Diphendramine Hydrochloride Oral Dispersible
Tablets: Preparation and Evaluation
K.
Vijaya Sri*, R. Harish Kumar Reddy and R. Mahesh
Malla Reddy College of
Pharmacy, Maisammaguda, Secunderabad,
Andhra Pradesh, India.
*Corresponding Author E-mail: vijayasree_2002@yahoo.co.in
ABSTRACT:
The purpose of this research was to make an attempt to
develop mouth dissolving tablets of diphenhydramine
hydrochloride. Mouth dissolving tablet offers a solution for pediatrics, adolescents and geriatrics patients
those have difficulty in swallowing tablets/capsules, resulting in improved
patient compliance. Diphenhydramine is used as anti
emetic, anti tussive for dermatosis
and pertusis and for hypersensitivity reactions. The
aim is to formulate different formulations of mouth dissolving tablets of diphenhydramine hydrochloride using different superdisintegrants like crospovidone
and croscarmellose sodium and subliming agent
menthol, by direct compression and sublimation method. Precompression
parameters were characterized for flow properties and prepared tablets were
evaluated for hardness, thickness, friability, weight variation, wetting time,
water absorption ratio, drug content, disintegration time and dissolution
studies. Invitro
dissolution studies show that release in tablets with a combination of superdisintegrant and subliming agent was good. Among all
the formulations, F9 (10% crospovidone and
menthol)showed maximum drug release of 99.76% in 12min.Hence it is evident from
this study that mouth dissolving tablets could be a promising delivery system
for diphenhydramine hydrochloride with good mouth
feel and improved drug bioavailability with better patient compliance.
KEY
WORDS: Mouth dissolving
tablet, super disintegrants, subliming agent, diphenhydramine hydrochloride, direct compression,
sublimation.
INTRODUCTION:
Fast disintegrating solid dosage forms have
received ever-increasing demand during the last decade, and the field has
become a rapidly growing area in the pharmaceutical industry because of the
advantages of easy administration to patients who have difficulty swallowing,
more rapid drug absorption, patient convenience, and improved patient compliance[1,2]. The popularity and
usefulness of the formulation resulted in the development of several related
technologies and processes such as freeze drying, tablet moulding,
direct compression, spray drying, rotary process and sublimation method[3,4].
Direct compression represents a simple and
cost effective tablet manufacturing technique. Use of conventional equipment,
commonly available excipients and limited number of
processing steps are the advantages of this technique. Directly compressed
tablet's disintegration and solubilization depends on
single or combined action of disintegrants, water
soluble excipients and effervescent agents[5]. The commonly used superdisintegrants are croscarmellose
sodium, crospovidone and sodium starch glycolate. In many
orally disintegrating tablet technologies based on direct compression, the
addition of superdisintegrants principally affects
the rate of disintegration and hence the dissolution. The key properties of
fast disintegrating tablets (FDTs) are fast absorption or wetting of water into
the tablets and disintegration of associated particles into individual components
for fast dissolution. This requires not only that excipients
should have high wettability, but also that the
tablet structure should have a highly porous network.
Diphenhydramine hydrochloride[6]is
a histamine H1 antagonist used as an antiemetic, antitussive, for dermatoses
and pruritus, for hypersensitivity reactions , as a
hypnotic, an antiparkinson, and as an ingredient in
common cold preparations. It is used for the treatment of symptoms associated
with Vertigo/ Menieres disease. Maisea
and vomiting, motion sickness and insect bite. The main goal of the present investigation was to
develop diphendramine hydramine
oral dispersible tablets consisting of crospovidone, croscarmellose sodium, mannitol
and dicalcium phsphate by
using direct compression technique and sublimation technique.
MATERIALS
AND METHODS
Diphenhydramine hydrochloride was received as a gift
sample from Hetero Drugs, Hyderabad India. Crospovidone,
croscarmellose sodium, starch, mannitol,
dicalcium phosphate, talc, magnesium stearate, menthol used was of analytical grade and procured
from commercial sources.
Formulation
of Diphenhydramine hydrochloride mouth dissolving
tablets by Direct compression method and Sublimation method
All the ingredients were passed through
sieve No.40. Diphenhydramine hydrochloride, mannitol, dicalcium phosphate and
starch were triturated in a glass mortar. Superdisintegrants
were incorporated in the powder mixture and finally magnesium stearate and talc were added as lubricant. This powder mass
was then loaded in to a blender (double cone) for obtaining a uniform powder
blend. The powder mix was weighed individually and compressed into tablets
using 6 mm punches are mention in the Table no.1.
Accurately weighed quantities of Diphenhydramine
hydrochloride, menthol, mannitol, dicalcium
phosphate and starch were mixed and passed through sieve no. 40. Superdisintegrants were incorporated in the powder mixture
and finally magnesium stearate and talc were added
and then subjected to compression. After compression the tablets were heated in
hot air oven at 60oC until constant weight was obtain to ensure the
complete removal of volatilizable component are
mention in the Table no.2
Evaluation
of tablets
Weight
Variation
Twenty
tablets were selected at a random and average weight was determined. Then
individual tablets were weighed and the individual weight was compared with an
average weight. None of the tablets deviated from the average weight by more
than ±5% [7].
% Weight variation = [(Average weight -
Individual
weight) / Average weight]*100
Table1:
Formulation design of mouth dissolving tablets of Diphenhydramine
hydrochloride by direct compression method
|
Ingredients(mg)
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
|
Diphenhydramine hydrochloride
|
12.5
|
12.5
|
12.5
|
12.5
|
12.5
|
12.5
|
|
Starch
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Mannitol
|
65
|
65
|
65
|
65
|
65
|
65
|
|
Dicalcium phosphate
|
51.5
|
46.5
|
41.5
|
51.5
|
46.5
|
41.5
|
|
Crospovidone
|
5
|
10
|
15
|
-
|
-
|
-
|
|
Croscarmellose sodium
|
-
|
-
|
-
|
5
|
10
|
15
|
|
Magnesium stearate
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Talc
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Total weight (mg)
|
150
|
150
|
150
|
150
|
150
|
150
|
Table
2: Formulation design of mouth dissolving tablets of Diphenhydramine
hydrochloride by sublimation technique
|
Ingredients(mg)
|
F07
|
F08
|
F09
|
F10
|
F11
|
F12
|
F13
|
|
Diphenhydramine hydrochloride
|
12.5
|
12.5
|
12.5
|
12.5
|
12.5
|
12.5
|
12.5
|
|
Starch
|
10
|
10
|
10
|
10
|
10
|
10
|
10
|
|
Mannitol
|
65
|
65
|
65
|
65
|
65
|
65
|
65
|
|
Dicalcium phosphate
|
46.5
|
41.5
|
36.5
|
46.5
|
41.5
|
46.5
|
51.5
|
|
Crospovidone
|
5
|
10
|
15
|
-
|
--
|
-
|
-
|
|
Croscarmellose sodium
|
-
|
-
|
-
|
5
|
10
|
15
|
-
|
|
Menthol
|
5
|
5
|
5
|
5
|
5
|
5
|
5
|
|
Magnesium stearate
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Talc
|
3
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Total weight(mg)
|
150
|
150
|
150
|
150
|
150
|
150
|
150
|
Friability
The
friability of ten tablets was determined using Rochefriabilator at 25 rpm
for 4 minutes. The tests were carried out in triplicate. The friability was
expressed in terms of weight loss and was calculated as the percentage (% ± SD)
of the initial weight according to the following equation:
f =W0 - W t / W0Ś
100%
where f= friability, W0=
initial weight of tablets before the tests, and Wt = tablets weight after the tests.% Friability of Tablets less than 1% are considered
acceptable.
Thickness
The thickness were
measured by using verniercalliper and values were
tabulated. Three tablets of each batch were measured.
Hardness
Hardness indicates the ability of a tablet
to withstand mechanical shock while handling. The hardness of the tablets was
determined using Monsanto hardness tester. It is expressed in kg/cm2. Three
tablets were randomly picked and hardness of the same tablets from each
formulation was determined. The mean and standard deviation values were also
calculated.
Drug
Content
20 tablets of each formulation were weighed
and powdered. The quantity of powder equivalent to 10 mg of Diphenhydramine
hydrochloride was transferred into a 100 ml standard flask and volume made up
with pH 6.8 phosphate buffer and absorbance of the resulting solution was
observed at 254nm. [8]
In-vitro Disintegration time
Many reports suggest that conventional DT
apparatus may not give correct value of DT for MDTs. The amount of saliva
available in the oral cavity is very limited (usually less than 6ml), whereas
the conventional DT apparatus uses a large amount of water with very rapid up
and down movements[9,10]. MDT is
required to disintegrate in such small amounts of saliva within a minute
without chewing the tablet. In a simplest method to overcome these problems, 6
ml of pH 6.8
phosphate buffer was taken in 25ml
measuring cylinder. Temperature was maintained at 37±20C. A ODT was put into it and time required for complete
disintegration of the tablet was noted.
Wetting
Time
Wetting time is closely related to the
inner structure of the tablets and to the hydrophilicity
of the excipient. It is obvious that pores size
becomes smaller and wetting time increases with an increase in compression
force or a decrease in porosity. The wetting time was measured by a
modification of the described procedure by Rawas-Qalaji
et al[11].
The tablet was placed at the center of two layers of absorbent paper fitted
into a rounded plastic dish with a diameter of 12 cm. After the paper was
thoroughly wetted with distilled water, excess water was completely drained out
of the dish. The time required for the water to diffusefrom
the wetted absorbent paper throughout the entire tablet was then recorded.
Water
Absorption Ratio
A piece of
tissue paper folded twice was placed in a small petri
dish containing 6 mL of water. A tablet was put on
the paper and the time required for complete wetting was measured. The wetted
tablet was then weighed. Water absorption ratio R, was determined using
following equation[12]
R= Wa - Wb
/ Wb Ś 100
Where, Wa= weight of tablet after
absorption, Wb= Initial weight of the tablet.
Invitro Dissolution Studies
The dissolution rate of diphenhydramine
hydrochloride from the oral dispersible tablet was studied in 900ml of pH 6.8
phosphate buffer usingElectrolab
TDT-08L USP dissolution test apparatus with
paddle stirrer at 50 rpm.A temperature of 37oC
+ 5oC was maintained throughout the study. One tablet containing 12.5 mg of diphenhydramine hydrochloride was used in each test. Samples of dissolution media (5 ml) were
withdrawn at time interval 2,4,6,8,10 and 12min and
assayed for diphenhydramine hydrochloride at
254nm. The sample of dissolution fluid
withdrawn at each time was replaced with fresh dissolution fluid. The dissolution experiments were conducted in
triplicate. Percentage cumulative drug
release values were calculated from the dissolution data.
Similarity
factor
FDA guidance documents consider some
approaches such as difference (f1)
and similarity (f2) factors to
analyze the dissolution data equivalence. The main advantage of the f1 and f2 equations is to provide a simple way to describe comparison of
data. The dissimilarity factor (f1)
should be computed using the following equation:
Where Rt
and Tt are the cumulative percentage of the drug
dissolved at each of the selected n time points of the reference and test
product, respectively.
The similarity factor (f2) is a
logarithmic transformation of the sum-squared error of differences between the
test Tjand reference products Rjover all time points, m.
Where wj
is an optional weight factor. This method is more adequate to compare dissolution profile when
more than three or four dissolution time points are available and can only be
applied if the average difference between Rj
and Tj is
less than 100. If this difference is higher than 100, normalization of the data
is required [7]. The dissolution measurements of the selected and market formulation should be
made under exactly the same conditions and same time interval like 2, 5 and 10
min.
Stability studies
The optimized formulation (F9) was wrapped in aluminum
foils and kept in petri dish at 40±20C/75±2%
RH and analyzed for
disintegration time, wetting time and in-vitro
dissolutions study for a period of three months.
RESULTS AND DISCUSSION:
Pre-compression parameters were conducted
for all formulations blend and were within I.P limits and mention the table 3.
Bulk density was found in the range 0.63to
0.71 g/sqcm and tapped density in the range of 0.81
to 0.91 g/sqcm
using these two density factors hausner`s
ratio and compressibility index were calculated. The powder blend of all
formulations hausner`s ratio less than 1.32 which
indicates better flow property and compressibility index between 17.54 to
20.31 which indicates fair flowability property. The fair flowability
property of the powder blend was also evidenced with angle of repose between
16.380 and 22.460 which is below 40.0All the
tablets were free from cracks, depressions, pinholes etc. The color of the tablets are
white and round in shape and surface of the tablets are smooth. Since the
powder material was free flowing, tablets were obtained of uniform weight due
to uniform die fill, with acceptable weight variations as per I.P. The
thickness was found to be minimum for F5(3.3mm) and
maximum for F7(3.6mm). The hardness of the tablet was found between 3.6- 4.4kg/cm2 indicating good mechanical resistance of
the tablets and parameters were found well within the specified limit for
uncoated tablets. The loss on friability was less than 1% the total weight of
the tablet which was found to be comparatively more for sublimed tablets than
that of directly compressed tablets. The percentage drug content of all
formulations were found to be the range between 98.64 100.37%.The wetting
time was found to be minimum for F9(32sec) and maximum for F4(58). The water
absorption ratio varied from 98.2 101.5. The in vitro disintegration time (DT) of the tablets was found to be
maximum of 62sec for F4 and tablets containing 10% crospovidone
and menthol (F9) showed disintegration time of 35sec which is minimum and
values are given
table no.4.
Table-3
Pre-compression parameters of Diphenhydramine
hydrochloride (Mean±SD n=3)
|
Formulation
|
Bulk density
|
Tapped density
|
Carrs index
|
Angle of repose0
|
Hausners ratio
|
|
F1
|
0.65±0.001
|
0.81±0.005
|
19.34±0.07
|
19.44±0.115
|
1.24±0.007
|
|
F2
|
0.67±0.005
|
0.85±0.005
|
18.82±0.05
|
18.44±.065
|
1.26±0.007
|
|
F3
|
0.65±0.005
|
0.85±0.005
|
18.85±0.09
|
17.46±.224
|
1.30±0.005
|
|
F4
|
0.66±0.003
|
0.84±0.001
|
17.96±0.02
|
18.01±.145
|
1.27±0.001
|
|
F5
|
0.67±0.005
|
0.85±0.001
|
17.54±0.12
|
19.75±.136
|
1.26±0.005
|
|
F6
|
0.65±0.001
|
0.86±0.005
|
19.12±0.11
|
16.38±.084
|
1.32±0.008
|
|
F7
|
0.68±0.005
|
0.81±0.005
|
19.95±0.09
|
21.16±.259
|
1.19±0.005
|
|
F8
|
0.70±0.001
|
0.88±0.005
|
19.71±0.07
|
21.74±.125
|
1.25±0.006
|
|
F9
|
0.63±0.005
|
0.81±0.003
|
20.13±0.12
|
21.89±.155
|
1.28±0.006
|
|
F10
|
0.66±0.005
|
0.85±0.001
|
20.14±0.05
|
22.46±.094
|
1.28±0.001
|
|
F11
|
0.69±0.003
|
0.91±0.005
|
19.91±0.09
|
20.74±.236
|
1.31±0.001
|
|
F12
|
0.71±0.001
|
0.88±0.001
|
21.32±0.05
|
22.38±.124
|
1.23±0.003
|
|
F13
|
0.70±0.004
|
0.90±0.005
|
20.31±0.07
|
21.33±3.117
|
1.28±0.005
|
Table 4 : Evaluation of diphenhydramine hydrochloride mouth dissolving tablets
|
Formulation
|
Weight variation
(mg)
|
Thickness (mm)
|
Hardness
(kg/cm2)
|
Friability
% w/w
|
Drug
Content
|
Wetting
time (sec)
|
Water absorption ratio
|
Disintegration
Time
(sec)
|
Dispersion time (sec)
|
|
F1
|
150±1.2
|
3.5±0.02
|
4.4±0.23
|
0.575±0.05
|
99.1±0.1
|
54±1
|
98.56±0.5
|
55±2
|
52±2
|
|
F2
|
149±0.81
|
3.5±0.01
|
4.4±0.25
|
0.589±0.14
|
99.0±0.1
|
51±1
|
100.3±.5
|
53±2
|
50±1
|
|
F3
|
150±1.5
|
3.4±0.02
|
4.3±0.25
|
0.568±0.09
|
98.7±0.0
|
48±2
|
101.5±0.1
|
50±2
|
45±2
|
|
F4
|
150±1.4
|
3.5±0.01
|
4.3±0.23
|
0.591±0.25
|
99.2±0.1
|
58±1
|
99.4±0.5
|
62±1
|
57±1
|
|
F5
|
151±1.2
|
3.3±0.01
|
4.4±0.22
|
0.582±0.02
|
100.0±0.1
|
56±1
|
98.3±0.4
|
60±2
|
54±1
|
|
F6
|
149±0.99
|
3.5±0.03
|
4.2±0.25
|
0.601±0.06
|
98.9±.0.2
|
55±1
|
97.5±0.9
|
57±1
|
53±2
|
|
F7
|
150±1.4
|
3.6±0.02
|
4.1±0.22
|
0.721±0.14
|
99.2±0.1
|
40±2
|
100.7±0.9
|
37±2
|
38±1
|
|
F8
|
151±1.6
|
3.5±0.01
|
4.1±0.24
|
0.715±0.09
|
100.7±0.1
|
38±2
|
99.6±0.3
|
36±1
|
37±1
|
|
F9
|
148±1.3
|
3.5±0.02
|
4.2±0.27
|
0.735±0.07
|
98.6±0.1
|
32±1
|
97.8±0.8
|
35±1
|
30±2
|
|
F10
|
151±0.94
|
3.5±0.02
|
3.8±0.25
|
0.709±0.03
|
99.3±0.1
|
48±1
|
101.2±0.7
|
47±1
|
46±1
|
|
F11
|
150±1.3
|
3.4±0.01
|
3.7±0.24
|
0.719±0.12
|
100.3±0.2
|
43±1
|
100.2±0.6
|
43±2
|
42±2
|
|
F12
|
151±1.2
|
3.4±0.02
|
3.9±0.31
|
0.700±0.04
|
99.1±0.1
|
41±2
|
98.2±0.5
|
39±2
|
38±1
|
|
F13
|
150±1.3
|
3.4±0.01
|
3.6±0.23
|
0.700±0.15
|
99.6±0.2
|
43±2
|
99.4±0.6
|
38±2
|
40±1
|
The highest dissolution rate was shown by
tablet prepared by superdisintegrant and menthol
followed by only superdisintegrant and minimum for
tablet prepared by menthol alone. Diphenhydramine
tablets formulated with 10% crospovidone and menthol,
gave a drug release of 99.76% at end of 12 min and was found to be an optimized
formulation(F9). Minimum dissolution rate of 87.2 at 12min was observed with
formulation containing only menthol (F13). Overall the MDT formulations of diphenhydramine
hydrochloride shows an average of 87.2% to 99.76% at end of 12 min. The data
for in vitro drug release of formulations was shown
in Fig.1and Table no.5. In vitro drug release data for all the
formulations F1 to F13 were subjected to release kinetic study according to
zero order and first order equation to ascertain the mechanism of drug release.
Among the zero order and first order, the
RČ values were found to be higher in first order.
Figure-1 Dissolution profiles of diphendramine
hydrochloride oral dispersible tablets
Table 5: Release kinetics of diphenhydramine hydrochloride mouth dissolving tablets
|
Formulation
|
Zero order (R2)
|
First order (R2)
|
DP
4
|
k-1
|
t1/2
|
|
F1
|
0.517
|
0.842
|
83.2±1.25
|
0.160
|
4.33
|
|
F2
|
0.507
|
0.853
|
86.4±0.80
|
0.178
|
3.89
|
|
F3
|
0.503
|
0.887
|
88.5±1.11
|
0.202
|
3.43
|
|
F4
|
0.547
|
0.859
|
80.4±0.81
|
0.151
|
4.58
|
|
F5
|
0.522
|
0.866
|
83.8±0.83
|
0.170
|
4.07
|
|
F6
|
0.534
|
0.878
|
82.1±1.05
|
0.165
|
4.20
|
|
F7
|
0.498
|
0.898
|
88.5±0.77
|
0.226
|
3.06
|
|
F8
|
0.491
|
0.835
|
91.8±0.28
|
0.268
|
2.58
|
|
F9
|
0.486
|
0.921
|
93.2±0.81
|
0.414
|
1.67
|
|
F10
|
0.503
|
0.793
|
86.7±1.01
|
0.185
|
3.74
|
|
F11
|
0.492
|
0.800
|
91.4±0.82
|
0.242
|
2.86
|
|
F12
|
0.487
|
0.797
|
90.2±0.79
|
0.213
|
3.25
|
|
F13
|
0.569
|
0.785
|
78.2±0.85
|
0.146
|
4.74
|
So all formulations followed first order
kinetics. The release kinetics of the drug is shown in table.5. First order rate constant was minimum for F13 (0.146hr-1) and maximum
for F9 (0.414hr-1). Half life was minimum for F9 (1.67hr) and
maximum for F13 (4.74hr). Dissolution rate at 4 min was minimum for F13 (78.2) and maximum for F9
(93.2).
ACKNOWLEDGEMENT:
The authors are thankful to Ch. Malla Reddy Chairman of Malla
Reddy college of Pharmacy, Hyderabad for providing the facility to carry out
the research work. The authors are thankful to Hetero Lab Ltd, Hyderabad, for
providing the gift sample of diphenhydramine
hydrochloride.
REFERENCES:
1.
Sastry SV, Nyshadham JR, Fix JA. Recent
technological advances in oral drug delivery- a review. Pharmaceutical Science and Technology Today. 3; 2000: 138-45.
2.
Habib W, Khankari RK, Hontz
J. Fast-dissolve drug delivery systems. Critical
Reviews in Therapeutic Drug Carrie r Systems. 17;2000: 61-72.
3.
Fu Y, Yang S, Jeong SH, Kimura S, Park K. Orally
fast disintegrating tablets: Developments, technologies, taste masking and
clinical studies. Critical Reviews in Therapeutic Drug
Carrie r Systems. 21; 2004: 433-75.
4.
Yu DG.,
Yang XL, Wang YG, Li XY, Xu HB. Zero-order controlled
- release tablets of helicid fabricated by three -
dimensional printing technology. China
Traditional Patent Medicine. 29;2007: 355-9.
5.
Ganesh Kumar Gudas, Manasa B, Rajesham VV, Kiran Kumar S, Prasanna Kumar J. Formulation and evaluation of fast
dissolving tablets of chlorpromazine HCL.
Journal of Pharmaceutical science and Technology. 2(1);2010: 99-102.
6.
Raphael GD, Angello JT, Wu MM, Druce HM: Efficacy of diphenhydramine
vs desloratadine and
placebo in patients with moderate-to-severe seasonal allergic rhinitis. Ann
Allergy Asthma Immunol. 2006 Apr;96(4):606-14.
7.
Indian Pharmacopoeia. Ministry of Health and Family Welfare.
Government of India, Vol ІІІ,
Delhi, 2007, pp.182.
8.
Yunxia B, Hisakazu S, Yorinobu Y, Kazumi D,
Akinobu O, Kotaro I. Preparation and Evaluation of
Compressed tablet rapidly disintegrating in the oral cavity. Chemical and Pharmaceutical Bulletin.
44(11); 1996: 2121-2127.
9.
Lachman L, Liebermann HA.
The Theory and Practice of Industrial Pharmacy. Vol
ІІ, Marcel Dkker, 2009, pp 297-299.
10.
Rawas-Qalaji MM, Simons FR, Simons KJ. Fast - disintegrating sublingual
tablets: Effect of epinephrine load on tablet characteristics. AAPS PharmSciTech.
7(41);
2006: E72-E78.