This document summarizes research on developing a rapid disintegrating tablet formulation of fluoxetine hydrochloride using a sublimation technique. Tablets were prepared by direct compression and wet granulation methods using various excipients like crospovidone, mannitol, ammonium bicarbonate, and camphor. The wet granulation method was found to produce tablets with more rapid drug release compared to direct compression. The optimized formulation F7 prepared by wet granulation with 10% crospovidone and 20% ammonium bicarbonate showed 99.26% drug release within 4 minutes and disintegrated within 37 seconds. Overall, the study demonstrated that a palatable, fast-disintegrating tablet of

1. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
ISSN
2348 –0882
Formulation and Development of Rapid Disintegrating Tablet of Fluoxetine Hydrochloride
Nikude AS*,
Institute of Pharmaceutical Education and Research, Wardha, Maharashtra, India.
===================================================================
granulation method 99.26 % drug was
ABSTRACT
Aim: The aim of present work was to
released at the end of 4 min. Dissolution
formulate rapid disintegrating tablet of
study of optimized batch of tablets F7
Fluoxetine HCLwith pleasant taste and
prepared by wet granulation method
better mouth feel by sublimation technique.
containing 20% ammonium bicarbonate
Materials and Methods: The fast
revealed most rapid release of drug, t90 for
disintegrating tablet is formulated by
batch F7 is less than 180 sec. Conclusion :
sublimation
technique.
The
super
Overall, from the present research work it
disintegrant used in present formulation was
can be concluded that by using the
crospovidone the other excipient used was
combination of 10% crospovidone as a
mannitol, Ammonium bicarbonate and
superdisintegrant and 20% Ammonium
camphor. Result and Discussion: The
bicarbonate (AB) as a subliming agent by
cumulative % of drug release of F7 batch of
wet granulation method, a well palatable,
wet granulation method was found to be
patient-friendly rapid disintegrating tablet
99.26% at the end of 4 min. Formulation F7
could be successfully prepared. The
prepared by direct compression method
prepared tablet showed sufficient strength
showed 99.71 % drug release at the end of 1
coupled with rapid disintegration as well as
min while formulation F7 prepared by wet
rapid dissolution.
Introduction
Fluoxetine Hydrochloride1-4
It is N-methyl-3-phenyl-3-[4(trifluoromethyl)phenoxy]propan-1-Amine
Hydrochlorid having molecular formula
C17H18F3NO.HCl. It belong to category
selective serotonin reuptake inhibitor,
antidepressant. The MDT was prepared by
sublimation technique.
Fig1. Fluoxetine Hydrochloride
=============================
Formulation of Rapid Disintegrating
Tablet
All the ingredients were weighed. Then they
were mixed together and specified volume
of alcoholic solution of PVP (10%) was
added and mixed to form coherent mass.
The wet mass was granulated using sieve no.
10 and dried for 30 min then Screened
Corresponding Author: Nikude AS Email
id: ashishnikude5@gmail.com Institute of
Pharmaceutical Education and Research,
Wardha, Maharashtra, India Received:
07.11.2013
Revised: 08.12.2013
Accepted: 10.12.2013
7

2. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
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through sieve no. 18. The dried granules
were then blended with colloidal silicon
dioxide, talc & magnesium stearate and
compressed into tablet using 8 mm flat-
2348 –0882
faced punch on single tablet punching
machine. Formulations of Fluoxetine HCl
Rapid disintegrating tablet by wet
granulation method are shown in Table 1.
Table no 1: Formulation of rapid disintegrating tablet by wet granulation method.
Compositions for Rapid Disintegrating Tablet of Fluoxetine Hydrochloride by Sublimation
Ingredients (Mg)
F1
F2
F3
Drug
10
10
Camphor
20
Ammonium Bicarbonate
Crospovidone
20
20
Sodium Saccharin
1
1
Colloidal Silicon Dioxide
2
2
Magnesium Stearate
2
2
Talc
4
4
Mannitol
q.s.
q.s.
Total
200
200
Technique (Direct Compression)
All the ingredients were weighed. Then they
were mixed and compressed into tablet
using 8 mm flat-faced punch on single tablet
F4
F5
F6
F7
10
10
10
10
10
30
40
20
30
40
20
20
20
20
20
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
q.s.
q.s.
q.s.
q.s.
q.s.
200
200
200
200
200
punching machine. Formulations of
Fluoxetine
Hydrochloride
Rapid
disintegrating tablet by direct compression
method are shown in Table 2.
Table no 2: Formulation of rapid disintegrating tablet by direct compression method.
Ingredients
(Mg)
Drug
Camphor
Ammonium
Bicarbonate
Crospovidone
Sodium
Saccharin
Colloidal
Silicon Dioxide
Magnesium
Stearate
Talc
Mannitol
Total
F1
F2
F3
F4
F5
F6
F7
10
-
10
20
10
30
10
40
10
-
10
-
10
-
-
-
-
-
20
30
40
20
20
20
20
20
20
20
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
q.s.
200
4
q.s.
200
4
q.s.
200
4
q.s.
200
4
q.s.
200
4
q.s.
200
4
q.s.
200
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3. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
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RESULT AND DISCUSSION
Drug Identification
By UV spectroscopy
Fig: 2 Reported UV scanning of Fluoxetine HCl in Clarke’s analysis of drug and poison
By Infrared Absorption Spectrophotometry
Fig3: Reported FTIR of Fluoxetine HCl in Clarke’s analysis of drug and Poison
90
%T
75
60
45
30
15
0
400
0
375
0
fluo
xetine
350
0
325
0
300
0
275
0
250
0
225
0
200
0
175
0
150
0
125
0
100
0
75
0
50
0
1/cm
Fig 4: FTIR Spectrum of Fluoxetine HCl
Table no 3: Evaluation of Tablet Prepared by Direct compression Method:
*Wetting
*Disintegration
*% Drug *Hardness
*(%) Water
Sr.
*(%)
time
time(sec.) ±SD
Formulation content
absorption
(kg/cm2)
No.
Friability±SD (Sec)
±SD
±SD
ratio±SD
±SD
1
F1
97.26±0.63 2.8±0.02
1.2±0.78
122±0.34 71.72±0.5 9
88±1.47
2
F2
98.34 ±0.57 1.2±0.12
2.3±0.73
42±0.42 89.05±0.7 0
30±0.58
3
F3
99.95 ±1.12 0.8±0.04
3.06±0.59
39±0.25 90.41±0.3 6
16±1,39
4
F4
99.97 ±1.99 0.7±0.03
3.8±0.64
8±0.13 97.75±0.4 0
13±0.42
5
F5
97.38 ±0.25 0.9±0.05
3.7±0.72
30±0.34 88.34±0.3 1
12±1.55
6
F6
97.42 ±0.16 0.6±0.01
4.7±0.33
21±0.28 94.29±0.5 9
09±1.15
7
F7
98.75 ±1.07 0.6±0.02
5.2±0.39
16±0.39 95.01±0.6 2
07±0.23
*Each value represents the mean (n=3) ± standard deviation
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4. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
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Table 4: Evaluation of Tablet Prepared by Wet granulation Method:
*Wetting
*Hardness
time
*(%)
Water
Sr. Formula
*% Drug
(kg/cm2)
*(%)
(Sec)
absorption
No.
tion
content ±SD
±SD
Friability±SD
±SD
ratio±SD
1
F1
100.75±0.85
4.2±0.1
0.20±0.04
231±0.54 53.38±0.53
2
F2
100.33±1.27
3.5±0.057
0.2±0.07
124±0.24 68.27±0.24
3
F3
101.58±1.52
3.6±0.057
0.4±0.06
94±0.65 70.43±0.36
4
F4
101.99±0.61
2.3±0.08
1.1±0.02
74±0.32 75.18±0.42
5
F5
98.93 ±1.12
3.9±0.02
0.28±0.04
102±0.45 69.25±0.28
6
F6
99.91 ±1.99
3.8±0.02
0.3±0.05
79±0.87 69.33±0.46
7
F7
98.65 ±0.57
3.4±0.03
0.5±0.08
71±0.35 72.38±0.92
*Each value represents the mean (n=3) ± standard deviation
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*Disinteg
ration
time(sec.)
±SD
244±0.35
97±0.09
87±0.07
64±0.31
65±0.24
49±0.15
37±0.13
Table 5: Cumulative % Drug Release for Rapid Disintegrating Tablet at Different Time
Interval with Direct Compression Method in SGF pH 1.2.
Sr. Time
F1
F2
F3
F4
F5
F6
F7
No. (min)
1
0
0
0
0
0
0
0
0
44.7± 60.57±
2
1
100.1±1.44 100.5±1.66 70.65±0.83 94.95±1.89 99.72±1.32
1.27
0.87
52.0± 73.59±
3
2
94.89±0.57
1.49
0.98
64.5± 97.91±
4
3
1.82
1.21
73.3±
5
4
0.86
94.98±
6
5
0.78
Each value represents the mean (n=3) ± standard deviation
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5. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
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Table 6: Cumulative % Drug Release for Rapid Disintegrating Tablet at Different Time
Interval with Wet Granulation Method in SGF pH 1.2.
Sr.N
o.
Time
(min)
F1
F2
F3
F4
F5
F6
F7
1
0
0
0
0
0
0
0
0
2
1
0
13.95±2.49
47.88±0.97
47.88±1.83
51.84±1.79
49.50±1.53
66.15±1.34
3
2
29.34±1.62
23.83±2.09
68.48±0.07
66.14±1.54
56.35±1.37
52.92±1.86
79.74±0.61
4
3
56.77±1.34
31.70±1.71
71.02±1.32
90.09±0.89
60.62±1.68
65.63±1.62
97.64±0.071
5
4
77.96±1.89
48.80±2.09
73.21±1.46
101.5±0.06
72.93±1.54
72.38±0.71.
99.26±0.063
6
5
89.55±0.91
56.18±1.53
77.90±2.01
80.44±1.79
98.97±0.93
7
6
91.85±0.63
71.34±1.82
86.20±0.49
96.99±0.82
102.66±0.68.
8
7
96.85±1.34
74.07±0.79
101.80±0.032
97.52±0.091
9
8
98.19±1.53
75.82±0.69
10
9
98.72±0.64
92.34±0.43
11
10
100.0±0.73
100.3±0.082
12
11
100.8±0.09
101.02±0.07
Each value represents the mean (n=3) ± standard deviation
% Cumulative Drug Release
120
F1
F2
F3
80
F4
F5
F6
F7
40
20
0
0
2
4
6
8
10
12
14
Ti me (mi n)
% Cumulative Drug Release
Figure 4: Dissolution Profile of Rapid Disintegrating Tablet of Batches F1 to F7 Prepared
by Direct Compression Method.
120
F1
F2
F3
80
F4
F5
F6
F7
40
20
0
0
2
4
6
8
10
12
14
Ti me(mi n)
Figure 5: Dissolution Profile of Rapid Disintegrating Tablet of Batches F1 to F7 Prepared
by Wet Granulation Method.
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not hygroscopic and can be used with
moisture sensitive active ingredient. It was
used as diluents for its pleasant taste and
better mouth feel by virtue of its negative
heat of dissolution.5-7
Evaluation of Rapid Disintegrating
Tablet of Fluoxetine HCl
The rapid disintegrating tablets from batches
F1 to F7 of both the methods i.e. direct
compression and wet granulation were
evaluated for tablet properties such as
hardness, friability, wetting time, water
absorption ratio, weight variation and
disintegration time. In Direct compression
method, the batches from F2 to F7 are more
friable. Friability of these batches does not
comply with USP or any other official
standards.
Effect of subliming agent type
The presence of highly porous structure in
the tablet matrix is the key factor for rapid
disintegration of rapid disintegrating tablets.
The conventional tablet did not disintegrate
rapidly because of low porosity. To improve
the porosity, volatile substances such as
camphor and ammonium bicarbonate (AB)
can be used in tableting process, which
sublimates from the formed tablets. The
effect of subliming agent type was studied
by preparing F2 and F5 batch containing
camphor and AB, respectively as a
subliming agents. The tablet containing
camphor showed very less hardness,
friability and short disintegration time as
compared to tablets containing ammonium
bicarbonate. It was observed that the tablets
containing camphor did not exhibit complete
removal of camphor irrespective of the
sublimation time and this is felt by the
stinging effect in the mouth1.
Also,
disintegration time of F5 batch is less than
that of F2 batch because of its highly porous
structure in the tablet matrix. Thus AB is
better as compared to camphor.
Effect of method of tablet preparation
DISCUSSION AND CONCLUSION
Preformulation study
On the basis of characterization of the drug,
it was concluded that the received drug
sample from Cadila Pharmaceuticals Ltd.
Ankaleshwar (Gujrat) India. Complies with
the
compendial
specifications
for
identification and other tests and was
suitable
for
preparation
of
rapid
disintegrating tablet.
Drug – Excipient Interaction Study
FTIR of the drug confirmed the presences of
all prominent peaks are at wave numbers
2986, 2712,1614,1329,1257 and 1122 cm-1
indicating its authenticity. Physical mixture
of drug and excipient was characterized by
FTIR analysis for any physical as well
chemical
alteration
of
the
drug
characteristics. FTIR spectrum shows
prominent bands at 3200.83 cm-1 (sec. NH
Stretching), 3032.85 cm-1 (aromatic CH
stretching), 2889.17 and 2865.06 cm -1
(aromatic
and
symmetric
aliphatic
stretching), 1306.68 cm-1 (C-O-C stretching
of ether) , 1615.27 cm-1 (C=C stretching )
and 1740.89 cm-1 (C=O Stretching of ester).
From results, it was concluded that there
was no interference in the functional group
as the principal peaks of the Fluoxetine
hydrochloride were found to be unaltered in
the drug excipient physical mixture. The
physical parameters of drug as well as
excipients concluded that these were
considerably good to formulate the tablet
using sublimation technique.
Formulation of Rapid Disintegrating
Tablet
Polyplasdone XL-10 which is known as
crosspovidone (CP) was present in an
amount of 10% used as a Superdisintegrants.
The disintegrating action of CP was owing
to its high capillary activity and rapid
swelling in all direction in presence of any
physiological fluid. This leads to the rapid
development of high internal stresses, which
causes the tablet to disintegrate. Mannitol is
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For this study F1, F2 & F5 batches of wet
granulation method were used to assess the
importance of subliming agent for the
formation of pores into tablet matrix, which
helps in rapid disintegration. F2 & F5 batch
shows improved disintegration time as
compared to F1 batch (244 sec) which is
kept as control batch (without subliming
agent).
Tablets with lower friability (≤ 0.5%) may
not break during handling on machines and
or shipping. The use of subliming agent
resulted in increased friability probably due
to increased porosity10-11
Disintegration Time and Friability of
Tablets
Disintegrating time is very crucial property
of rapid disintegrating tablet. It is essential
to determine exact disintegrating time of
rapid disintegrating tablet. Hence in the
present study disintegrating time is
evaluated by in vitro and in vivo
disintegration test method. It was observed
that when crospovidone was used in
concentration of 10%, the disintegrating
time was found to be 88 sec. & 244 sec. in
F1 batch of direct compression & wet
granulation method respectively. The result
shown in table 6 & 7 indicate that
concentration-dependent disintegration was
observed in batches prepared using camphor
& ammonium bicarbonate as a subliming
agent. The porous structure is responsible
for faster water uptake; hence it facilitates
wicking action of crospovidone in bringing
about faster disintegration. It is worthwhile
to note that as the concentration of camphor
& ammonium bicarbonate increased, the
wetting time & disintegrating time is
decreased in both the methods i.e. direct
compression & wet granulation.
Tablets with lower friability (≤ 0.5%) may
not break during handling on machines
and/or shipping. The use of subliming agent
resulted in increased friability probably due
to increased porosity36. Batches from F2 to
The method of tablet preparation plays an
important role in the physical properties of
the prepared tablets; all the batches of both
the method (direct compression & wet
granulation) were used to investigate this
effect on the preparation of rapid
disintegrating tablet of Fluoxetine HCl. The
final blend in direct compression method F4,
F6 and F7 have very poor flowability, while
granules prepared by wet granulation method
exhibites good flowability. In addition, F2 to
F7 batches of direct compression method
have not acceptable hardness, friability This
is because of higher porosity of the tablets
which loses the internal strength of tablets
and tablets become more friable, while in
case of wet granulation method, PVP restore
its binding property with other excipients
after sublimation process36, 66.The result
suggests that the wet granulation method is
preferable to the direct compression for
preparation of rapid disintegrating tablets of
Fluoxetine HCl.
Effect of subliming agent concentration
Formulae F2 to F7 of wet granulation
method were used to study the effect of
concentration of subliming agent (Camphor
& Ammonium bicarbonate) on properties of
rapid disintegrating tablet. The results in the
table indicate that the wetting time decreases
with increase in concentration of camphor &
ammonium bicarbonate, which may be
attributed to the increase in water uptake
rate by the porous structure formed after
sublimation. Due to formation of pores into
tablet matrix, more physiological fluids is
available to the amorphous open structure of
the particles of crospovidone which results
in rapid swelling in all direction of particles.
This leads to rapid development of high
internal stresses which causes the tablet to
disintegrate
rapidly.
When
higher
percentage of subliming agent is used, more
porous and consequently more mechanically
weak tablets are produced8-9
Effect of presence of subliming agent
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8. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
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matter of seconds and almost all the drug
will be released instantaneously.
The in vitro dissolution profile in fig. 15 and
fig. 16 indicated faster and maximum drug
release from formulation F7 in comparison
with all batches of both the methods.
Formulation F7 prepared by direct
compression method showed 99.71 % drug
release at the end of 1 min while formulation
F7 prepared by wet granulation method
99.26 % drug was released at the end of 4
min. The rapid drug dissolution might be
due to easy breakdown of particles due to
porous structure formation into the tablet
matrix after sublimation of ammonium
bicarbonate.
Dissolution study of optimized batch of
tablets F7 prepared by wet granulation
method containing 20% ammonium
bicarbonate revealed most rapid release of
drug, t90 for batch F7 is less than 180 sec.
References
1)
www.Drugbank.com. [Accessed on
7Feb.2010]
2)
Martindale. The complete drug
reference: London; RPS publishing.
Edi 35th 2007: vol.1; 351-359.
3)
Moini J. Drug therapy for the nervous
system: antipsychotic and anti
depressant
drug;
Fundamental
ST
Pharmacology; 1
ed.Melbourne:
Cengage learning; 2010: p.70-71.
4)
Moffat, Osselton MD, Widdop B.
Clark’s analysis of drugs and poisons.
(Edis.) 3rd Edi; Vol. 2.
5)
Rowe CR, Sheskey PJ, Weller PJ.
Lactose,
In:
Handbook
of
Pharmaceutical Excipients, 4th edi,
Pharmaceutical Press, London. U.K.
2003.
6)
http://www.wikipedia/camphor.Acces
sed 05/12/2009. [Last Acessed on 12
Jan 2010]
7)
United State Pharmacopeias 24 / NF
19, (2000) Asian Edition, The official
compendia of
Standards, United
F7 of wet granulation method showed good
mechanical integrity as compared to same
batches of direct compression, but the
disintegrating time was a little longer than
the arbitrarily chosen value of less than 50
sec. only F7 batch of wet granulation
method & F2 to F7 batch of direct
compression showed better result in case of
disintegrating time i.e. less than 50
sec.Moreover, a good correlation (R2c =
0.9067 & R2a = 0.9643) between the
concentration of subliming agent (Camphor
& Ammonium bicarbonate) & friability is
observed respectively. Because when a
higher percentage of subliming agent is
used, more porous & consequently more
mechanically weak tablets are produced36.
Similarly, good correlation (R2c = 0.9508 &
R2a = 0.9932) between the concentration of
subliming agent (camphor & AB) and
disintegrating time is observed which is
shown in table 14 & 15 and fig. 19 & 20.
These high values of correlation coefficient
for percentage friability and disintegrating
time indicate a good fit. The correlation
coefficient values between in vivo and in
vitro disintegration time of the tablet
prepared by direct compression and wet
granulation
are
0.977
and
0.986
respectively.
In Vitro Dissolution Studies
For all oral solid dosage forms, dissolution
study serves as a control test. The same is
true for rapid disintegrating tablets. This is
because batch to batch consistency can be
assured, and dissolution data of the tablets
are
frequently
predictive
of
the
bioavailability of the product. The
cumulative % of drug release of F7 batch of
wet granulation method was found to be
99.26% at the end of 4 min. As the
concentration of subliming agent increases,
the time for drug release decreases because
at the higher concentration of subliming
agent, more porous tablets was formed
which easily get disintegrated within the
14

9. Int. J. Pharm. Res. Sci.,2013, 01(1),7-15.
8)
9)
ISSN
states Pharmacopial Convection Inc.
Rockville, pg no. 2135
Khalid KA, Ahmed AH, Mowafaq
MG, Alaa A. Formulation and
optimization of orodispersible tablet
of Diazepam. AAPS Pharm.Sci.Tech.
2010;
2(1):356-61.doi:
10.1208/s12249-010-9387-y.
Gohel M, Patel M, Amin A, Agrawal
R, Dave R, Bariya N. Formulation
Design and optimization of Nimsulide
Using Vacuum Drying Technique.
AAPS Pharm.Sci.Tech. 2004, 5(36):
10)
11)
15
2348 –0882
1-6.
Gohel M, Patel M, Amin A, Agrawal
R, Dave R, Bariya N. Formulation
Design and optimization of Nimsulide
Using Vacuum Drying Technique.
AAPS Pharm.Sci.Tech. 2004, 5(36):
1-6.
Shashaku K. Fast disintegrating solid
formulations of anirectom. Jpn Kokai
Tokyo Koho. 1999; Japanese patent
11 13 662.