Development and In Vitro Evaluation of Fast
Dissolving Tablets of Tapentadol
Prathibha Suvarna1, Ravi Kumar2*, Yamunappa1, Pooja Shetty1, Narayana
Swamy V.B.3
1M.Pharm (Pharmaceutics)
Research Scholar, Karavali College of Pharmacy
Mangalore.
2Department of Pharmaceutics,
Karavali College of Pharmacy Mangalore.
3Department of Pharmacognosy,
Karavali College of Pharmacy Vamanjoor
Mangalore.
*Corresponding Author E-mail: ravikumar300@gmail.com
ABSTRACT:
The objective of this research was to formulate fast dissolving tablets
of tapentadol that disintegrate in the oral cavity
upon contact with saliva and there by improve therapeutic efficacy. Tapentadol is used for the treatment of moderate to severe
pain for both acute (following injury, surgery, etc.) and chronic
musculoskeletal pain). Fast dissolving tablets of tapentadol
were prepared by direct compression method comprising of three different superdisintegrants-Sodium starch glycollate,
Crosscarmellose sodium and Crosspovidone
(2%, 4%, 6% and 8%) and diluent viz: microcrystalline
cellulose. Twelve formulations were prepared and evaluated for hardness,
thickness, friability, weight variation, drug content, in
vitro disintegration time, in vitro dispersion time, wetting time,
water absorption ratio and in vitro dissolution studies. FTIR and DSC
studies revealed that there was no chemical interaction between the drug and
the excipients. Formulation M12 was found to be the
best on the basis of wetting time, in vitro disintegration time and in
vitro drug release. The formulation M12 containing microcrystalline
cellulose as diluent and crosspovidone (8%) as disintegrant was found to be the optimized combination.
Stability studies were carried out at 250C±20C/60%±5% RH
and 400C±20C/75%±5% RH for formulation M12 for 60 days.
The results of stability studies indicated no significant changes with respect
to physicochemical properties, in vitro disintegration time, wetting
time and in vitro drug release.
KEY WORDS: Fast dissolving tablets, tapentadol,
Superdisintegrant, Direct compression, Sodium starch glycollate, Crosscarmellose
sodium, Crosspovidone.
INTRODUCTION:
The oral route of administration still continues to be the most
preferred and popular route about 80% of total dosage forms are administered
due to its manifold advantages including ease of ingestion, pain avoidance,
versatility and most importantly patient compliance. Many pharmaceutical
dosages are administered in the form of pills, granules, powders and liquids.
Generally, a pill design is for swallowing intact or chewing to deliver
a precise dosage of medication to patients. The pills, which include tablets
and capsules, are able to retain their shapes under moderate pressure. However,
some patients, particularly pediatric and geriatric
patients, have difficulty swallowing (dysphagia) or
chewing solid dosage forms. Many pediatric and
geriatric patients are unwilling to take these solid preparations due to fear
of choking1. In order to assist these patients,
several fast-dissolving drug delivery systems have been developed, which
include Orally Disintegrating Tablets and Oro Dissolving Films. Oral fast
dissolving drug delivery system (OFDDS) is one such novel approach to increase
consumer acceptance by virtue of rapid disintegration, self-administration
without water or chewing1. Oral cavity is that area of mouth
delineated by the lips, cheeks, hard palate, soft palate and floor of mouth.
The oral cavity consists of two regions.
(a) Outer oral vestibule, which is bounded by cheeks, lips, teeth and gingival(gums).
(b) Oral cavity proper, which extends from teeth and gums back to the fauces (which lead to pharynx) with the roof comprising the
hard and soft palate. The tongue projects from the floor of the cavity. The drug
administered via the oral mucosa gain access to the systemic circulation
through a network of arteries and capillaries. The major artery supplying the
blood to the oral cavity is the external carotid artery. The venous back flow
goes through branches of capillaries and veins and finally taken up by the
jugular vein. Orally disintegrating tablets (ODT) are solid unit dosage forms
like conventional tablets, but are composed of superdisintegrants, which help
them to disintegrate the tablet rapidly in saliva and are swallowed without
water as tablet disintegrate in mouth, this could enhance the clinical effect
of drug through pregastric absorption from the mouth,
pharynx, esophagus. This leads to an increase in the
bioavailability by avoiding first pass liver metabolism. Oral disintegrating
tablets (ODT) are not only indicated for people who have swallowing
difficulties, but also are ideal for active people. Orally disintegrating
tablets are also called as mouth dissolving tablets, orodispersible tablet’, quick disintegrating tablets, rapid dissolving
tablets, porous tablets and rapimelts2.
US FDA defined orally disintegrating tablet as “A
solid dosage form containing medicinal substances, which disintegrates rapidly,
usually within a matter of seconds, when placed upon the tongue”. Recently
European pharmacopoeia also adopted the term ‘orodispersible tablet’ as a tablet that is to be placed in the mouth where it
disperses rapidly before swallowing2. Despite various terminologies used, orally disintegrating tablets are
here to offer unique form of drug delivery with many
advantages over the conventional dosage forms. The US Food and Drug Administration 2008
publication of guidance for industry: Orally
Disintegrating Tablets. Three main points stand out in the final guidance3:ODTs should have an in vitro disintegration time of
approximately 30 sec o less (using United States Pharmacopeia disintegration
test or equivalent). Generally, the ODT tablet weight should not exceed 500 mg, although the
combined influence of tablet weight, size, and component solubility all factor
into the acceptability of an ODT for both patients and regulators. The guidance
serves to define the upper limits of the ODT category, but it does not
supersede or replace the original regulatory definition mentioned. In other
words, disintegration within a matter of seconds remains the target for an ODT4. The drug selected for investigation is Tapentadol which is
a centrally-acting synthetic opioid analgesic
used for moderate to severe pain like labor pain,
postoperative surgical pain, traumatic pain and cancer pain. Tapentadol can be administered orally, intravenously or
rectally. Tapentadol is rapidly absorbed orally is
subjected to first pass metabolism and absolute bioavailability is only approximately
32%. It is bitter in taste. The objective was to formulate taste masked tapentadol fast dissolving tablets leading to an increase
in bioavailability of the drug, quick onset of pharmacological action and
increase in patient compliance due to ease of administration.
MATERIALS
AND METHODS:
Materials:
Tapentadol was obtained from Lupin Pharmaceuticals,
Mumbai, India as gift sample. All the other solvents, reagents and
chemicals used were of either Pharmacopoeial or
analytical grade.
Methods:
1. Drug excipients compatibility study:
Compatibility of Tapentadol with superdisintegrants was established by infrared spectral
analysis. The samples were mixed with potassium bromide in a ratio of 1:99 in
agate mortar and pestle and mixed thoroughly. This mixture was then loaded in
FTIR to get an IR spectrum. IR Spectral analysis was carried out to investigate
the changes in chemical composition of the drug after combining it with the excipients.
2. PREPARATION OF TAPENTADOL FAST DISSOLVING TABLETS:
Tapentadol tablets
each containing 75 mg of Tapentadol were prepared by
direct compression method. The different superdisintegrants
used were Sodium starch glycollate, Crosscarmellose sodium and Crosspovidone
in different concentrations. The diluent used was microcrystalline cellulose
along with other excipients. The study was intended
to compare the disintegration efficiency of these superdisintegrants
in various concentrations (2%, 4%, 6% and 8%) and to select the best possible
diluent-superdisintegrant combination among the
various superdisintegrants used. Accurate quantities
of Tapentadol, superdisintegrants
(preferred superdisintegrants in different
concentrations), microcrystalline cellulose, aspartame, talc
and magnesium stearate were weighed and passed
through mesh #60. All the ingredients except lubricant were thoroughly blended
in a glass mortar with pestle for 15 min.
Table 1:
Composition of FDT’s of Tapentadol with MCC as
diluent
INGREDIENTS
(mg/tablets) |
FORMULATIONS |
|||||||||||
M1 |
M2 |
M3 |
M4 |
M5 |
M6 |
M7 |
M8 |
M9 |
M10 |
M11 |
M12 |
|
Tapentadol |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
75 |
Sodium Starch Glycollate |
4 |
8 |
12 |
16 |
- |
- |
- |
- |
- |
- |
- |
- |
Crosscarmellose Sodium |
- |
- |
- |
- |
4 |
8 |
12 |
16 |
- |
- |
- |
- |
Crosspovidone |
- |
- |
- |
- |
- |
- |
- |
- |
4 |
8 |
12 |
16 |
Microcrystalline Cellulose |
113 |
109 |
105 |
101 |
113 |
109 |
105 |
101 |
113 |
109 |
105 |
101 |
Aspartame |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
Magnesium Stearate |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
Orange flavour |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
Talc |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
Aerosil |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
Total weight (mg) |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
200 |
After sufficient mixing lubricant
was added and mixed for additional 2 to 3 min. Before compression, hardness was
adjusted. 75 mg of Tapentadol were compressed on
10-station rotary punching machine, each weighing 200 mg. The compositions of Tapentadol fast dissolving tablets was given in table 1.
EVALUATION OF FAST DISSOLVING TABLETS
PRE-COMPRESSIONAL STUDIES:5-14
1. Angle of Repose
(Ө):
The frictional force in a loose powder or granules can be measured by
angle of repose. Angle of repose is defined as the maximum angle possible
between the surface of a pile of the powder and horizontal plane. The angle of
repose of API powder was determined by the funnel method. The accurately
weighed powder blend was taken in the funnel. The height of the funnel was
adjusted in such a way that the tip of the funnel just touched the apex of the
powder blend. The powder blend was allowed to flow through the funnel freely on
to the surface. The diameter of the powder cone was measured and angle of
repose was calculated using the following equation.
Ө = tan-1
(h/r)
Where, Ө is the angle of repose, h is the height of pile and r
is the radius of the base of pile.
2.
Bulk Density and Tapped density:
Loose bulk density (LBD) and tapped bulk density (TBD) of tablet blends
were determined using bulk density apparatus. Tablet blend was passed through
#18 sieve to break the clumps and transferred to 100ml
graduated cylinder. Initial volume was observed. The cylinder was tapped
initially 200 times from a distance of 14 ±2 mm. The tapped volume was measured
to the nearest graduated unit. This was repeated for other tablet blends. The
LBD and TBD were calculated in g/ml using following formula:
LBD = weight of the powder / volume of the packing
TBD = weight of the powder /
tapped volume of the packing
3. Carr’s Index:
The Compressibility Index of the powder
blend was determined by Carr’s compressibility index. It is a simple test to evaluate
the BD and TD of a powder and the rate at
which it is packed down. The formula for Carr’s Index is as below,
Carr’s Index (%) = [(TBD-LBD) x100]/TBD
Where, LBD = Loose Bulk Density and TBD = Tapped Bulk Density
4. Hausner ratio:
The Hausner’s
ratio is a number that is correlated to the flowability
of a powder or granular material. The Hausner ratio of the
powder was determined by the following:
equation:
Hausner ratio = TBD / LBD
Lower Hausner
ratio (<1.25) indicates better flow properties than higher ones (>1.25).
5.
Total
porosity:
Total porosity was
determined by measuring the volume occupied by a selected weight of a granule (Vbulk) and the true volume of the granule (The space
occupied by the powder exclusive of spaces greater than the intermolecular
spaces).
Porosity
(%) = V bulk - V x100
Vbulk
POST-COMPRESSIONAL STUDIES5-14
A. General appearance:
The fast dissolving tablets, morphological characterization which
includes size, shape, colour, presence or absence of odour, taste surface
texture was determined.
B. Thickness and
diameter:
Five tablets were picked from each formulation randomly and thickness
and diameter was measured individually. It is expressed in mm and standard
deviation was also calculated. The tablet thickness and diameter was measured
using vernier calliper.
C. Hardness:
Hardness indicates the ability of a tablet to withstand mechanical
shocks while handling. The hardness of the tablets was determined using
Monsanto hardness tester. It is expressed in kg/cm2. Five tablets were randomly
picked and hardness of the same tablets from each formulation was determined.
The mean and standard deviation values were also calculated.
D. Friability test:
Friability test is performed to assess the effect of friction and
shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for the purpose. Preweighed
sample of ten tablets were placed in the Friabilator,
which was then operated at 25 rpm for 4 minutes or ran upto
100 revolutions. After 100 revolutions the tablets were dusted and reweighed.
Compressed tablets should not lose more than 1% of their weight. The %
friability was then calculated by the following formula:
Percentage friability =
(Initial weight - Final weight /Initial weight) × 100
E. Weight variation:
20 tablets were selected randomly from each formulation and weighed
individually to check for weight variation. The US Pharmacopoeia allows
a little variation in the weight of a tablet. The following percentage
deviation in weight variation is allowed: In all the formulations the
tablet weight was 200 mg, hence 7.5% weight variation
was allowed.
F. Drug content
uniformity:
Twenty tablets were weighed and powdered. Powder equivalent to 75 mg
drug was transferred into a 100 ml volumetric flask. Volume was made with
phosphate buffer pH 6.8. After few minutes the solution was filtered; rejecting
first few ml of the filtrate. 10ml of filtrate was taken in a 50 ml volumetric
flask and diluted up to the mark with phosphate buffer pH 6.8 and analyzed
spectrophotometrically at 272 nm. The concentration of Tapentadol
(in μg/ml) was calculated by using the standard
calibration curve of Tapentadol.
G. Wetting time and
water absorption ratio:
A piece of tissue paper folded twice was placed in a small petridish (i.d = 6.5 cm)
containing 6 ml of water. A tablet was placed on the paper and the time
required for complete wetting was then measured. The water absorption ratio, R,
was determined using the following equation,
R = Wa - Wb / Wb × 100
Where, Wb is the weight of the tablet before
water absorption and Wa is
the weight of the tablet after water absorption.
H. In vitro dispersion time:
One tablet was placed in a beaker containing 10 ml of phosphate buffer
pH 6.8 at 37 ± 0.5ºC and the time required for complete dispersion was
determined.
I. In vitro disintegration
time:
In vitro disintegration time was performed by apparatus specified in USP at 50
rpm. Phosphate buffer pH 6.8, 900 ml was used as disintegration medium, and the
temperature of which was maintained at 37±2°C and the time in second taken for
complete disintegration of the tablet with no palpable mass remaining in the
apparatus was measured in seconds.
J. In vitro drug release
studies:
In vitro release studies were carried out using tablet dissolution test apparatus
USP XXIII. Two objectives in the development of in vitro dissolution
tests are to show that
the release of the drug from the tablet is as close as possible to 100%
and that the rate of drug release is
uniform batch to batch and is the same as the release rate from those batches
proven to be bio available and clinically effective. In vitro drug
release studies were carried out using dissolution apparatus USP type XXIII at
50 rpm. The dissolution medium consisted of 900 ml of Phosphate buffer pH 6.8
maintained at 37±10C. The drug release at different time intervals
was measured using a double beam UV Spectrophotometer at 272 nm.
K. Data Analysis:
Various models were tested for explaining the kinetics of drug release.
To analyze the mechanism of the drug release rate kinetics of the dosage form, the
obtained data were fitted into zero-order, first order, Higuchi, Korsmeyer-Peppas release model and Hixson-Crowell equation.
L. Stability Studies:
Stability of a drug has been defined as the ability of a particular
formulation, in a specific container, to remain within its physical, chemical,
therapeutic and toxicological specifications. The purpose of stability testing
is to provide evidence on how the quality of a drug substance or drug product
varies with time under the influence of a variety of environmental factors such
as temperature, humidity and light, and enables recommended storage conditions,
re-test periods and shelf lives to be established. ICH specifies the length of
study and storage conditions:
Long term testing 250C ± 20C/60%±5% RH for 12
months
Accelerated testing 400C ± 20C/75% ±5% RH for 6
months
In the present study, stability studies were carried out at 250C
± 20C/60% ±5% RH and 400C± 20/75% ± 5% RH for
a period of 60 days for the selected formulation (M12). The formulation was
then evaluated for changes in the physicochemical properties, wetting time, in
vitro disintegration time and in vitro drug release.
RESULTS
AND DISCUSSION:
The present study was to formulate fast dissolving tablets of Tapentadol using superdisintegrants
(sodium starch glycollate, crosscarmellose
sodium and crosspovidone) in different concentrations
and diluent microcrystalline cellulose along with other excipients
by direct compression method. The prepared tablets were evaluated for
physiochemical properties, wetting time, water absorption ratio, in vitro dispersion
time, in vitro disintegration time, in vitro dissolution studies
and stability studies.
Drug-Excipients
Compatibility Studies:
Fourier Transform Infrared (FTIR) Spectroscopy:
Physical mixture of Tapentadol and formulative ingredients were subjected for IR spectroscopic
analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectras
showed similar characteristic peaks at their respective wavelengths with minor
differences. The similarity in the peaks indicated the compatibility of drug
with formulation excipients. IR spectra of the
physical mixture of drug with formulative ingredients
were depicted in figure 1 to 5.
Figure 1: FT-IR Spectra of Physical mixture of Tapentadol+SSG
Figure 2: FT-IR Spectra of Physical mixture of Tapentadol + CCS
Figure 3: FT-IR Spectra of Physical mixture of Tapentadol + CP
Figure 4: FT-IR Spectra of Physical mixture of Tapentadol + M12
Figure 5: FT-IR Spectra of Physical mixture of Tapentadol + MCC
Differential Scanning Calorimetry (DSC):
The DSC thermograms of pure Tapentadol HCl showed melting
endothermic peak at 205.5°C indicating crystalline nature of Tapentadol HCl, followed by
exothermic peak which may be due to decomposition of Tapentadol
HCl. The endothermic peak for the drug in physical
mixture, showed minor changes in the melting endotherm
of drug could be due to the mixing of drug and excipients,
which lower the purity of each component in the mixture and may
not necessarily indicates potential incompatibility. The result showed that
drugs were compatible with excipients. DSC thermograms of drug and physical mixture of drug and excipients were shown in figure 6-7.
Figure 6: DSC thermogram
of Tapentadol HCl
Figure 7: DSC thermogram
of Physical mixture of Tapentadol + Excipients
EVALUATION PARAMETERS:
A) PRECOMPRESSIONAL PARAMETERS:
Blended drug/excipient mixture of all the
formulations were subjected for various precompressional
evaluation parameters such as bulk density, tapped density, compressibility index, hausner’s ratio and
angle of repose who’s values were found to be within limit and had favorable flow properties for compression, reported in
table 2. All the formulations showed good passable compressibility index and
good angle of repose.
Table 2: Pre compression evaluation of tapentadol powder blend containing MCC
Formulation Code |
Angle of Repose |
Bulk Density (gm/cc) |
Tapped Density (gm/cc) |
Carr’s Index % |
Hausner Ratio |
Bulkiness (cc/g)* |
M1 |
27.3±0.02 |
0.54±0.04 |
0.73±0.03 |
22.8±0.01 |
1.32±0.01 |
1.75±0.01 |
M2 |
27.9±0.03 |
0.55±0.02 |
0.72±0.01 |
18.7±0.02 |
1.24±0.01 |
1.75±0.01 |
M3 |
26.3±0.04 |
0.57±0.03 |
0.67±0.02 |
19.9±0.01 |
1.24±0.01 |
1.72±0.02 |
M4 |
26.3±0.02 |
0.55±0.03 |
0.67±0.02 |
16.9±0.03 |
1.22±0.03 |
1.79±0.03 |
M5 |
27.6±0.04 |
0.55±0.01 |
0.70±0.02 |
19.9±0.04 |
1.27±0.02 |
1.82±0.03 |
M6 |
26.9±0.05 |
0.54±0.03 |
0.73±0.03 |
21.5±0.02 |
1.35±0.04 |
1.72±0.01 |
M7 |
30±0.02 |
0.53±0.01 |
0.67±0.01 |
20.8±0.02 |
1.26±0.05 |
1.89±0.02 |
M8 |
28.0±0.03 |
0.57±0.01 |
0.74±0.02 |
23.1±0.01 |
1.29±0.02 |
1.75±0.04 |
M9 |
32.6±0.01 |
0.56±0.02 |
0.74±0.02 |
23.7±0.01 |
1.30±0.04 |
1.79±0.05 |
M10 |
28.1±0.01 |
0.57±0.02 |
0.71±0.03 |
19.0±0.01 |
1.24±0.02 |
1.75±0.02 |
M11 |
27.3±0.02 |
0.54±0.04 |
0.73±0.03 |
22.8±0.01 |
1.32±0.01 |
1.75±0.01 |
M12 |
27.9±0.03 |
0.55±0.02 |
0.72±0.01 |
18.7±0.02 |
1.24±0.01 |
1.75±0.01 |
*All
values are expressed as mean ± SD, n=3.
B) POST-COMPRESSIONAL PARAMETERS:
All the tablet formulations were evaluated for parameters such as shape,
colour, thickness, hardness, friability, weight
variation, drug content, in vitro disintegration time, in vitro dispersion
time, wetting time, water absorption ratio, in vitro dissolution
studies, model fitting of release profile and stability studies.
a) General appearance:
All the fast
dissolving tablets from each batch were found to be flat, white in color,
circular in shape and having good physical appearance. There was no change in
the color and odour of the tablets from all the
batches.
b) Thickness and diameter:
Thickness
and diameter of all prepared fast dissolving tablets was measured by using
calibrated vernier callipers.
Tablet thickness should be controlled within ± 0.1% variation of standard value
to facilitate packaging and consumer acceptance. The tablets showed thickness
and diameter in the range of 2.701 mm to 2.709 mm, 6.01 to 6.03 mm respectively.
c)
Hardness:
Tablets require certain amount of strength, hardness to withstand
mechanical shocks during manufacture, packaging and shipping. The hardness was
found to be in the range of 3.2 to 4.0 kg/cm2. The obtained
results revealed that the tablets were having good mechanical strength and
compactness.
d) Friability:
Adequate
tablet hardness and resistance to friability are necessary to prevent damage to
the tablet during manufacture, packing and transport. % Friability of tablets
less than 1% was considered acceptable .Percent friability ranged from 0.24 to
0.55%.
e) Weight variation:
The
average weight of Tapentadol fast dissolving tablet
was 200mg. the weight variation was found to be in the range of 199.17 mg to
203.55 mg. The obtained results indicated that all tablets of different
formulations were within the I.P specifications.
f)
Mouth
feel:
The prepared
formulations were subjected for mouth feel. The volunteers felt good taste in
all the formulations. As the drug is bitter the presence of Aspartame and
orange flavour in all the formulations showed good,
palatable taste.
g)
pH:
pH of the solution of all the tablets was found to be
between 7.1 to 7.5, which suggest that the tablets can be conveniently
administered orally and will not cause any discomfort.
h)
Drug
content:
To
evaluate a tablet’s potential for efficacy the amount of drug in the tablet
need to be monitored from tablet to tablet and batch to batch. The percentage
drug content was found to be in the range of 98.00% to 99.78 %( table3).
Table
3: Post compression evaluation of tapentadol FDT’s
containing MCC
Formulation Code |
Thickness (mm)* |
Diameter (mm)* |
Hardness (kg/cm2)* |
Friability (%)** |
Weight variation test (mg)*** |
Drug Content (%)*** |
pH |
Mouth feel |
M1 |
2.703±0.01 |
6.02±0.02 |
3.4±0.24 |
0.37±0.01 |
201.00 ± 1.01 |
98.70±0.73 |
7.4 |
+ |
M2 |
2.701±0.04 |
6.01±0.02 |
3.5±0.25 |
0.33±0.02 |
203.55 ± 1.11 |
98.55±0.09 |
7.5 |
+++ |
M3 |
2.705±0.01 |
6.03±0.02 |
3.3±0.27 |
0.39±0.4 |
200.30 ± 1.12 |
99.30±0.56 |
7.4 |
++ |
M4 |
2.709±0.03 |
6.01±0.01 |
3.5±0.23 |
0.24±0.03 |
202.55 ± 1.17 |
99.78±0.28 |
7.2 |
+ |
M5 |
2.704±0.06 |
6.01±0.03 |
3.7±0.25 |
0.27±0.01 |
201.00 ± 1.05 |
98.65±0.51 |
7.5 |
+++ |
M6 |
2.701±0.03 |
6.01±0.04 |
3.6±0.26 |
0.34±0.02 |
199.80 ± 0.11 |
98.58±0.44 |
7.2 |
+ |
M7 |
2.704±0.02 |
6.03±
0.04 |
3.2±0.24 |
0.29±0.01 |
202.25 ± 1.22 |
98.29±0.75 |
7.1 |
+++ |
M8 |
2.701 ± 0.01 |
6.01±0.03 |
3.8±0.23 |
0.35±0.03 |
200.05 ± 1.15 |
98.90±0.65 |
7.1 |
++ |
M9 |
2.702±0.04 |
6.03±0.02 |
3.7±0.24 |
0.32±0.04 |
201.05 ± 1.17 |
99.47±0.47 |
7.2 |
+++ |
M10 |
2.701±0.03 |
6.02±0.01 |
3.5±0.25 |
0.24±0.04 |
200.30 ± 1.06 |
99.35±0.53 |
7.5 |
++ |
M11 |
2.705±0.04 |
6.01±0.02 |
3.2±0.23 |
0.29±0.02 |
202.11 ± 1.22 |
98.85±0.63 |
7.2 |
++ |
M12 |
2.703±0.01 |
6.01±0.03 |
3.5±0.24 |
0.35±0.01 |
201.55 ± 1.15 |
98.51±0.71 |
7.5 |
++ |
*All
values are expressed as mean ± SE, n=5; **All values are expressed as mean ±
SE, n=10; ***All values are expressed as mean ± SE, n=20; += Average; ++=
good, +++= excellent
Water Absorption Ratio:
Water
absorption ratio, which is an important criterion for understanding the
capacity of disintegrants to swell in presence of
little amount of water, was calculated. It was found to be in the range of
53.21 to 78.83 in formulations containing MCC as diluent (figure 8). The Water absorption ratio increased with
increase in the concentration of superdisintegrant
from 2-8 %. The water absorption ratio was found to be in the increasing order.
This increase was due to the water up taking ability of the superdisintegrants.
More the superdisintegrant concentration greater was
water absorption. Water absorption
ratios for all these formulation batches varied in the following decreasing order:
Crosspovidone > Crosscarmellose
sodium > Sodium starch glycollate.
Wetting Time:
Wetting time is an
important parameter related to water absorption ratio, which needs to be
assessed to give an
insight to the disintegration
properties of the tablets. Wetting is closely related to the inner structure of
the tablets and the hydrophilicity of the excipients. Wetting time was used as a parameter to
correlate with disintegration time in oral cavity. This is an important
criterion for understanding the capacity of disintegrants
to swell in presence of little amount of water. Since the dissolution process
of a tablet depends upon the wetting followed by disintegration of the tablet,
the measurement of wetting time may be used as another confirmative test for
the evaluation of dispersible tablets.
It was found that formulation containing sodium starch
glycollate and MCC (M1) showed wetting time 46 sec.
whereas those containing crosspovidone and MCC (M12)
showed least wetting time of 25 sec (figure 8).
Figure 8: Comparison of wetting time and
water absorption ratio of various formulations of Tapentadol
FDT’s containing MCC
In
vitro Disintegration Time:
Disintegration,
the first important step for a drug absorption from a solid dosage form after
oral administration was preliminarily focused. The internal structure of
tablets that is pore size distribution, water penetration into tablets and
swelling of disintegration substance are suggested to be the mechanisms of
disintegration. This indicates that the tablets would disintegrate almost
instantaneously when they will come in contact with even slight amount of
saliva in the mouth. Disintegration time was determined as per I.P. for all the
formulations. Least in vitro
disintegration time was shown by formulation containing crosspovidone
and MCC (M12). Disintegration time was
observed in the increasing order of Crosspovidone
< Crosscarmellose Sodium < Sodium Starch Glycollate.
In
vitro Dispersion Time:
In vitro dispersion time was measured by the time taken to
undergo uniform dispersion. All formulations showed rapid dispersion within
seconds. Formulated fast dissolving tablets containing MCC as diluent showed
dispersion time less than 59 seconds (figure 9).
Figure 9:
Comparison between in vitro disintegration
time and in vitro dispersion time of various formulations of tapentadol FDT’s containing MCC
In vitro Dissolution Studies:
The IN VITRO drug release characteristics
were studied in phosphate buffer pH 6.8 using tablet dissolution apparatus USP
XXIII. The samples were withdrawn at different time intervals and analyzed at
272 nm and the cumulative percentage drug released was determined.
Microcrystalline cellulose as diluents:
The IN VITRO dissolution data of
formulations were shown in figure 10, 11 and 12. Formulation M1, M2, M3 and M4
released 89.11 %, 92.56 %, 93.76 % and 94.50 % drug respectively in 15 mins. Formulation M5, M6, M7 and M8 released 90.01 %, 92.17
%, 96.34 % and 97.02 % drug respectively in 15 mins.
Formulation M9, M10, M11 and M12 released 92.97 %, 95.84 % and 97.87 % and
98.90 % drug respectively in 15 mins. IN VITRO
dissolution studies revealed that the release rate of Tapentadol
from fast dissolving tablet containing Crosspovidone
(M12) was maximum i.e 98.90%.
Figure 10: Comparison
of dissolution profile of various formulations of Tapentadol
FDT’s containing MCC+SSG (M1-M4)
Figure 11:
Comparison of dissolution profile of various formulations of Tapentadol FDT’s containing MCC+CCS (M5-M8)
Figure 12: Comparison of
dissolution profile of various formulations of Tapentadol
FDT’s containing MCC+CP (M9-M12)
Data Analysis:
The
results of in vitro dissolution
studies obtained from these formulations were plotted in Zero order, First
order, Higuchi and Korsmeyer-Peppas release model and
Hixson-Crowell equation to study the mechanism of drug release. The correlation
coefficient (r) for drug release kinetic models was tabulated in table 4 for
formulations containing microcrystalline cellulose. The formulations M1 showed
Higuchi Matrix which described the drug release, as a diffusion process based
on the Fick’s law, square root time dependent.
Formulations M2 to M11 showed First
order Model and formulation M12 showed Hixson Crowell Model which was used to
describe that dissolution occurred in planes that were parallel to the drug
surface if the tablet dimensions diminished proportionally, in such a manner
that the initial geometrical form was kept constant at all time.
Table 4: Model fittings of release
profile of formulated Tapentadol FDT’S containing MCC
as diluent using different models
FORMULATION CODE |
MATHEMATICAL MODELS
(KINETICS) |
|||||
Zero Order |
First Order |
Higuchi Matrix |
Peppas |
Hixson Crowell |
Best Fit Model |
|
M1 |
0.826 |
0.942 |
0.980 |
0.776 |
0.949 |
Higuchi
matrix |
M2 |
0.771 |
0.985 |
0.955 |
0.721 |
0.938 |
First
order |
M3 |
0.734 |
0.931 |
0.929 |
0.764 |
0.917 |
First
order |
M4 |
0.726 |
0.935 |
0.932 |
0.749 |
0.911 |
First
order |
M5 |
0.752 |
0949 |
0.942 |
0.755 |
0.930 |
First
order |
M6 |
0.736 |
0.939 |
0.935 |
0.748 |
0.934 |
First
order |
M7 |
0.719 |
0.940 |
0.939 |
0.743 |
0.920 |
First
order |
M8 |
0.709 |
0.920 |
0.918 |
0.747 |
0.915 |
First
order |
M9 |
0.721 |
0.942 |
0.921 |
0.749 |
0.917 |
First
order |
M10 |
0.751 |
0.930 |
0.929 |
0.750 |
0.920 |
First
order |
M11 |
0.780 |
0.941 |
0.932 |
0.755 |
0.956 |
Hixson
crowell |
M12 |
0.781 |
0.944 |
0.935 |
0.759 |
0.959 |
Hixson
crowell |
Stability Studies:
Stability studies of formulation M12 were performed at 250C±20C/60%
±5% RH and 400C ±20C/75% ± 5% RH for a period up to 60
days. The formulations were selected for stability studies on the basis of
their high percentage cumulative drug release and also results of in vitro disintegration time,
wetting time and in vitro dispersion studies. The
results obtained for physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release of formulation M12
at 250C ± 20/60%±5% RH and 400C ± 20/75%±5%
RH were shown in table 5 to 6. There was no change in color and shape of the
tablets when stored at 250C ± 20C /60% ± 5% RH and 400C±20C
/75% ±5% RH and observed every 20 days interval upto
60 days. Formulation M12 showed not much variation in any parameter. From these
results it was concluded that formulations were stable and retained its
original properties.
Table 5: Results of stability study of
formulation M12 stored at 250C ± 20C/ 60% ± 5% RH
Formulation Code |
Tested in days |
Thickness (mm) |
Hardness (Kg/cm2) |
Friability (%) |
Weight variation (mg) |
% Drug content |
M12 |
20 |
2.703±0.01 |
3.5±0.23 |
0.32 |
201.45±1.15 |
98.45 |
40 |
2.702±0.04 |
3.5±0.24 |
0.31 |
201.50±1.10 |
98.42 |
|
60 |
2.701±0.02 |
3.5±0.26 |
0.34 |
201.10±1.05 |
98.46 |
Table 6: Results of stability study of
formulation M12 stored at 400C± 20C/ 75% ± 5% RH
Formulation Code |
Tested in days |
Thickness (mm) |
Hardness (Kg/cm2) |
Friability (%) |
Weight variation (mg) |
% Drug content |
M12 |
20 |
2.709±0.04 |
3.5±0.24 |
0.32 |
201.05±1.20 |
98.49 |
40 |
2.703±0.08 |
3.5±0.23 |
0.31 |
201.50±1.79 |
98.43 |
|
60 |
2.708±0.04 |
3.5±0.21 |
0.34 |
201.21±1.03 |
98.44 |
CONCLUSION:
In the present work, an attempt was made to develop fast dissolving
tablets of Tapentadol as an improved and better
patient compliant dosage form. From the study conducted and from the
observations and the results obtained thereof, following conclusions were
drawn:
Ø FTIR studies
concluded that drug and excipients were compatible
with each other.
Ø The formulated
tablets were satisfactory in terms of hardness, thickness, friability, weight
variation, drug content, wetting time, water absorption ratio, in vitro disintegration
time, in vitro dispersion time and in vitro drug release.
Ø Formulations
containing superdisintegrant Crosspovidone
showed least wetting time and in vitro disintegration time.
Ø As the superdisintegrant concentration increases, the wetting time
and in vitro disintegration time on tablets decreases.
Ø Formulation M12 was
found to be the best on the basis of wetting time, in vitro disintegration
time and in vitro drug release.
Ø The formulation M12
containing microcrystalline cellulose as diluent and crosspovidone
(8%) was found to be the optimized combination.
REFERENCES:
1. Parakh S R, Gothoskar
A V. A review of mouth dissolving tablet technologies. Pharm
Tech 2003;27(11):92-98.
2. Suresh
B, Rajendar KM, Ramesh G, Madhusudan YR. Orodispersible Tablets An overview. Asian
Journal of Pharmaceutics 2008;2:10-15.
3. Guidance
for Industry Orally Disintegrating Tablets published by centre for drug
evolution and research, accessed at http://www.fda.gov/cder/guidance/index.html.
4. William
RP, Tapash KG. Orally disintegrating tablets.
Pharmaceutical Technology 2005.
5. Subrahmanyam CVS. Textbook of physical pharmaceutics.
Delhi: Vallabh Prakashan;
2005:28-32.
6. Subrahmanyam CVS, Thimmasetty
J, Shivanand KM, Vijayendraswamy
SM. Laboratory manual of industrial pharmacy. Delhi: Vallabh
Prakashan; 2006: 32.
7. Ministry
of Health and Family Welfare (India). Indian Pharmacopoeia. New Delhi: The
Controller of Publications; 1996.
8. Banker
SG, Anderson NR. Tablets. In: Lachman L, Lieberman
HA, Kanig JL, editors. The theory and practice of
industrial pharmacy. 3rd ed. Bombay: Varghese Publishing House; 1991.
9. United
States of Pharmacopeia-National Formulary. USP 30 –
NF 25. Rockville, MD: The United States Pharmacopeial
Convention Inc; 2007. Vol 1.p.644, 242, 645, 731 and
634.
10. Jacob
S, Shirwaikar A, Joseph A, Srinivasan
K. Novel Co-Processed Excipients of Mannitol and Microcrystalline Cellulose for Preparing Fast
Dissolving Tablets of Glipizide. Indian J Pharm Sci 2007; 69(5): 633-39.
11. Sweetman SC, editor. Martindale: The Complete
Drug Reference. 33rd ed. London: Pharmaceutical Press; 2002:1235--7.
12. Jha SK, Vijayalakshmi P, Karki P, Goli D. Formulation and
evaluation of melt-in-mouth tablets of haloperidol. Asian J Pharm
2008; 2(4): 255-60.
13. United
States Pharmacopoeia, “In vitro Dissolution”.
Asian edition. United States Pharmacy Convention Inc; 2000:1941-3.
14.
Shukla V, Manvi
FV. Effect of different superdisintegrants on isoniazid dispersible tablet for oral tuberculosis. Der Pharma Chemica
2010; 2(4): 65-78.
Received on 22.02.2016 Accepted
on 15.03.2016
© Asian Pharma Press All
Right Reserved
Asian J. Pharm. Res. 6(1): January -March, 2016; Page 11-21
DOI: 10.5958/2231-5691.2016.00003.4