FORMULATION AND EVALUATION OF IMMEDIATE RELEASE TABLETS OF TRAMADOL HCL USING DIFFERENT SUPERDISINTEGRANTS

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FORMULATION AND EVALUATION OF IMMEDIATE RELEASE
TABLETS OF
TRAMADOL HCL USING
DIFFERENT
SUPERDISINTEGRANT
S

Mayur Inamdar*
1
, Pooja Abhang
1

1
Oriental College of Pharmacy, Sector
-
2, Near Sanpada Railway station, Sanpada (E),

Navi Mumbai
-
400705.

Email:
mayurinamdar7@gmail.com


















*Corresponding author:

Mr. Mayur Ashok Inamdar

Research Scholar

Department of Pharmaceutics

Oriental College of Pharmacy, Sector
-
2,

Near Sanpada Railway station, Sanpada (E),

Navi Mumbai
-
400705

Email:
mayurinamdar7@gmail.com

Telephone:
8108146663














ABSTRACT
:

The objective of this research was to formulate

an

immediate
release tablet

of
Tramadol HCL
for rapid action, by using a suitable diluents and super
-
disintegrants. Faster disintegration of
the tablet administrated orally minimizes absorption time and improves its bioavailability in
less time. Immediate Release tablet of analgesic dru
g is formulated
by direct compression

using super disintegrant croscarmellose sodium, sodium starch glycolate and
Starcap

1500.
Tramadol an opioid analgesic drug has been used as an add
-
on treatment in adults and
children
and
has

been proved to be efficien
t in managing relief from pain and including pain
after surgery
. The powder blend was evaluated for

the pre
-
compression parameters such as
bulk density, compressibility, angle of repose etc. The prepared batches of tablets were
evaluated for hardness, weig
ht variation, friability, drug content, disintegration time and in
-
vitro dissolution profile and found satisfactory. The drug release from immediate release
tablets increased with increasing concentration of superdisintegrants and was found to be
highest w
ith formulations containing sodium starch glycolate with 10% concentration.


KEYWORDS:

Tramadol HCL
,
superdisintegrants,
Sodium starch glycolate,
Starcap 1500
,
Croscarmellose
.


































INTRODUCTION

The oral route of administration
has so far received the maximum attention with respect to
research on physiological and drug constraints as well as design and testing of products.

(1)

Oral ingestion has been the most convenient and commonly used route of drug administration
because of it
s flexibility and dosage form design.

(2)

Tramadol hydrochloride is a centrally
acting opioid analgesic structurally related to codeine and morphine used in the treatment of
moderate to severe pain in diverse conditions. Combined with low dependence/abuse
potential, it has proven to be of significant advantage over other agents, especially in the
elderly.

(3)


Tramadol hydrochloride has been proved to be effective in both experimental and
clinical pain without causing serious cardiovascular or respiratory s
ide effects.

(4)

Tramadol
hydrochlor
ide is freely soluble in water.

(5)
The half
-
life of the drug is about 5.5 hours and the
usual oral dosage regimen is 50 to 100 mg every 4 to 6 hours with a maximum dosage of 400
mg/day.

Tramadol possesses
weak agonist

actions at
the μ
-
opioid receptor, releases serotonin, and
inhibits the reuptake
of norepinephrine
. The analgesic action of
Tramadol

has yet to be fully
understood, but it is believed to work through modulation of serotonin and norepinephrine in
addition t
o its mild agonism of the
μ
-
opioid receptor. The contribution of non
-
opioid activity
is demonstrated by the fact that the analgesic effect of
Tramadol

is not fully antagonised by
th
e μ
-
opioid receptor antagonist.
Tramadol is used in the treatment of modera
te to severe
pain. Also used in the treatment of sever to chronic pain when the treatment needed around
the clock. It is the lightest and most compact than other dosage forms. It is bearing objective
like rapid dispersion, patient convenience and complianc
e. The main aim of
IR

technology

is
to

achieve improved bioavailability, rapid onset of action, chemical stability and patient
convenience and compliance.

(6
, 7
)


MATERIALS AND METHOD

Tramadol Hydrochloride, Microcrystalline
cellulose (
MCC)

(Avicel PH 102) and Magnesium
stearate were obtained as gift samples from Rubicon Research Pvt. Ltd.
Starcap 1500

were
obtained as gift sample from
Colorcon
Mumbai
. Sodium starch
glycolate (
SSG)

(Primojel)
and Croscarmellose sodium (Primellose) were obtai
ned as gift samples from
Colorcon A
sia
Pvt Ltd (Mumbai).

Double distilled water was used throughout the experiment. All other
reagents were of analytical grade.


ANALYTICAL METHOD VERIFICATION
(8)

To determine the λ max in UV Spectrophotometer (Shimadzu 18
00) a

standard stock solution
of 100 µg/ml

of Tramadol HCl was
examined

between 200 to 400 nm. The λ max was found
to be 271 nm

Specificity
:

The specificity was checked by dissolving 400 mg of placebo in 900 m
l

of 0.1 N HCl and
sonicated for 30 minutes. The solution was then filtered using Whatmann Filter paper and the
UV absorbance was taken at λ max of 271 nm.

Linearity
:

Specific volume of

aliquots were withdrawn from the standard stock solution into different

volumetric flasks and diluted with 0.1 N HCl so as to prepare the solutions

of 10, 20, 40, 60,
80 and 100 µ
g/m
l
. The
absorbance of these solutions was

taken at λ max of 271 nm using 0.1
N HCl as blank.




FORMULATION OF IMMEDIATE RELEASE TABLET OF DRUG BY

DISINTEGRANT ADDITION METHOD:

Tramadol HCL Immediate release tablets were prepared by

using direct compression

method
after incorporating different superdisintegrants such as,

C
rosscarmellose sodium (Ac
-
Di
-
Sol),
Starcap 1500

and sodium

starch glycolate in different concentrations.
Microcrystalline
c
ellulose (MCC)

was used as directly compressible diluents.
The super disintegrant were
used to formulate the tablets. All the materials were passed through mesh no.60 prior to
mixing. Tramadol
, MCC, Sodium starch Glycolate (SSG), Crosscarmellose sodium and
Starcap1500 were mixed using a glass mortar pestle.
Nine formulations

of Tramadol
hydrochloride tablets
were prepared

and each formulation contained one of the three
disintegrant in

different

concentration. Tablet weight was 200 mg; 8 mm punch

was used for
compression
.




PHARMACO TECHNICAL EVALUATION OF TRAMADOL HCL IMMEDIATE
RELEASE

TABLET:

PRECOMPRESSION PARAMETERS:
(9,

10,

11)

1. Bulk density (Bd)

The term bulk density refers to a measure used to describe a packing of particles. The bulk
density of
powder
was obtained by dividing the mass of a powder by the bulk volume in cm3
(V). The standard method (USP) was adopted for measurement of bulk density

and following
equation was used for calculation.

Bd =




Where, M = weight of samples in grams, V= bulk volume of powder in cm3.


2. Tapped density

(T
d
)

The tapped density or poured density attained after mechanically tapping a container
containing the powder sample. The standard method described in USP was followed and
tapped density was calculated using equation given below:

Td =
=





Where, M = weight of samples in grams and Vp = final tapped volume of powder in cm
3
.


3. Carr’s index

An indirect method of measuring powder flow from bulk densities was developed by Carr. A
low Carr’s index implies a good initial packing arrangement, with

less volume of voids. As
the value of these indices increases, the flow of the powder decreases. In general, however,
Carr’s index below 16% indicates good flowability while values above 35% indicate
cohesiveness14. Carr’s index of each sample was calcula
ted according to equation given
below:

CI =
100

(








)

4. Hausner’s ratio

Hausner’s ratio measures the powder ability to settle and permit an assessment of the relative
importance of interparticulate interactions. Hausner’s ratio is calculated as

the ratio of bulk
density to tapped density. The Hausner’s ratio less than 1.25 indicates good flow; the values
between 1.25 to 1.5 assure that adding glidant will improve flow ability.

HR=






Where, V
0
: unsettled apparent volume, V
f
: final tapped
volume


5. Angle of Repose

Angle of repose has been defined as the maximum angle possible between the surface of pile
of powder and horizontal pla
ne. The angle of repose
was determined by the fixed height
funnel method. The angle of repose was calculated b
y substituting the values of the base
radius ‘r’ and pile height ‘h’ in the following equation:

tan


=



Therefore;


= tan

1

(




)

6. Determination of flow rate

Ten grams (10g) (
w
) of the
powder

were passed through dry glass funnel and allowed to flow
through the funnel orifice. The time taken for the powder to flow through the orifice (
t
) was
noted and the flow rate was computed as;




8. Percent compressibility (%C)

It is an important
measure that can be obtained from bulk density measurements. It is th
e
simple test to evaluate the V
0

and V
f

of powder and the rate at which it packed down. The
following formula was used to compute the percent

compressibility.












Where,

V
f

= packed bulk density

V
0

= apparent bulk density


POST COMPRESSION PARAMETERS:


1. Weight variation:
Twenty

tablets were selected randomly from each batch and weighed
individually on electronic balance. The individual weight is then compared with the aver
age
weight for the weight variations.


2. Hardness:
The

hardness of the tablet was determined using Pfizer hardness tester.


3.
Wetting

time study:
The experiment was designed to evaluate the water uptake rate by the
tablet. 25 ml of water was placed in a
Petri dish. The band of the filter paper, supported on
the glass slide, was partially dipped in water.

A tablet was placed on the surface of filter
paper band. The uptake of water occurred from the lower surface of
tablet. The

time required
for water to re
ach the centre of the upper surface of the tablet was noted.


4. Water absorption ratio:
Test was done with the same procedure as that of wetting time.
In this test, initial weight of the tablet was noted before placing it on the Petri dish. After
complete

wetting, the wet tablet was then weighed. Water absorption ratio, R was determined
using equation,

R=







× 100

W
a
= weight of the tablet before absorption.

W
b
= weight of the tablet after absorption.


5. Friability

(12)

The tablets were
carefully dedusted prior to testing. Accurately weigh the tablet sample, and
place the tablets in the drum. Rotate the drum 100 times, and the tablets were removed. The
tablets were then reweighed after removal of fines and the percentage of weight loss wa
s
calculated. A maximum mean weight loss from the three samples of not more than 1.0% is
considered acceptable for most products.












100

6. Disintegration test

The disintegration
time was

measured using disintegration test apparatus as per the USP. One
tablet
was

placed in each tube of the basket. The basket with the bottom surface made of a
stainless
-
steel screen (mesh no.10) were immersed in water bah a 37± 2°C. The
time required
for com
plete disintegration of the tablet in each tube was

determined using a stop watch.


7.

Drug
Content

Ten tablets from each batch were powdered. The powdered

sample equivalent to 100 mg of
drug was transferred to a

volumetric flask. 100 m
l

of 0.1 N HCl was added, mixed

and
filtered. 1 m
l

of filtrate was diluted to 10 m
l

with 0.1N

HCl and analyzed against blank by
UV spectrophotometer at

271nm. (UV 1800, Shimadzu)


8
.
Fourier
Transform Infrared (FTIR
) spectroscopy

FTIR spectra were recorded
by mixing dried powder with potassium bromide

(KBr)

of IR
grade using a Jasco, FTIR
-
4100 model. Pellets were prepared with KBr by

means of
hydraulic press at a pressure of 50 units. The scanning range was 400 to 4000 cm
-
1
.



Results and Discussion:

The study was designed to evaluate the immediate release tablets of
Tramadol

hydrochloride.

No interference of placebo was found at λ max of Tramadol HCL. Hence, the UV method
used for estimation of Tramadol HCL in formulation is specific. The results of the linearity of
Tramadol HCl are summarised in Table
-
3. The calibration curve of
%
concentra
tions of
Tramadol hydrochloride versus respective absorbance was plotted (Fig.2). The representative
linear equation was
y
= 0.005x+0.014, where
x
is concentration and
y
is the absorbance. The
correlation coefficient was 0.999, indicating good linearity in

the concentration range of 10
-
100 µ
g/m
l
.

All the batches were evaluated for flow properties. The angle of repose for all the batches
was found to be between 28.68 °to 38.76° indicating good flow. A Hausner’s Ratio between
1.06 to 1.30 and Compressibility
index between 5%
-

22% indicated good flow. Thus, the
formulation showed the required flow properties for direct compression. The values for angle
of repose, Hausner’s Ratio and Compressibility Index of individual batches are represented in
Table 1.

All th
e batches were evaluated for physical parameters such as weight variation, drug
content, hardness, friability, water absorption ratio and disintegration time.

The tablets with
different formulations were found to be between the weight ranges of 195 to 204
mg.

The
drug content of tablets with different formulations was found to be highly uniform within the
range of 97.94% to 99.45%. A hardness value of tablets for all the batches was maintained
between 3.26 to 4.01Kp. All the batches satisfied the

friability

requirement as the percent

friability values of tablets were less than 1%.
Wetting time is used as an indicator of the ease
of tablet disintegration and found to be 16
-
30sec. Water absorption ratio ranged from 18.24
-
36.37.
Disintegration time for B9 batch
was found to be more as compared to other batches.
All the other batches showed the disintegration time below 5 minutes. The hardness,
friability, drug content
,

disintegration time, water absorption ratio and wetting time values are
represented in Table 2.

FT
-
IR studies revealed that there was no physico
-
chemical interaction between Tramadol
HCL and other excipients. It is showed in fig.1


Conclusion:

In the present work efforts have been made to develop Tramadol HCl Immediate release
tablet as a promising approach to
give the rapid action by
using

different

Superdisintegrants
.

The results showed that the
disintegration time was increased with increasin
g concentration
of superdisintegrants
. Sodium starch glycolate,

Croscarmellose Sodium and Starcap

1500 was
compared a
nd the best formulation (F9) containing 10% Sodium starch glycolate showed
minimum disintegration time.


Reference:

1.

Lehman KA. Tramadol hyd
rochloride in acute pain.

Drugs.

1997;

53:25

33.

[
PubMed
]

2.

Gurudev Singh Raina, Rajeev Taliyan and P.L. Sharma,

Pathophysiology of
neuropathic pain: a systemic review,

IJPSR, Vol. 3,
Issue 10,2012

3.

Robinson JR and Lee VH. Controlled Drug Delivery Systems. 2nd edition New York:
Marcel Dekker inc, 2005.

4.

Kumar P, Singh S e. al. “Development And Biopharmaceutical Evaluation Of
Extended Release Formulation Of Tramadol Hydrochloride Based On
Osmotic
Technology”, Acta Pharm, 2009, 59 (1):15

30.

5.

Raval SB, Prajapati R., et al. “Formulation And Evaluation Of Tramadol
Hydrochloride Mouth Dissolving Tablet”,Journal of Global Pharma Technology,
2010; 2(11):17
-
22.

6.

O'Neil MJ,


Heckelman

PE, The Merck Index: An Encyclopedia of Chemicals, Drugs,
and Biologicals, ,13
th

edition., Merck and Co., Inc., USA, 2001.

7.

Gillian M
,
Tramadol Sustained
-
Release Capsules Keating, ,

Adis Drug Profile

Drugs: Volume 66
-

Issue 2
-

pp 223
-
230,2006

8.

Byline: K. Srinivasan, J. Alex, A. Shirwaikar, S. Jacob, M. Sunil Kumar, S. Prabu,

Simultaneous derivative spectrophotometric estimation of aceclofenac and tramadol
with paracetamol in combination solid dosage forms,


Indian Journal of
Pharmaceutical Sciences

,
1
July 2007

9.

Staniforth, J.N. (1996). Powder flow. In: Aulton M. E. (Ed). Pharmaceutics
-

the
science of dosage form design. Churchill Livingston, pp 600
-
615.

10.

M. C. Gohel, A. F. Amin, Munira Momin, Seema Bazaz, M. K. panchal,
“Preliminary investigations in

matrix based tablet formulations of diclofenac sodium
containing succinic acid treated guar gum.” in Bollettino Chimico Farmaceutico
137(6) 1998.

11.

United States of Pharmacopoeia Convention (USP), USP
-
24 NF
-
19, Rockville, USA,
1999.

12.

Yeole CN, Darekar SS, et
. al. Formulation and Evaluation of Immediate Release
Tablet of Paroxetine Hydrochloride,Journal of Pharmacy Research
,
2010, 3(8):1736
-
1738



Table 1:
Formulation of Tramadol hydrochloride immediate release Tablets.



Table 2
: Evaluation of Precompressed powder blend

Sr.
No

Properties


B1

B2

B3

B4

B5

B6

B7

B8

B9

1

Bulk
density(g/ml)

0.56

0.54

0.46

0.57

0.65

0.42

0.44

0.52

0.42

2

Tapped
density(g/ml)

0.62

0.70

0.51

0.62

0.72

0.55

0.53

0.58

0.55

3

Carr’s index

6.56

22.52

11

9.9

7.03

23.63

15

10.34

23.63

4

Hausner’s ratio

1.06

1.28

1.12

1.14

1.08

1.30

1.12

1.11

1.30

5

Flow rate(sec)

12

9.99

13.0

11

7.0

15.0

10.0

10.0

15.0

6

Angle of repose

37.1

37.65

30.54

34.6

32.42

31.80

31.54

38.65

31.80

8

Compressibility

5.9

22.32

12.11

11

6.56

30.95

13.11

10.52

30.95




Table 3: Evaluation of immediate release tablets of
Tramadol

HCl

Ingredients Batch
code (mg)

B1

B2

B3

B4

B5

B6

B7

B8

B9

Tramadol HCL

50

50

50

50

50

50

50

50

50

MCC

143

141

138

143

141

138

143

141

138

Starcap 1500

05

07

10

_

_

_

_

_

_

Crosscarmellose

Sodium

_


_


_


05

07

10

_


_


_


Sodium starch

Glycolate (SSG)

_


_


_


_


_


_



05


07

10

Magnesium
stearate

2

2

2

2

2

2

2

2

2

Batch code

Weight
variation

(mg)

Hardness

(kg/cm2)

Friability

(%)

Drug

Content
(%)

Disintegration
time (sec.)

Water
absorption

ratio (%)

Wetting

time (sec.)


B1

198
-
202


3.71 ±0.02


0.42±0.03


98.10


65±2.00


25.89±1.11


21.00± 1.12


B2

197
-
203


3.83 ±0.12


0.33±0.06


98.65


52±2.00


18.24±2.13


19.00± 0.61


Table 3:
Absorbance of
different concentrations of Tramadol HCL in 0.1 N HCL

Concentration (µg/ml)

Absorbance

10

0.067

20

0.1445

40

0.2352

60

0.344

80

0.4158

100

0.5301

120

0.6211

140

0.7466

160

0.8552


Figure 1
.
FT
-
IR of Tramadol H
ydrochloride.






B3

196
-
201


4.01 ±0.26


0.24±0.05


99.35


45±1.00


19.45±2.10


16.33± 1.55


B4

198
-
202


3.81 ±0.03


0.53±0.05


99.29


34±0.00


32.45±1.63


23.87± 0.36


B5

197
-
201


3.26 ±0.13


0.43±0.01


99.20


31±1.00


28.69±1.55


22.67± 0.52


B6

195
-
204


3.49 ±0.23


0.52±0.04


98.88


27±2.00


29.09±1.52


22.34± 1.58


B7

199
-
203


3.72 ±0.06


0.35±0.02


97.94


33±2.00


35.89±1.32


30.39± 0.58


B8

198
-
204


3.64 ±0.01


0.38±0.01


99.45


24±2.00


36.37±1.96


25.01± 1.01


B9

196
-
201


4.10 ±0.01


0.42±0.03


98.96


21±1.00


37.09±1.92


27.33± 0.59

Fig.
2
:
Calibration Curve for Tramadol HCL in 0.1 N HCL