Vous êtes sur la page 1sur 14

IAJPS 2017, 4 (12), 4626-4639 V. B.

Khot et al ISSN 2349-7750

CODEN [USA]: IAJPBB ISSN: 2349-7750

INDO AMERICAN JOURNAL OF

PHARMACEUTICAL SCIENCES
http://doi.org/10.5281/zenodo.1123244

Available online at: http://www.iajps.com Research Article

OPTIMIZATION OF GRANULATION TECHNIQUES FOR


DEVELOPMENT OF TABLET DOSAGE FORM
V. B. Khot*1, D.A. Bhagwat2, J. I. D’Souza2, S. S. Shelake3, S. V. Patil4
1
Mandar Education Society’s, College of Pharmacy, Pedhambe, Ratnagiri, MS, India.
2
Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, MS, India.
3
Department of Pharmaceutics, Ashokrao Mane College of Pharmacy, Peth-Vadgaon, MS, India.
4
Department of Pharmaceutics, Shree Santkrupa College of Pharmacy, Ghogaon, Karad, MS,
India.
Abstract:
The purpose of this study was to optimize the best granulation techniques for development of tablet dosage form.
The present study explains comparative study of different wet granulation techniques including Planetary mixer
granulation, Rapid mixer granulation, Fluid bed granulation with Direct compression method. Similar
formulations were used to evaluate Planetary mixer granulation, Rapid mixer granulation and Fluid bed
granulation method. The granules prepared by different techniques were evaluated for particle size distribution,
porosity, spherisity, bulk density, flow property and compressibility, compatibility and tablet properties of
Diclofenac sodium tablet. The fluid bed granulation technique had superior flow properties, compressibility,
compactibility measured by Kawakita, Hekel, Walker and Leuenberger equation. The granules prepared by
Fluid bed granulation showed better tablet properties (weight uniformity, hardness, friability and
disintegration, drug content, dissolution) and accelerated stability study compared to other granulation
techniques so finally, it was concluded that Diclofenac sodium tablets prepared by using fluid bed granulation
which meets the required specification compared to other wet granulation techniques and direct compression
method.
Key words: Granulation technique, Flowability, compressibility, compactibility, Diclofenac sodium tablet.
Corresponding author:
V. B. Khot, QR code
Mandar Education Society’s, College of Pharmacy,
Pedhambe, Ratnagiri,
MS, India.
Email: vbkhot.tkcp@gmail.com

Please cite this article in press as V. B. Khot et al., Optimization of Granulation Techniques for Development
of Tablet Dosage Form, Indo Am. J. P. Sci, 2017; 4(12).

www.iajps.com Page 4626


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

INTRODUCTION: The purpose of study was to investigate the effect


Most product formulators see wet granulation of planetary mixer granulation, Rapid mixture
technology as a universally applicable means of granulation and Fluid bed granulation on
tablet processing. The wet granulation techniques granulation properties like particle size distribution,
to be most preferred due to various advantages porosity, spherisity, bulk density, flow property and
including improving flow property, compression compressibility, compatibility, tablet properties and
characteristics, better distribution of colour and accelerated stability study of Diclofenac sodium
reduces dust hazards. So that to optimize the best tablet and based on above evaluation parameter to
wet granulation technology is important for optimize the best granulation techniques for
development of tablet dosage form. Direct development of tablet dosage form.[9,10,11]
compression is one of the popular methods for
preparation of tablet However, it is often necessary 1. MATERIALS AND METHODS:
to improve poor content uniformity, flowability, 1.1 Materials
compression and compactibility to produce tablet The mixture consisted of Diclofenac sodium
of adequate quality. These properties are (model drug, Neon labs Ltd Palghar, India), 40%
commonly enhanced by wet granulation.[1] Wet (W/W); lactose monohydrate (Filler, Pharmatose
granulation is widely used process of granulation in 350M for wet granulation,41.3% (W/W); lactopress
the pharmaceutical industry. It involves addition of spray dried-250 for direct compression, 43.12 %
a liquid solution (with or without binder) to (W/W);DFE Pharma India, LLP, Bangalor),
powders, to form a wet mass. The wet mass is dried microcrystalline cellulose (Filler/ dry binder,
and then sized to obtained granules. The liquid Avicel PH 101, VerGo Pharma Research
added binds the moist powder particles by a Laborataries Pvt. Ltd, Goa) 13.7%(W/W);
combination of capillary and viscous forces in the polyvinylpyrrolidone (binder, Povidone K90,
wet state. More permanent bonds are formed BASF India Ltd., Navi Mumbai) 2.5% (W/W);
during subsequent drying which leads to the Crosspovidone (disintegrating agent, Research
formation of agglomerates.[2] This can be achieved Fine Lab, Mumbai) 2% (W/W);and magnesium
by using Planetary mixer granulation, Rapid mixer stearate (Lubricant, BASF India Ltd., Navi
granulation and Fluid bed granulation. Fluid bed Mumbai) 0.5% (W/W) etc. [All chemicals used
granulation has some advantages compared to other were of analytical grade.]
granulation method. . Fluid bed granulation method
is selected for production of porous and free- 2.2 Characterization of Diclofenac
flowing granules, which enables to form tablets sodium
with high mechanical strength at low compression The organoleptic properties of drug were
pressure. Simultaneous granulation and drying determined including nature, color, solubility.
removes the need for additional drier and all Melting point: The melting point was determined
granulation process performed in one unit so saving by using open capillary method.
time, transfer losses and labour costs.[3]
2.3.2 FTIR Spectroscopy
Kawakita analysis revealed improved flowability IR Spectrum interpretation
for formulations prepared by direct compression The infrared absorption spectrum of pure
and wet granulation technique. Compressibility is Diclofenac sodium was recorded on FT-IR
the powder’s ability to deform under pressure, and Spectrophotometer (Model- Agilent) and the
compactibility is the ability to form mechanically spectrum analysis was done for functional
strong compacts. Compressibility is often described groups.[12]
by the change in the relationship between relative
density, porosity and applied pressure represented 2.3.3 X-ray Diffractometry
by heckle and walker models. [8] Compactibility is The X-ray diffraction patterns of drug were
nonlinear plot of tensile strength with respect to determined using a Bruker D2 Phaser powder X-
product of compaction pressure and relative density ray diffractometer. Samples were irradiated with
represented by Leuenberger equation.4Litrature monochromatized CuK alpha radiation (1.542 A0)
addresses each type of granulation process and analyzed between 10 and 70 (2ϴ) at a scan rate
individually and in detail.[5] Comparison was of 0.1° 2θ per min. [12]
found between a low shear, high shear, and fluid
bed granulation during low dose tablet process 2.3.4 Drug - Excipients compatibility studies of
development.[6] A Comparison was also found physical mixture
between the different granulation techniques for The infrared absorption spectrum of pure
Lactose Monohydrate.[7] Another reference Diclofenac sodium and physical mixer of drug and
compared impact of wet and dry granulation versus excipients was recorded on FT-IR
a direct tableting mixer and a compressibility and Spectrophotometer (Model- Agilent) The IR
compactibility study of real tableting mixtures.[8] spectroscopy was used to investigate and predict

www.iajps.com Page 4627


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

any physiochemical interaction between drug and was set like Inlet temperature 500C, Product
different excipients. temperature 400C, exhaust temperature 500C,
atomization air-1.1 bar, blower drive speed-14%,
2.3.5 X-ray diffractometry of drug, excipients air flow 130 cfm, spray pump speed 14 rpm and
and formulation spray rate 10 gm/min. At the end point the product
The X-Ray diffraction study was conducted for temperature was 540C and inlet air temperature was
evaluation of change in crystalline nature of pure 700C. The moisture content of granules during the
drug by process or addition of other polymers. The operation was continuously monitored. The
sample was analyzed by using Brooker D2 Phaser operating conditions such as inlet air temperature
powder X-Ray Diffractometer and was scanned and airflow rate were controlled during granulation.
from 10° to 70° 2θ. Then the granules were passed through 30# and
lubricated with Mg-stearate.
2.4 Preparation of granules
Granules were prepared according to the 2.4.4. Mixture for direct tableting (DC)
procedures enumerated and described below. Weighted Diclofenac sodium(100gm), Lactopress
Before preparation of granules, all materials were spray dried- 250 (107.8gm), Avicel PH
sieved manually through a sieve with a mesh size 101(35.95gm), Crosspovidone (5gm) were mixed
of 0.8 mm. The weighted amounts of powders were for 10min. Magnesium stearate (1.25gm) was
the same for all mixtures: Diclofenac sodium added then mixing for 2 min was performed.
(100gm), Pharmatose 350M (103.5gm), Avicel PH-
101 (34.25gm), PVP K-90 (6.25gm), 2.5 Evaluations of granules
Crosspovidone (5gm).[8] 2.5.1 Moisture content
Five grams (5g) of each powder sample was
2.4.1. Planetary mixer granulation (PMG) accurately weighed and dried at 105°C in the oven
Weighted powders without PVP-K 90 were mixed to constant weight. The sample was reweighed and
in a mixing bowl of planetary mixer granulator weight loss calculated.[13]
(Kenwood, Kolkata, India). All ingredients were
mixed at low speed then 5% binder was added then 2.5.2 Particle size distribution
mixture was mixed at high speed. With the help of The particle size distribution for all mixtures (50 g
wet mass consistency and physical properties of sample) was determined by sieve analysis using
granules end point of granules was determined. vibrating shaker using the following sieves size
Wet granules were sieved using a sieve with a (µm): 500, 355, 250, 180and 150. The sieving
mesh size 16 ≠. Then granules were transferred to lasted for 10 min. Results was represented as
the fluid-bed dryer and dried at an inlet air particle size distribution and also as the particle
temperature 600C and air flow of 60 rpm. Drying size at which 50% (w/w) of particles were below
lasted for 40 min. after that dried granules were the given size denoted as median particle diameter
sieved using a sieve with a mesh size of 30≠. d50.[7,8,15]
2.4.2. Rapid mixer granulation (RMG)
Weighted powders were mixed with a Rapid mixer 2.5.3 Span value of granules [14]
granulator for 2 min at an impeller speed of 150 Span value determined by using sieving method.
rpm. 4.5 % binder was added into the mixed Span value was calculated by using d10, d50 and
ingredients and then granulate was kneaded for 180 d90 values
s. at an impeller speed of 250 rpm and the chopper
speed of 2500 rpm. With the help of wet mass
consistency and physical properties of granules end
point of granules was determined .Wet granules
were sieved using a sieve with a mesh size 16 ≠. Where, d90 =90% of particles are below the
Then granules were transferred to the fluid-bed particle diameter
dryer and dried at an inlet air temperature 600C and d10 = 10% of particles are below the particle
air flow of 60 rpm. Drying lasted for 40 min. Dried diameter
granules were sieved using a sieve with a mesh size d50 = median particle diameter
of 30≠.
2.5.4 Particle shape [5,7]
2.4.3. Fluid bed granulation (FBG) Motic microscope (Optical microscope with
Weighted powders without PVP-K-90 were mixed cammera motic image plus version, 2.0 MI) was
in a fluid bed processor (Pam glatt, Mumbai) The used to determine the shape of granule. By using
parameter was set like process time-420 min, pouse Motic microscope radius, perimeter and area of
time-40 sec, shaking time-10 sec, shaking speed- granule was determined. The Form factor was used
500 msec. Then 8.33% (w/w) aqueous solution of to determine the sphericity of granules. Form factor
PVP-K-90 was sprayed. After that the parameter was calculated by using following formula

www.iajps.com Page 4628


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

2.5.7 Bulkiness [17]


Bulkiness is determined by using specific bulk
volume or bulk density. Bulkiness determined by
using following formula

2.5.5 Bulk and tapped densities


Bulk Density and Tap Density were subjected to
Bulk and Tap density determination. Tapping
cylinder method was used for determining bulk and
2.5.8Porosity of granules [17]
tap density of granules were taken in 10 ml
Porosity is the ratio of void volume to the bulk
measuring cylinder. Initial volume (Bulk volume)
volume. The void volume is calculated by using
and the volume after 100 tapings (Tap volume)
following formula
were measured. From the results of Bulk and Tap
densities, the Hausner’s ratio and Carr’s Index
were calculated.[7] Void volume (v) = v bulk (untapped)-v true (tapped)

2.5.6 Flow properties of tableting mixture


[16,18]
Porosity is expressed in percentage so the porosity
was calculated by using following formula
The flowability was determined by measuring the
Carr’s index, and Hausner’s ratio, angle of repose,
flow time.
Porosity ( = 100
The bulk and tapped densities were used to
determine the Carr’s index, and Hausner’s ratio.
2.5.9 Kawakita plot
The Carr’s index and Hausner’s ratio were
Flowability was determined using the Kawakita
calculated according to following equations
analysis.

The formulation (10) gm was poured into a 50 ml


glass measuring cylinder. The heaped particles in
the cylinder were then levelled off horizontally and
the bulk volume Vo was accurately measured.
Tapping was afterwards initiated mechanically and
the change in volume of the powder column VN
was noted after N no. of tap. The Kawakita
equation is given by:
1. Angle of repose: The end of a funnel was placed
2 cm above a flat base. Powder was filled into the
funnel, so that after releasing the powder out of the
funnel the top of the resulting cone reached the end
of the funnel. The powder was released from the
Where a and bare constants; a describes the degree
funnel. From the height of the cone(h) and the
of volume reduction at the limit of tapping and is
diameter at the base (d) the angle at the base, the
called compactibility; 1/b is called cohesiveness,
angle of repose, (α) was determined.
C, the degree of volume reduction is calculated
from the initial volume Vo and tapped volume VN
as

2. Flow rate: 10 gm of granule was placed in funnel


and time was measured to flow of granules from
Numerical values for constants aand 1/bwas obtained
the funnel. Flow rate were determined as the ratio
from the slope, of plots of N/C versus number of taps
of mass (g) to time (seconds) using a steel funnel
N.18
with an orifice diameter of 10 mm.
2.6 Formulation of Diclofenac sodium tablet
1. Wet granulation method: The granules were
mixed with 0.5% Mg-stearate
2. Direct compression method: Mixture for direct
tableting was used

www.iajps.com Page 4629


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

2.7 Compaction studies [8] equation where x is hardness (in kg/cm2) and d and
2.7.1 Heckel plot t are the diameter and thickness of the compacts (in
Preparation of compacts: 250mg Diclofenac mm), respectively.
sodium tablet were made using 10Kg/cm2 to
120Kg/cm2 compression pressures in KBr pellet
press machine. Compacts were made at each
compression level. Before compression, the die and
the flat-faced punches were lubricated Mg-stearate. Leuenberger analysis was performed by fitting the
The hardness, dimensions and weight of compacts data in the following equation. A nonlinear plot of
were determined. The relative density was tensile strength with respect to product of
calculated as the ratio of apparent density of the compaction pressure P and relative density was
compact to the true density of the powder. The data obtained.
obtained using this ‘ejected tablet method’ was
used to obtain Heckel plots.

Heckel Analysis:
The Heckel model was based on the assumption Where, x maxis maximum tensile strength (kg/cm2),
that the process of pore reduction during p will be infinite and will be equal to 1, and γ is
compression. The degree of compact densification
compression susceptibility.[18]
with increasing compression pressure is directly
proportional to the porosity as follows:
2.8 EVALUATION OF TABLETS
2.8.1 Thickness
Thickness of tablet was determined using
calibrated Vernier caliper.[20]

2.8.2 Hardness
Where, D is the relative density of the compact, P
For each formulation, the hardness of six tablets
is applied pressure, K (slope; Heckel coefficient),
was determined using the Pfizer hardness tester.
K is the slope of the straight portion of the graph,
The tablet was held along its oblong axis in
reflects the reduction in porosity or the resistance
between the two jaws of the tester. At this point,
to volume reduction of granules and A (y-intercept)
reading should be zero kg/cm2. Then constant force
are regression coefficients of the linear portion of
was applied by rotating the knob until the tablet
the curve, and ε is porosity. Yield pressure (Py),
fractured. The optimum hardness regarded for
which is the reciprocal value of the slope (K) of the
uncoated tablet is 4-6 kg/cm2.[19]
Heckel plot was a measurement of the material’s
compressibility. Greater slopes indicate a greater
2.8.3 Weight variation test
degree of plasticity hence better compressibility of
Randomly selected twenty tablets were weighed
the material.
individually and together. Average weight was
calculated. Each individual tablet weight was
2.7.2 Walker plot
compared against the calculated average.[19]
The Walker equation plots the specific volume of
the powder compact against the logarithm of the
2.8.4 Friability test19
axial pressure applied
The friability of a sample of 6 tablets was measured
using a Roche friabilator (Remi electronics,
V’=w’log P+V’sp
Mumbai). 6 previously weighed tablets were
rotated at 25 rpm for 4 min. The tablets were
where V’ is the specific volume of a tablet and w’
dedusted and again weighed. A loss of less than 1
is the Walker coefficient expressing the volume
% in weight is generally considered acceptable.
reduction corresponding to one decade change in
Percent friability was calculated as follows
pressure P obtained by linear regression analysis,
and V’ sp is the specific volume at pressure 1.

2.7.3 Leuenberger Equation


The compression susceptibility parameter for
2.8.5 Drug content
compact formed by direct compression and wet
The tablets were finely powered and a quantity of
granulation technique indicated that the maximum
powder equivalent to 100mg of diclofenac sodium
crushing strength is reached faster at lower pressure
were accurately weighed and transferred to 100ml
of compression
volumetric flasks containing approximately 50ml
For compactability assessment, tensile strength of
of buffer solution (pH6.8) and analysed for the
the compacts was calculated by the following
content of diclofenac sodium using UV-visible

www.iajps.com Page 4630


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

spectrophotometer at 276nm. The drug content of room temperature (RT) and accelerated stability
each sample was estimated.[20] conditions. The samples were designated as time 0,
3, 6, 9, 12, 18 and 24 months for RT and 0, 1, 2, 3
2.8.6 Disintegration test and 6 month for accelerated studies. Samples
The disintegration time of the uncoated tablet was designed for RT storage were kept at 25±2°C and
performed with help of disintegration test apparatus 60±5% relative humidity (RH). The samples in the
using phosphate buffer (pH 6.8) media at 370C ± accelerated stability study were kept at 40±2°C and
0.50C. The time taken for six randomly selected 75±5% RH in humidity chamber. Samples were
tablets to disintegrate in each case was tested for its appearance, disintegration, dissolution
recorded.[21] and assay using the previously described procedure
to evaluate the stability of tablets. The percent
2.8.7 In-vitro drug release studies dissolution, assay, appearance and hardness of the
In-vitro drug release study of Diclofenac sodium tablets stored at room temperature for 24
was done by using USP dissolution test apparatus months.[21]
II. The study was conducted at 50 rpm using 900
ml of pH 6.8 phosphate buffer maintained at 370C- 3. RESULT AND DISCUSSION:
0.50C by using a constant temperature bath. The 5 3.1 Characterization of drug
ml sample was withdrawn from the dissolution The powder was found to be White to slightly
apparatus at 10 min time intervals up to 60 min. the yellowish, slightly hygroscopic, crystalline powder.
sample were replaced with fresh dissolution Diclofenac sodium is soluble in ethanol, methanol
medium and then absorbance was measured by and water. The melting point was found in the
using UV-visible spectrophotometer at λmax of range of 284-285 0C. All observed parameters was
276 nm. Cumulative percentage drug release was found to be similar and complies with the standard
calculated using an equation obtained from a specifications. Hence the drug sample was
standard curve. The graphs of % cumulative release considered as a pure.
Vs time were plotted.[21]
3.1FTIR Spectroscopy
2.9 Stability study of tablets The IR spectrum (Figure 1) of the Diclofenac
Samples of Diclofenac sodium tablets were blister sodium showed similar characteristics peaks to that
packed in aluminum foil. These samples were then of reported spectra of Diclofenac sodium. From the
subjected for stability study according to ICH FTIR study the sample of Diclofenac sodium was
guidelines where zone II was selected as storage identified.
conditions (ICH 2003). Tests were conducted at

Fig. 1: FTIR Spectra of Diclofenac sodium

Fig. 2: XRD of pure Diclofenac sodium

www.iajps.com Page 4631


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

3.2 X-ray diffractometry:


The X-Ray diffraction patterns of pure Diclofenac
sodium were illustrated in Figure 5The 79.8% of 3.3 Drug and polymer compatibility
drug was found to be in crystalline form 20.2% was 3.1.1 FTIR spectroscopy
in amorphous form. The IR spectra of drug and physical mixture show
The characteristic peaks of Diclofenac sodium similar characteristic functional peaks. This
appeared at a diffraction angle of 20.180at similarity in peaks indicates the compatibility of
maximum intensity of 2527 and several sharp Diclofenac sodium with the excipients.
diffraction peaks suggesting that the drug is present
in crystalline form.

Fig.3: IR spectra of drug and physical mixtur of pharmatose 350M

Fig. 4: IR spectra of drug and physical mixture of Avicel PH 101

3.1.2 X- ray diffractometry of drug, excipient 101 and formulation was showed characteristic
and formulation sharp peak in the range of 2ϴ scattered. The
TheFigure8, 9shows non-interactive peaks of pure decrease in the peak intensity was observed in
drug, excipients like Pharmatose 350M,Avicel PH formulation.

Fig. 5: XRD of Diclofenac sodium, Pharmatose 350M and F2 formulation

Fig. 6: XRD of Diclofenac sodium, Avicel PH 1O1 and F2 formulation

www.iajps.com Page 4632


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

3.4 Formulation of granules processes of pharmaceutical materials, especially


Wet granulation method was used for preparation when drying wet granules in narrow ranges such as
of granules. PMG, RMG and FBG were used for ±0.1%. Similar batch-to-batch variability in LOD
preparation of granules. values are commonly observed for regular
pharmaceutical intermediate products such as
3.5 Evaluation of granules granulates and tableting mixtures.
3.5.1 Moisture content
Loss on drying is known that the moisture content in 3.5.2 Particle size distribution
granules or powders can influence the hardness and Tableting mixtures were prepared using different
therefore compactibility of the tablets produced. granulation methods PMG, RMG, FBG and DC
Therefore, all tableting mixtures produced were The particle of PMG(P2), RMG(R2), FBG(F2)
dried to an approximately equal moisture level. It mixtures were considerably d50 values of around
was established that the loss on drying (LOD) values 342µm, 350µm, 409µm, respectively and particles
of the tableting mixtures produced were the of the DC (D1) mixtures were considerably
following: PMG 1.50%, RMG 1.75%, FBG 1.65%, smaller, with d50 values of around 93.75µm.
and DC 1.25%. All LOD values are within the range Larger particles in the size range of 125–1250 µm.
of 1.25–1.75% and may be considered comparable The larger particle size of agglomerates compared
or approximately equal because it is known that with the DC mixture is expected due to the
moisture content is difficult to control during drying granulation process.

Fig.7: Cumulative mass distribution of compression mixtures


a numerical particle size was given as the median
A good powder formulation has a uniform particle particle diameter d50.
size distribution. If the particle size distribution
was not uniform, the powder can segregate 3.5.3 Span value of granules:
according to the different particle sizes. A uniform Lowest span value shows the narrow particle
particle size distribution insures uniform size distribution. Here FBG showed lowest span
dissolution rate, compaction process and value so the FBG showed narrow particle size
flowability, so it was important to evaluate these distribution compare with PMG, RMG and DC
parameters. Thus, in order to compare the mixtures, method.

Fig. 8: Span value of granules

www.iajps.com Page 4633


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

Form factor of granules: granules so that bulk density of PMG was


Formfactor gives a measure of sphericity and a intermediate in value between those of FBG and
perfect sphere has a formfactor value of unity.FBG RMG. PMG produce fluffier, more porous granules
showed formfactor value of unity so that FBG have than RMG. The bulk density of fluid bed
high sphericity compare to the RMG, PMG and DC granulation is decrease compare to direct
method. If the particles have more sphericity then compression.
flow rate of granule decreases. FBG showed the
less flow rate because the sphericity of granules. Tapped density of FBG was less compare to RMG,
Table 1: Form factor of granules PMG and DC method. The tableting mixture
Granulation P2 R2 F2 D1 density obviously plays an important role in
batches powder compressibility.
Form factor 0.6866 0.5929 1.000 0.999
In case of direct compression have also same 3.5.6 Flow properties of tableting mixture
formfactor value of unity because lactopress spray The flow properties results are shown in Table 6, 7
dried-250 a direct compressible vehicle present in and 8. The flow propertiesas dictated by the Carr
to DC method. index, the Hausner ratio, Angle of repose and the
Bulk density flow time are entirely consistent with one other.
After granulation bulk density of FBG was Ingeneral, flow properties of wet granulated
decreased compare to RMG, PMG and DC method. mixtures are superior to other mixtures.FBG shows
FBG showed decreases in bulk density with excellent flow property. The RMG, PMG and DC
increase in granule voidage but in case of RMG method shows good flow property. DC mixture
bulk density increase during kneading step. The shows good flow properties due to the usage of
void between granules was compressed and granule directly compressible main component of the
densify. PMG cannot compress the voids between formulation.

Fig. 9: Bulk density of granules after granulation

Fig. 10: Tapped densities of granulation batches

Fig. 11: Carr’s Index of granules

www.iajps.com Page 4634


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

Fig. 12: Angle of repose of granule after granulation


3.5.7 Bulkiness 3.5.9 Kawakita Plot
Granules prepared by FBG have higher bulkiness The value of ‘a’ was least, and ‘b’ was maximum
compare to the RMG, PMG and direct compression indicating good flowability. The value of ‘a’
method. It may be due to the large amount of indicated compressibility or densification due to
voidage is present in FBG. tapping and ‘b’ as rate of achieving final packing.
Table 2: Bulkiness of granules Figure 21 showed the kawakita plots for Diclofenac
Granulation P2 R2 F2 D1 sodium granules containing selected diluents and
batches PVP as binder, where a fairly linear relationship
between N/C and N is obtained at all compression
Bulkiness 1.549 1.760 3.225 1.883 pressures used with correlation coefficient ≥ 0.99
3.5.8 Porosity of granules for all the formulations, and hence, the equation
Granules prepared by FBG was porous than that of can be used to predict the densification
PMG and RMG. It may be due to the consolidation mechanisms Values of 1/b and 1/ab were obtained
time was limited to granule drying time, which was from the slope and intercept of the plots
of order of second, rather than minutes. Thus respectively. It was observed from Table 11(which
process changes that reduce drying time (higher showed the Kawakita constants) that values of ‘a’
bed temperature, lower liquid flow rate, and were smaller in the formulations with FBG than in
smaller drop size) will decreases granule density the formulations with DC, PMG and RMG
(increase granule porosity). Granules prepared by implying that the better the fluidity of the FBG.
RMG showed lower porosity results in increased From Kawakita analysis, it was found that FBG
granule strength. granules densified the least (small compressible
Table 3: Porosity of granules value) but attained the final packing state more
slowly than DC formulation. The lower values of a
Granulation P2 R2 F2 D1 and 1/b for the FBG granule formulation indicate
batches better flowability and lesser cohesiveness than the
direct compression formulation.
Porosity (%) 16.4 15.9 17.3 15.9

Fig. 13: Kawakita plot

www.iajps.com Page 4635


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

3.6 Formulation of Diclofenac sodium tablet compression pressure was increased, the granules
Tablets were prepared by addition of 0.5% Mg- showed plastic deformation. Materials with higher
stearate into the prepared granules. Tablets were k values undergo more plastic flow and such
prepared by wet granulation method and direct materials often form strong tablets at relatively low
compression method. compaction force. Crushing strength of tablets
correlated with the values of k; Increased the slope
.7 Compaction Studies value increased degree of plasticity and better
Heckel and walker plot was used determine the compressibility formed. Here FBG have higher k
compressibility of granules. values compare to the PMG, RMG and DC
method. FBG mixture has excellent compressibility
3.7.1 Heckel plot it may be due to its higher porosity to compare
K represents the Heckel coefficient (slope of the PMG, RMG and direct compression method. It
Heckel plot) and mPy represents yield pressure as was evident that the achieved linearity of the
its inverse value. A (y-intercept) are regression Heckel curves was satisfactory, as demonstrated by
coefficients of the linear portion of the curve. The high values of R2 ≥0.971. The best linearity was
FBG mixture is most compressible, with Py (for observed in the FBG mixture. The FBG mixture
F2) 1.1748 followed by the PMG, RMG and DC was most compressible.
mixtures have Py 2.0967, 2.1610, 1.7921
respectively, Low value of py indicates faster onset The tableting mixture density obviously plays an
of plastic deformation. important role in powder compressibility. Usually,
powders were more porous are considered more
Heckel data for DC formulation and granule show compressible. For instance, if the porosity of two
no linearity at the early stages of compression due mixtures of the same material is equal the mixture
to particle rearrangement and the initial with lower bulk and/or tapped density was likely to
fragmentation. The higher value of intercept (A) be more compressible. This positive relationship
for granules implies a higher degree of was observed between the tapped densities and the
fragmentation than for DC formulation. When the Heckel coefficients of the mixtures studied.

Fig. 14: A positive correlation between the tapped densities of tableting mixtures and their Heckel
coefficients (K).

3.7.2 Walker plot: These results demonstrate exactly the same order of
The Walker plots of compression for the respective compressibility as the Heckel model and the
mixtures showed even better linearity compared to positive correlation between these two methods
the Heckel plot. The Walker model once again that was observed. It was important to emphasize
proved that FBG was most compressible mixture the Walker model’s slightly better discriminative
with w of 24.9 PMG, RMG and DC mixtures power over the Heckel model to differentiate
considerably lower compressibility measured. tableting mixture compressibility.

www.iajps.com Page 4636


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

Fig. 15: A typical Walker plot: PMG mixture prepared by PMG and RMG mixture prepared by RMG

3.8 Evaluation of tablets: compare to the wet granulation method. But


Tablet for all the formulation were evaluted for percentage friability for all formulation was below
parameter such as thickness, hardness, weight 1%, indicating that friability was within the
variation, drug content and friability. Results are prescribed limits.
summarised in Table 4.
3.8.5 Drug content
3.8.1 Thickness All formulation showed good uniformity in drug
Thickness of tablet within the priscribed limit. content among different formulations of tablet and
percentage of drug content was within the
3.8.2 Hardness prescribed limit.
FBG higher hardness compare to the RMG, PMG
and DC method. FBG shows higher hardness at 3.8.6 Disintegration test for tablet:
low compression force compare to RMG, PMG and Here In wet granulation method FBG tablet
DC method but all hardness of tablets are within disintegrate fast in phosphate buffer pH 6.8
the prescribed limit. compare to tablet produced by the RMG and PMG.
But direct compression method shows faster
3.8.3 Weight variation test disintegration compared to the wet granulation
In weight variation test used to show the content method.
uniformity of drugs. Average weight in mg (within All the tablet formulation showed acceptable
the limit ±5%). Average percentage deviation of all properties and complied with specification for
formulations was found to be within limit and weight variation, drug content, hardness, friability
hence, all formulations passed the test for and disintegration.
uniformity of weight as per official requirement.
3.8.7 In- vitro drug release studies:
3.8.4 Friability test Direct compression shows fast release compare to
Friability of FBG was less than RMG, PMG and wet granulation method. In wet granulation FBG
DC method. DC method shows higher friability showed fast release compared to PMG and RMG.
Table 4: Evalution of tablet parameters
Sr.
Parameter PMG RMG FBG DC
No.
1 Thickness* (mm) ± SD 4±0.05 4.1±0.04 4±0.01 4.2±0.04
Hardness*(Kg/cm2) ±
2 4.8±0.115 4.6±0.115 5.0±0.115 4.8±0.115
SD
Average weight* (mg) Within the limits Within the limits Within the Within the
3
± SD (±5%) (±5%) limits (±5%) limits (±5%)
4 Friability* (%) ± SD 0.53±0.05 0.68±0.02 0.46±0.01 0.78±0.02
Drug content* (%)±
5 98.73±1.96 99.27±08 100±0.66 98.48±2.44
SD
Disintigration test
6 (min) 15 14 13 12
(Average time taken)
Mean Mean
Mean cumulative Mean
cumulative % cumulative %
% release within cumulative %
7 Dissolution test release within release within
60 minutes release within 60
60 minutes 60 minutes
(92.2%) minutes (90.0%)
(96.7%) (97.0%)

www.iajps.com Page 4637


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

Fig.16: Dissolution profile of formulation P2, R2, F2 and D2

Fig. 17:Dissolution profile of stability study of F2 batch

3.8.8 Drug Release Kinetic of fines 29.12% was produced, something that is
All the formulation were studied for kinetic release typically observed in PMG processes. The flow
like different mechanisms first order, Higuchi, properties of Fluid bed granulated mixtures were
Hixon crowell, zero order or Korsmer- Peppas superior shown by the kawakita equation; however,
model. From this study it was observed that from all tableting mixtures had acceptable flow
all formulation batch showed more best fitted properties for tablet production on a KBr tablet
model was Korsymer- Peppas model except DC press machine. Tablets produced from Fluid be
method granulated mixtures had lower friability at all
compression pressures. The results of
3.9 Accelerated Stability Study compressibility studies using Walker and Heckel
Table 36 showed that there was no considerable analyses show that the FBG mixture has the best
change in thickness, hardness and drug content of compressibility and Leuenberger equation show
F2 formulation before and after accelerated that FBG mixtuer has the best
stability study. Also there was no significant compactibilityfollowed by the PMG, RMG and DC
difference found between dissolution profile of F2 mixtures, which are comparable to each other. All
formulation before and after stability. Hence tablet the tablet formulations showed acceptable
prepared by wet granulation to be stable. properties and complied with specification for
weight variation, drug content, hardness, friability
CONCLUSION: and disintegration. Fluid be granulated mixtures
Various powder agglomeration processes have a had lower friability compare to the other batches.
great impact on the tablet compaction process. In In case of in- vitro drug release for wet granulation
order to investigate the loss on drying, particle size techniques FBG showed faster drug release
distribution, porosity, spherisity, bulk density, flow compare to the RMG and PMG. But in- vitro drug
property and compressibility, compatibility, tablet release for FBG compare with DC method. The DC
properties (weight uniformity, hardness, friability method showed faster drug release compare to the
and disintegration, drug content, dissolution) and FBG. In case of Accelerated stability study of FBG
accelerated stability study of Diclofenac sodium there was no considerable change in physical
tablet for that complex tableting mixtures of appereance, thickness, hardness, drug content and
Diclofenac sodium were precisely characterized. In- vitro drug release. Finally by evaluation of
FBG show loss on drying within prescribed limit. different granulation properties and tablet
Fluid bed granulation processes resulted in the properties, it was conclude that FBG is best wet
formation of narrower particle size distribution, granulation method compare to RMG, PMG and
high porosity, spherisity, lower bulk density DC method.
compared to PMG, RMG in which a higher amount

www.iajps.com Page 4638


IAJPS 2017, 4 (12), 4626-4639 V. B. Khot et al ISSN 2349-7750

REFERENCES: International Journal of Research in Pharmaceutical


1. Kaur H. Processing technologies for and Biomedical Sciences, 2011; 2(2):788–807.
pharmaceutical tablets: a review. International 12. Tita B, Fulias A, Bandur G, Ledeti I, Tita
Research Journal of Pharmacy, 2012;3(7):20–23. D. Application of Thermal Analysis to Study the
2. Agrawal R, Yadav N. Pharmaceutical Compatibility of Sodium Diclofenac with Different
processing: A review on wet granulation Pharmaceutical Excipients. Rev. Chem.
Technology. International Journal of (Bucharest), 2011;62(4): 443–454.
Pharmaceutical Frontier Research, 2011;1(1):65– 13. Autamashih M, Isah AB, Allagh TS.
83. Heckel and kawakita analysis of granules of the
3. Aulton ME. 2007. Pharmaceutics, The crude leaves extract of Vernonia gelamensis
design and manufacture of medicines, Summers, prepared using polyvinylpyrolidone as binder.
M.P., Granulation. Third edition, Churchill International Journal of Pharmacy and
Livingstone, Edinburgh. Pharmaceutical Sciences, 2011;3(4):144–147.
4. Singh SP, Patra CN, Dinda SC. A 14. Zhigang S, Naiqi Y, Richard C. Adams.
comparative evaluation of the flow and compaction Particle Size Specifications for Solid Oral Dosage
characteristics of Gymnema sylvestre leaf powder. Forms: A Regulatory Perspective. The Review of
Journal of Advanced Pharmaceutical Research, American Pharmaceutical Business and
2010;1:1-11. Technology, 2010; 13(4):162-170.
5. Parikh DM. 2009. Handbook of 15. Brittain HG. 2002. Particle Size
Pharmaceutical Granulation Technology. second Distribution, Part –III Determination by analytical
edition, Taylor and francis group, New York. sieving, Pharma. Tech.
6. Debra SH. Comparison of low shear, high 16. Kaerger JS, Edge S, Price R. Influence of
shear, and fluid bed granulation during low dose particle size and shape on flowability and
tablet process development. Drug Development compactibility of binary mixtures of paracetamol
Industrial Pharmacy, 2004;30(3):259–266. and microcrystalline cellulose. European Journal of
7. Shelake S, Khade V, Sangave P, Patil S. Pharmaceutical Sciences, 2004;22:173–179.
Development And Evaluation of Colon Specific 17. More HN, Hajare AA. 2004. Practical
Drug Delivery System Via pH and Microbial Pharmaceutics (Physical pharmacy), Manas
Triggered Mechanism for Colon Cancer. Am. J. Prakashan, Kolhapur.
PharmTech Res, 2017; 7(5):219-228. 18. Singh SP, Patra CN, Dinda SC. A
8. Maja S, Ilija I, Franc V, Sasa B. Systematic Study on Processing Problems and In-
Compressibility and compactibility study of real vitro Release of Saraca indica Caesalpiniaceae
tableting mixtures: The impact of wet and dry Bark Powder Tablets. Tropical Journal of
granulation versus a direct tableting mixture. Pharmaceutical Research, 2012; 11(3):387-395.
International Journal of Pharmaceutics, 19. Shelake S. S, Gaikwad RG, Patil SV,
2011;414:131–139. Mevekari FI, Patil SS. Development of solid
9. Indian Pharmacopoeia Government of India, dispersion tablet of Carvedilol to improve
Ministry of Health and Family Welfare, The Solubility. Indian drugs, 2016;53(01):54–59.
controller of publications. New Delhi, Vol–II, 20. Giri TK, Parveen N, Thakur D, Alexander
1996, 514. A. In vitro Evaluation of Commercially Available
10. Prasanthi NL, Murthy TEGK. Design and Enteric Coated Tablet Containing Diclofenac
Development of Controlled Release Diclofenac Sodium. International Journal of Research in
Sodium Capsules. International Journal of Pharmaceutical and Biomedical Sciences,
Advances in Pharmaceutical Sciences, 2010; 2012;3(2):875–881.
1:263–266. 21. Zaid AN, Qaddomi A. Development and
11. Bharathi A, Kalyana NS, Ramana Reddy stability evaluation of enteric coated Diclofenac
G. Formulation and In Vitro Evaluation of sodium tablets using Sureteric. Pak. J. Pharm. Sci.,
Diclofenac Sodium Sustained Release Matrix 2012;25(1):59–64.
Tablets using Melt Granulation Technique.

www.iajps.com Page 4639