Haas Pvt. Ltd. (Mumbai), Tulsion-343,
Tulsion-344, Tulsion-335, Tulsion-339, Micpol-1061 were obtained from ThermaxIndia Ltd., (Pune), Indion-234, Indion-214 were obtained from Ion exchange India Ltd, (Mumbai). All other
reagents used in present work were of analytical grade.
Preparation
of Drug: Resin complex
Cation exchange resins (both strong and weak cation exchange resins) were weighed accurately. Each of
the ion exchange resin was 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 of drug: resin (1:1, 1:2, 1:3), keeping the quantity of drug
constant. The percent drug complexed was determined
U.V. spectrophotometrically at 229.8 nm.
Percent drug complexed:
The resins showing optimum percent drug complexation
were selected for further study. 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. The percent drug complexed is shown
in Table No: 1. The
reported values of percent drug complexed are average
values of three readings.
Drug release study at simulated salivary
fluid (SSF):
Drug
release study of the selected drug: resin complex was studied at SSF to
determine the amount of the drug that would be released in mouth during the
administration of formulation. The bitterness of the taste is related with the
amount of drug released in the mouth. Hydroxyzine hydrochloride
plain was used as a control to study its rate of release at the pH of mouth.
Solid drug: resin complex
equivalent to 10 mg of drug was subjected to release rate study. The complex
was accurately weighed and added to 5ml simulated salivary fluid pH 6.8.
Aliquot was withdrawn after interval of 1 min. Sample was filtered through Whatmann filter paper. The
filtrate was analyzed by Shimadzu UV-250 1PC double beam spectrophotometer at
λ max 231.2nm. Drug concentration in the sample
was determined. The reported values of
percent drug released are average values of three readings. As shown in Table No: 2.
From this study, the resinate showing less amount of drug release (Less than 5%)
was selected for further study, as the amount released is insufficient to
impart bitter taste9 E.g.
Tulsion-343 (1:2, 1:3), Tulsion-344 (1:2, 1:3), Indion-234 (1:1, 1:2, 1:3)
In Vitro release studies
The
selected resinates (Accurately weighed quantity
equivalent to 10 mg. of drug) were subjected to In Vitro dissolution studies
using
USP type II (Paddle) apparatus at 50 rpm with
temperature 370 C ±0. 50 C. dissolution study was carried
out using 900 ml simulated gastric fluid (SGF). After certain time interval, 10
ml of dissolution medium was withdrawn and filtered; the filtrate was analyzed
by Shimadzu UV-250 1PC double beam spectrophotometer at λ max 231 nm. The
drug release data was fitted in various release kinetic equations such as zero
order, first order, higuchi equation, Hixon crowell, and Korsemayer peppas. Percent cumulative
drug release data from complexes in simulated
gastric fluid is shown in Fig No:
Figure No: 1 Percent cumulative drug release
from complexes in SGF
Table No: 1
Percent drug complexed in various ratios of cation exchange resins
|
Ratio Drug: Resin (% w/w) |
Percent drug complexed
|
||||||||
|
Tulsion-343**
(H+)* |
Tulsion-344**
(Na+)* |
Tulsion-339
(K+)* |
Micpol-1061
(H+)* |
Indion-214
(H+)* |
Indion-234
(K+)* |
Amberlite-IRP88
(H+)* |
Amberlite-IRP64
(K+)* |
Tulsion-335
(H+)* |
|
|
1:1 |
19.30±1.30 |
10.51±1.21 |
93.54±0.83 |
90.22±0.45 |
2.49±0.66 |
83.18±1.12 |
Nil |
Nil |
3.55±0.496 |
|
1:2 |
90.44±0.80 |
40.01±0.38 |
94.74±0.76 |
91.83±0.46 |
17.87±0.47 |
91.00±0.65 |
Nil |
Nil |
22.44±1.06 |
|
1:3 |
98.95±1.02 |
85.04±0.80 |
95.62±0.51 |
92.63±0.64 |
28.75±0.78 |
91.78±0.4 |
1.52 ±0.68 |
5.12±0.67 |
35.38±1.02 |
*- Exchangeable ion; ** - Strong cation
exchange resin
Table No: 2
Percent drug released in simulated salivary fluid after 60 sec.
|
Ratio of Drug: Resin |
Percent drug release in simulated
salivary fluid |
||
|
1:1 |
1:2 |
1:3 |
|
|
Drug:
Tulsion- 343 |
0.252±0.011 |
0.179±0.012 |
0.131±0.011 |
|
Drug:
Tulsion- 339 |
15.620±0.031 |
13.792±0.608 |
10.664±0.608 |
|
Drug:
Indion-234 |
7.451±0.192 |
5.260±0.110 |
2.438±0.499 |
|
Drug:
Tulsion-344 |
0.304±0.031 |
0.281±0.16 |
0.146±0.019 |
|
Drug:
Micpol-1061 |
18.022±0.324 |
15.742±0.652 |
11.510±0.169 |
|
Pure
Drug |
98.833±0.664 |
||
Evaluation of selected resinate
1.
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 groups, each group contain
three subjects, as shown in Table No: 3.
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.
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 |
|
Tulsion 343 |
|
|
1:2 (A) |
2.222 |
|
1:3 (B) |
1.333 |
|
Indion 234 |
|
|
1:1 (A) |
2.444 |
|
1:2 (B) |
1.444 |
|
1:3 (C) |
1.111 |
|
Tulsion 344 |
|
|
1:2 (A) |
2.222 |
|
1:3 (B) |
1.444 |
The pure
drug without complexation with ion exchange resin was used as a control having
an average bitterness value of 5. 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 panell6, 11. Average bitterness values of drug: resin
complexes shown in Table No: 4
2.
Assay of drug: resin complexes:
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.
The data obtained is shown in Table No:
5. The reported values of percent drug content are
average values of three readings.
Table No. 5:
Assay of drug: resin complexes
|
Ratio
of Drug: Resin (% w/w) |
Percent drug content |
||
|
Tulsion-343 |
Tulsion-344 |
Indion-234 |
|
|
1:1 |
- |
- |
99.242±0.928 |
|
1:2 |
97.803±0.712 |
97.736±0.647 |
98.793±0.529 |
|
1:3 |
97.048±1.022 |
96.043±1.187 |
98.282±1.136 |
3.
Evidence of
complex formation:
A)
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 The
data obtained is shown in the Fig No: 2.
Figure No: 2 DSC Curves of A) Hydroxyzine
hydrochloride,
B) Indion -234, C) Drug-resin complex
B)
FT-IR Spectroscopy:
FT-IR spectrum of the Drug, Indion-234 and drug:
Indion-234 (1:3) was recorded on Shimadzu
FTIR-8400 S over the wave number 4000 to
500 cm-1. The spectrum of the dug, Drug: Indion-234 (1:3) and
Indion-234, and is shown in Fig No: 3.
Figure No: 3 FTIR spectrum of A)Indion-234 Resin; B) Drug:
Resin Complex; C) Hydroxyzine
hydrochloride
C) 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, Cu Ka radiation, voltage 40kV and a current of 20 mA. The scanning rate employed was 1°/min over the 5°to 50° diffraction angle (2q) range. The X-RD patterns of drug powder, resin (Indion-234), and
drug-resin complex were recorded and shown in Fig. No: 4.
4.
Accelerated Stability Study:
The selected resinate (drug-Indion-234)
was subjected to accelerated stability studies by storing the
resinate (in amber coloured
rubber stoppered vials) at 400C ±
20C /75% RH ±5% RH for six months as per ICH guide lines. At
intervals of one month, three month and, six months, the resinate
complexes were visually examined for any physical changes ,
change in drug content, and in vitro dissolution profile.
Figure No: 4 X-Ray Diffraction pattern of A) Drug- resin complex B)
Indion-234 C) Hydroxyzine hydrochloride
RESULT AND
DISCUSSION:
1.
Data of
percent complexation and released was subjected to two way ANOVA. It can be
stated that, percent drug complexation is dependent on drug: resin ratio as
well as type of resin. These two factors also plays important role in release
of drug. Strong resins like T-343 and T-344 shows near by
50% drug release in two hrs. in SGF. While weak cation exchanger like I-234 releases more than 90% drug
within 30 min. this is because drug bind tightly with strong resins and loosely
with weak resins. Exchangeable ion present on resin is also showing effect on
percent complexation, as relative selectivity changes from one ion to other.
2.
Taste Evaluation:
The data obtained from drug released in SSF and taste
evaluation by panel of 9 members gives evidence of taste abatement of drug.
3.
Evidence of complex formation:
a)
DSC studies:
DSC Thermogram
of pure drug shows sharp endothermic peak at 184°C, 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.
b)
Infrared (IR) study:
FTIR spectra of drug
shows peak for ter. amino group at 1300 cm-1 wave number which is
absent in drug – resin complex of I-234.this gives the evidence of
complexation.
c)
X-ray diffraction study:
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 XRPD of resin (I-234)
showed diffused peaks. Only diffused peaks were observed in the diffraction
pattern for the complex regardless of presence of drug. According to the data
from XRPD, 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. The X-ray diffractometry results show formation of complex of drug
with the resin.
4.
Accelerated stability study:
Accelerated
stability studies (at 400C ±
20C /75% RH±5% RH) on the selected resinate
indicate that there are no significant change in drug content and in vitro
dissolution profile (p < 0.05).
CONCLUSION:
Bitter taste of Hydroxyzine hydrochloride was successfully
masked by strong cation resins like T-343 and
T-344, which shows sustained drug release, also weak cation
exchange resins like I-234, which shows rapid drug release. Drug released from
these resinates follows first order release kinetics.
DSC, FTIR, X-ray diffraction, drug content study gives the evidence of complex
formation. Accelerated stability study shows that formed resinates are stable.
REFERENCES:
1.
www.sinoapi.com/pharmacopoeia/Jp15/JP2192-30.3pdf.
2.
Current Index of
Medical Specialties, Jan-Apr 2008, 488,178.
3.
Sugao, H., Yamazoki, S., Shizawa, H. and Yano, K., J. Pharm. Sci., 1998
87(1), 96.
4.
Vimladevi, M. and Babu. P.S.S., In;
Jain, N.K., Advances in Controlled and Novel drug delivery, 1st Edn. CBS Publishers and Distributors, New Delhi, 2001, 290.
5.
Nanda, A., Kandarpu, R. and Garg, S.,”An update of taste masking technology for oral
pharmaceuticals” Indian J. Pharm. Sci.,
2002, 64(1), 10.
6.
Patravale,V., prabhu,N.,” Taste masking
of quinine sulphate” Indian J. Pharm. Sci., 2005, 64(1), 233.
7.
Manek, S.P. and Kamat, V.S.,”Evaluation of Indion CRP
244 and CRP 254 as sustained release and taste masking agents” Indian J. Pharm. Sci., 1981, 43,
209-212.
8.
Agrawal, R., Mittal, R. and Singh, A.,”Studies of Ion-exchange resin complex of chloroquine phosphate” Drug Dev. Ind. Pharm., 2000,
26, 773.
9.
Pisal, S., Zainnuddin, R., Nalawade, P., Mahadik, K. and Kadam, S., AAPS PharmSciTech., 2004,5(4),
Article No. 64
10. Kunin, R. and Myers, R.J., “In; Ion exchange resins”, John
Wiley and sons, Inc., New York, 1950, 1-4.
11. Borodkin S, Yunker M.H, “ Interaction
of amine drug with polycarboxylic acid ion exchange
resin” J Pharm Sci. 1970; 59,481-486
Received on 17.05.2011
Accepted
on 04.06.2011
©
A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage Forms and
Technology. 3(4): July-Aug. 2011,
130-134