INTRODUCTION:
Recent advances in novel drug delivery
system aims to enhance the safety and efficacy of the drug molecule by
formulating a dosage form being for the administration [1]. Fast
dissolving tablets are solid dosage form containing medicinal substances which
disintegrate rapidly, usually within few seconds when placed upon tongue
requiring no additional water to facilitate swallowing [2].
Advantages of this drug delivery system include administration without water,
convenience of administration and accurate dosing as compare to liquids, easy
portability, ability to provide advantages of liquid medication in the form of
solid preparation, and rapid dissolution/absorption of the drug, which may
produce rapid onset of action. Some drugs are absorbed from mouth; pharynx and
esophagus as the saliva passes down in to stomach and in such cases
bioavailability of drug is increased, pre-gastric absorption can result in
improved bioavailability and as result of reduced dosage form, improved
clinical performance through a reduction of unwanted effects [3].
Chemical structure of Pregabalin (PRG) is shown in figure 1. It is an
antiepileptic and structurally related to the inhibitory neurotransmitter
aminobutyric acid (GABA). It was approved for adjunctive treatment of partial
seizures in adults currently [4].
Chemical Name:
(S)-3-(aminomethyl)-5-methylhexanoic acid
Figure 1: Structure of Pregabalin.
Pregabalin exhibits anti-seizure activity,
and is useful for treating, among other conditions, epilepsy, pain,
physiological conditions associated with psychomotor stimulants, inflammation,
gastrointestinal damage, alcoholism, insomnia, fibromyalgia, and various
psychiatric disorders, including anxiety, depression, mania, and bipolar
disorder [5,6]. In the United States, Pregabalin has been approved
for the treatment of diabetic peripheral neuropathy, postherpetic neuralgia,
and as an adjunctive treatment for partial onset seizures in adults [7].
MATERIALS AND
METHODS:
Materials:
Pregabalin was obtained as a gift sample
from Mehta API Pvt Ltd, Mumbai. Crospovidone was obtained as gift sample from
Kawarlal and Co, Chennai. Microcrystalline cellulose (Avicel PH 101),
Croscarmellose Sodium, and Sodium starch glycolate were purchased from Loba
Chemicals, Mumbai. All other chemicals and reagents used were of analytical
grade.
Methods:
Preparation of fast dissolving tablets of
Pregabalin [8]:
The critical parameters to formulate a fast
dissolving tablet are choice of superdisintegrant and optimization of
concentration of superdisintegrant. The main criteria for fast dissolving
tablets is to disintegrate or dissolve rapidly in oral cavity in 15-60 seconds,
without need of water and should have pleasant mouth feel. The
superdisintegrants Ac-Di-Sol, Crospovidone, Sodium Starch Glycolate were used
to formulate the tablets as shown in formulation table 1. A blend of all
ingredients was made in a pestle and motor followed by addition of talc and
magnesium stearate. The mixture was triturated mixed for 10 minutes. The blend
of drug-excipients was compressed into tablets with 8 mm die.
Table 1: Formulation
table of fast dissolving tablet of pregabalin.
|
Ingredients
|
Formulation
|
|
F1
(mg)
|
F2
(mg)
|
F3
(mg)
|
F4
(mg)
|
F5
(mg)
|
F6
(mg)
|
|
Pregabalin
|
100
|
100
|
100
|
100
|
100
|
100
|
|
Micro-crystalline Cellulose
|
80
|
80
|
80
|
80
|
80
|
80
|
|
Sodium
starch glycolate
|
8
|
2
|
2
|
12
|
-
|
-
|
|
|
|
|
|
|
|
|
|
Crospovidone
|
2
|
8
|
2
|
-
|
12
|
-
|
|
Ac-Di-Sol
|
2
|
2
|
8
|
-
|
-
|
12
|
|
Magnesium Stearate
|
2
|
2
|
2
|
2
|
2
|
2
|
|
Aspartame
|
3
|
3
|
3
|
3
|
3
|
3
|
|
Talc
|
1
|
1
|
1
|
1
|
1
|
1
|
|
Mannitol (q.s)
|
200
|
200
|
200
|
200
|
200
|
200
|
Pre-compression parameters:
Bulk density [9]:
It is the ratio of total mass of powder to
the bulk volume of powder. It was measured by pouring the weight powder (passed
through standard sieve # 20) into a measuring cylinder and initial volume was
noted. This initial volume is called the bulk volume.
From this, the bulk density is calculated
according to the formula mentioned below. It is expressed in g/ml and is given by:
Db = M/ Vb ___________ (1)
Where, Db is bulk density.
M is the mass of powder.
Vb is the bulk volume of the powder.
Tapped Density [9]:
It is the ratio of total mass of the powder
to the tapped volume of the powder. Volume was measured by tapping the powder
for 750 times and the tapped volume was noted. It is expressed in g/ml and is
given by:
Dt = M / Vt ___________ (2)
Where, Dt is tapped density
M is the mass of powder
Vt is the tapped volume of the powder.
Compressibility Index [9]:
It is calculated by the following formulae:
I = Dt – Db / Dt X 100 ______ (3)
Where, Dt is the tapped density
of the powder and
Db is the bulk density of
the powder.
Hausner’s ratio [9]:
Hausner ratio is an indirect index of ease
of powder flow. It is calculated by the following formula:
Hausner ratio = 𝑇𝑎𝑝𝑝𝑒𝑑 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 (𝑇𝐵𝐷)/𝐵𝑢𝑙𝑘 𝑑𝑒𝑛𝑠𝑖𝑡𝑦 (𝐿𝐵𝐷) _________ (4)
Where TBD is tapped density and LBD
is bulk density. Lower hausner ratio (< 1.25) indicate better flow
properties than higher ones (>1.25).
Angle of Repose [9]:
Angle of repose was determined using fixed
funnel method. The blend was poured through a funnel that can be raised
vertically until a maximum cone height (h) was obtained. Radius of the heap (r)
was measured and angle of repose was calculated using formula:
𝜃 = 𝑡𝑎𝑛−1 (h/𝑟) ___________ (5)
Where, θ is angle of repose,
h is height of pile and
r is the radius of the base pile
Fourier transform infra red spectroscopy
(FTIR):
Infrared spectrum was taken for the pure
Pregabalin (Figure 3). FT-IR studies was carried by KBr disk method using
computer mediated Fourier transformed infrared spectroscopy ( Jasco FT/TR
4100).
Post compression
parameters:
Uniformity of weight [10, 11]:
Every individual tablet in a batch should
be in uniform weight and weight variation in within permissible limits. The
weights were determined by using digital balance. Weight control is based on a
sample of 20 tablets.
Thickness:
The thicknesses of the tablets were
determined using a Vernier caliper, 20 tablets from each batch were used and
average values were calculated.
Hardness [10, 11]:
Hardness was determined by taking six
tablets from each formulation, using a Monsanto Hardness Tester.
Friability Test [10]:
The pre-weighed tablets were placed in the
friabilator (Roche-type friabilator) which was then operated for 100rpm, then
dusted and reweighed. The Conventional compressed tablets that lose less than
0.5-1.0% of their weight are generally considered acceptable.
% Friability = (Wi – Wf / Wi ) Χ 100
___________ (6)
Where, Wi is initial weight of tablets.
Wf is final weight of tablets.
Wetting time and water absorption ratio [12]:
The wetting time of tablets was measured
using a simple procedure. A piece of tissue paper folded twice was placed in a
small petri-dish containing 10 ml of distilled water. A tablet having amaranth
powder on the upper surface was placed on the filter paper. Time required to
develop red color on the upper surface of tablet was recorded as wetting time.
The same procedure without Amaranth dye
powder was followed for determining the water absorption ratio R was determined
according to the following equation:
R = [(Wa – Wb)/Wb ]× 100 ___________ (7)
Where, Wb and Wa were the weights of the
tablet before and after use.
In vitro Disintegration Time [10]:
The in-vitro disintegration time was
determined by using disintegrating apparatus. A tablet was placed into each of
the six tubes of the apparatus and one disk was added to each tube. The time
was recorded after completion of the disintegration of the tablets.
Drug Content [13]:
Ten tablets were powered and the blend
equivalent to 5 mg of Pregabalin was weight and dissolved in suitable quantity
of pH 6.8 solutions. Solution was filtered and diluted and drug content
analyzed spectrophotometrically at 210 nm using UV/Vis spectrophotometer (Jasco
V-630 Spectrophotometer).
In vitro dissolution study [14, 15]:
The release of from FDT was determined
using USP dissolution testing apparatus 2. The dissolution test was performed
using 900 ml of phosphate buffer pH 6.8 at 37 ±0.5°C and 50 rpm. A sample (10
ml) of the solution was withdrawn from the dissolution apparatus at different
time intervals and the samples were replaced with fresh dissolution medium. The
samples were filtered through a 0.45μ membrane filter and diluted to
suitable concentration with buffer pH 6.8. Absorbance of these solutions was
measured at 210 nm using a UV/Vis spectrophotometer. Cumulative percentage drug
release was calculated using an equation obtained from a standard curve.
Drug release kinetics [16, 17, 18]:
In order to investigate the drug release
mechanism from tablets, the % cumulative drug release data was analyzed with
following mathematical models.
Model Equation
Zero order
kinetics Q = Qo – Kot
___________ (7)
First order kinetics Q = Qo (1 −
e−K1t) _______ (8)
Higuchi square root model Qt = KH t˝ ___________ (9)
Hixson-Crowell
cube root model Qo⅓ – Qt⅓ = KHC t
_10)
Korsmeyer- peppas
model Qt/ Q∞= Kktn ________
(11)
Where, Qt − amount of drug released at
time t.
Qo − initial amount of drug.
And Ko, K1, KH, KHC
and KK are the coefficients of equations. The most appropriate model
was selected on the basis of goodness of fit test. The zero order kinetic
describes the systems in which the drug release rate is independent of its
concentration. The drug releases slowly (assuming that the area does not change
and no equilibrium conditions are obtained). The first order kinetics describes
the systems in which drug release rate is concentration dependent. Higuchi
model describes the release of water-soluble drug from an insoluble matrix as a
diffusion process based on the Fick’s law and is square root time dependent.
The Hixson-Crowell cube root law describes the drug release from a system
depends upon the change in surface area or diameter of particle or system and
involves no diffusion mechanism. Korsmeyer-Peppas model describes the fraction
of drug release relates exponentially with respect to time. This model is
generally used to analyze the release of pharmaceutical polymeric dosage forms,
when the release mechanism is not well known or when more than one type of
release phenomena could be involved.
Accelerated
stability studies [19]:
Stability studies were carried out on
optimized formulation. The tablets were stored at 40 ± 20°C/ 75 ±5 % RH for
duration of one month. After an interval of one month samples were withdrawn
and tested for various physical tests and drug release study.
RESULT AND
DISCUSSION:
Pre-compression
parameters:
The properties like bulk density, tapped
density, compressibility index, Hausner ratio, and angle of repose were
calculated and all estimated parameters found within the limits (Table 2)
CONCLUSION:
The Fast Dissolving Tablets have potential
advantages over conventional dosage forms, with their improved patient
compliance; convenience bioavailability and rapid onset of action had drawn the
attention of many manufacturers over a decade.
Thus from above results, it can be
concluded that the crospovidone is having better disintegrant property than
that of croscarmellose sodium, sodium starch Glycolate and lower concentration
of Crospovidone. Stability study shows that that there was no significant
change in hardness, friability, drug content, and dissolution profile of the
selected formulation. Thus, Crospovidone can be successfully used in the
formulation of fast dissolving tablets.
ACKNOWLEDGEMENTS:
The authors are grateful to Dr. C. S.
Magdum, Principal and Dr. S. K. Mohite, Vice Principal of Rajarambapu College
of Pharmacy, Kasegaon, for providing necessary facilities to carry out the
research work and to Mehta API Pvt. Ltd., Mumbai and Kawarlal and Co, Chennai
for providing gift sample of the drug and polymer respectively.
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