FORMULATION AND EVALUATION OF TABLETS CONTAINING POORLY WATER SOLUBLE DRUG BY MADG METHOD

Abstract

Tablet is a unit solid dosage form containing active ingredient with or without suitable excipient. These are most widely used dosage form. [1] The main objective of the design and manufacture of the compressed tablet is to deliver orally correct amount of drug in the proper form over proper time and at desired location, so as to have suitable chemical integrity protected at the point of its action. The physical design, manufacturing process, and complete chemical makeup of the tablet can have a profound effect on the efficiency of the drug being administered. [2] Poorly water soluble drugs are associated with slow drug absorption leading eventually to inadequate and variable bioavailability [3] and nearly 40% of the new chemical entities currently being discovered are poorly water-soluble drugs. [4] Based upon their permeability characteristics, the biopharmaceutics classification system (BCS) classifies such drugs in two major classes, i.e., Class II and IV. The BCS class II drugs are poorly water-soluble entities with high permeability. Most formulation strategies for such drugs are targeted at enhancing their fine dispersion at absorption level. [5] Ibuprofen being poorly water-soluble drug known to demonstrate dissolution or solubility limited absorption. The bioavailability of the drug is low, yet its rate of absorption is quite inconsistent and delayed with time. Based upon its aqueous solubility and various dissolution parameters, the drug bioavailability can unambiguously be regarded as limited solely to dissolution. [6] The main focus on moisture activated dry granulation method is better than other granulation method in case of poorly soluble drug tablets.

Full text

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FORMULATION AND EVALUATION OF TABLETS CONTAINING
POORLY WATER SOLUBLE DRUG BY MADG METHOD.
Devendra Sharma1, M.D. Godbole2, Ameya Lanjewar*2 and Sushil Burle1
1Department of Pharmaceutics HI-Tech College of Pharmacy, Chandrapur.
2Department of Pharmaceutics Kamala Nehru College of Pharmacy Butibori, Nagpur.
ABSTRACT
Tablet is a unit solid dosage form containing active ingredient with or
without suitable excipient. These are most widely used dosage form.[1]
The main objective of the design and manufacture of the compressed
tablet is to deliver orally correct amount of drug in the proper form
over proper time and at desired location, so as to have suitable
chemical integrity protected at the point of its action. The physical
design, manufacturing process, and complete chemical makeup of the
tablet can have a profound effect on the efficiency of the drug being
administered.[2] Poorly water soluble drugs are associated with slow
drug absorption leading eventually to inadequate and variable
bioavailability[3] and nearly 40% of the new chemical entities currently being discovered are
poorly water-soluble drugs.[4] Based upon their permeability characteristics, the
biopharmaceutics classification system (BCS) classifies such drugs in two major classes, i.e.,
Class II and IV. The BCS class II drugs are poorly water-soluble entities with high
permeability. Most formulation strategies for such drugs are targeted at enhancing their fine
dispersion at absorption level.[5] Ibuprofen being poorly water-soluble drug known to
demonstrate dissolution or solubility limited absorption. The bioavailability of the drug is
low, yet its rate of absorption is quite inconsistent and delayed with time. Based upon its
aqueous solubility and various dissolution parameters, the drug bioavailability can
unambiguously be regarded as limited solely to dissolution.[6] The main focus on moisture
activated dry granulation method is better than other granulation method in case of poorly
soluble drug tablets.
KEYWORD: MADG, Tablets, Ibuprofen.
World Journal of Pharmaceutical Research
SJIF Impact Factor 7.523
Volume 6, Issue 3, 1523-1537. Research Article ISSN 2277– 7105
*Corresponding Author
Ameya Lanjewar
Department of
Pharmaceutics Kamala
Nehru College of Pharmacy
Butibori, Nagpur.
Article Received on
19 Jan. 2017,
Revised on 09 Feb. 2017,
Accepted on 01 March 2017
DOI: 10.20959/wjpr20173-8055

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INTRODUCTION
Tablet manufacturing process can be broadly classified as granulation and direct
compression. Granulation process may be defined as the size enlargement process in which
fine or coarse particles is converted into physically stronger and larger agglomerates having
good flow properties, better compression characteristics and uniformity and a process for
collecting particles together by creating bonds between them. It is the most widely used
technique in the pharmaceutical industry for the preparation of materials for tableting.
Granulation may be either wet granulation or dry granulation i.e., by using binder solution or,
by using dry binder. Pharmaceutical granules typically have a size range between 0.2 to 4.0
mm, depending on their subsequent use. Most of formulation in tablet manufacturing is by
wet granulation process.[7] Granulation is the process in which primary powder particles are
made to adhere to form larger, multi particle aggregates called granules.Granulation method
can be broadly classified into two types[4,5,6,7]
DRY GRANULATION
WET GRANULATION
MOISTURE ACTIVATED
DRY GRANULATION
Dispensing and Shifting
Dispensing and Shifting
Dispensing and Shifting
Dry mixing
Dry mixing
Dry mixing
Slugging
Slugging
Granulation
Granulation
Half lubrication
Lubrication
Pre-drying
Pre-drying
Compression
Compression
Shifting
Shifting
Milling
Drying
Drying
Shifting
Pre-mixing (unlubrication)
Pre-mixing (unlubrication)
Final lubrication
Lubrication
Lubrication
compression
Compression
Compression
Moisture Activated Dry Granulation (MADG) was developed in response to the
difficulties experienced with wet granulation, in terms of endpoint, drying and milling. Wet
granulation process endpoint is very sensitive to granulation time and shear. The wet granules
need to be dried to a narrow range of moisture contents, which is difficult. The dried granules
need to be milled, but the milled granules often have either too many fines or too many
coarse particles (or both) — an undesirable bimodal distribution.
MADG is a very simple and innovative process where granules are created with water and a
granulating binder, as in wet granulation, but are not heat dried or milled. This process helps
to minimize end point sensitivity.

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MOISTURE ACTIVATED DRY GRANULATION (MADG) MADG is a very simple and
innovative process where granules are created with water and a granulating binder, as in wet
granulation, but are not heat dried or milled. This process helps to minimize endpoint
sensitivity.
It is applicable to many of the pharmaceutical industry's granulation needs for solid dosage
form development and can be described as a 'one-pot' granulation process.
MATERIAL AND METHOD
Ibuprofen BP was procured as a gift sample from ZIM Laboratories Ltd, Nagpur,
Maharashtra. Colloidal anhydrous silicon (Aerosil) was procured as a gift sample from ZIM
Laboratories Ltd, Nagpur, Maharashtra.Maize starch was procured from ZIM Laboratories
Ltd, Nagpur, Maharashtra. Lactose DC was procured from ZIM Laboratories Ltd, Nagpur.
PVP K30 (Povidone) was procured from ZIM Laboratories Ltd, Nagpur, Maharashtra.
Microcrystalline cellulose was procured from ZIM Laboratories Ltd, Nagpur, Maharashtra.
Talcum was procured from ZIM Laboratories Ltd, Nagpur, Maharashtra. All other chemicals
used were of analytical grade.
Formulation and development
MADG is a process in which moisture is used to activate granule formation, without the need
to apply heat to dry the granules. There are two main stages in MADG:
1. Agglomeration 2. Moisture distribution/ Absorption
During agglomeration, drug is mix with fillers and binder in the powder form, to obtain a
uniform mixture. This blend constitutes approximately 50-80% of formula weight. While
mixing, a small amount of water (0.5-5%) is sprayed as small droplets onto the powder blend,
which moistens the binder and makes it tacky. The binder facilitates the binding of the drug
and excipients as they move in a circular motion forced by the mixer blades. The process
does not results in larger lumps formation as the amount of water used in this process is very
small as compared to the other conventional wet granulation techniques. The particle size of
the agglomerates generally falls in the range of 150-500 μm.
In moisture distribution/absorption, moisture absorbents, such as microcrystalline cellulose or
silicon dioxide, are added while mixing continues. When they come into contact, the moisture
absorbents pick up moisture from the moist agglomerates, resulting in moisture redistribution
within the mixture. When this happens, the entire mixture becomes relatively dry. While

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some of the moisture is removed from the wet agglomerates, some of these agglomerates
remain almost intact and some usually the larger particles may break up. This process results
in granulation with more uniform particle size distribution.[34]
Flow chart: Method for preparation of Ibuprofen tablet 400mg
Evaluation of Ibuprofen tablets
The Ibuprofen tablets were evaluated for following parameters;
1) Appearance 3)Weight variation
2) Friability 4)Disintegration time
5) Drug release study (in-vitro) 6) Dimensions
7) Hardness 8) Drug content
9) DSC 10) X-ray diffraction (XRD)
11) Scanning electron microscopy 12)Stability testing
Preformulation study
Flow characterization A. Bulk density
B. Tapped density
Bulk density = weight of sample in gram / volume occupied by the
sample

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C. Hausner’s ratio and Compressibility index
In recent years the compressibility index and the closely related Hausner’s ratio have become
the simple, fast and popular methods for predicting powder flow characteristics. Both the
compressibility index and the Hausner’s ratio were determined by using bulk density and the
tapped density of a powder.[54]
i. Hausner’s ratio
ii. Compressibility index
Bulk density – Tapped density
Carr’s index = × 100
(%) Tapped density
Table 6.8: Limits of Compressibility index and Hausner ratio
a. Angle of repose
Tan θ = h/r
Where,
h = Height of pile, r = Radius of the base of pile, θ = Angle of repose
Table 6.9: Flow properties and corresponding angles of repose
Table 6.10: Formulation flow characterization
FORMULATION
MOISTURE
(%)
BD
(g/cm3)
TD (g/cm3)
HR
CI
(%)
FLOEABI
LITY
Angle of
repose
I01
2
0.576
0.703
1.22
19.34
Fair
36
I02
2
0.586
0.727
1.24
19.34
Fair
37
I03
2
0.576
0.603
1.04
4.48
Excellent
26
I04
2
0.576
0.703
1.22
19.34
Fair
38
I05
2
0.576
0.603
1.04
4.48
Excellent
25
I06
2
0.637
0.765
1.17
15.29
Good
31
I07
0.5
0.576
0.703
1.22
19.34
Fair
38
I08
1
0.586
0.727
1.24
19.39
Fair
37
I09
1.5
0.614
0.727
1.18
15.54
Good
32
I10
2
0.630
0.750
1.17
13.69
Good
33
I11
2.5
0.576
0.603
1.04
4.48
Excellent
26
I12
3
0.637
0.752
1.18
15.29
Good
33
I13
3.5
0.576
0.603
1.04
16.33
Fair
36
I14
0.0
0.576
0.703
1.22
19.34
Fair
37
WG1
4
0.621
0.746
1.20
16.8
Fair
37

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Particle size
Measurement of particle size involves the electromagnetic sieve shaking of the sample
through the series of successively arranged sieves (Sieve No. 20, 30, 40, 60, 80, 100 and
receiver) and weighing the portion of the sample retained on each sieve and calculation of
same.
Table 6.11: Particle size analysis of formulation batches
Batch No
sieve Number
20
40
60
80
I01
3.8
7.3
9.58
29.11
I02
4.3
8.6
12.56
31.88
I03
4.3
8.6
12.56
31.88
I04
5.3
10.76
15.12
32.43
I05
6.41
12.62
17.46
33.27
I06
6.40
12.56
16.46
28.56
I07
5.1
9.80
14.12
31.46
I08
4.2
8.5
12.56
30.90
I09
6.40
12.56
16.46
28.56
I10
3.8
7.3
9.58
29.11
I11
4.3
8.6
12.56
31.88
I12
4.3
8.6
12.56
31.88
I13
5.3
10.76
15.12
32.43
I14
6.41
12.62
17.46
33.27
WG1
3.1
5.8
12.58
28.64
Table: Formulations of Ibuprofen tablet 400mg
Batch
No.
Composition
Drug
(mg)
Lactose
DC (mg)
Aerosile
(mg)
MCC
(mg)
Starch
(mg)
PVP
K30
(mg)
Deprogel
(mg)
Talc
(mg)
Magnesium
stearate
(mg)
Moisture
(%)
Time
(min.)
RPM
I01
400
60
4
80
60
16
12
0
8
q.s.
20
100
I02
400
100
8
12
60
16
16
4
4
q.s.
20
100
I03
400
120
5
12
56
14
16
4
3
q.s.
20
100
I04
400
128
5
20
50
10
20
5
2
q.s.
25
100
I05
400
139
4
20
50
10
20
5
2
q.s.
25
150
I06
000
361.4
10.4
52
130
26
52
13
5.2
q.s.
30
150
I07
400
139
4
20
50
10
20
5
2
0.0
30
150
I08
400
139
4
20
50
10
20
5
2
0.5
30
150
I09
400
139
4
20
50
10
20
5
2
1.0
30
150
I10
400
139
4
20
50
10
20
5
2
1.5
30
150
I11
400
139
4
20
50
10
20
5
2
2.0
30
150
I12
400
139
4
20
50
10
20
5
2
2.5
30
150
I13
400
139
4
20
50
10
20
5
2
3.0
30
150
I14
400
139
4
20
50
10
20
5
2
3.5
30
150
WG1
400
139
4
20
50
10
20
5
2
4.5
30
150

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Formulation of tablets using most suitable approach of MADG
Ingredients mentioned in table 6.15 were used for the formulation of modified tablets of
Ibuprofen by MADG process. The ingredients were weighted, mixed in geometrical order
and compressed by 15.6 x 8 mm size punch to get a 100 tablets each weighing 650 mg using
14 station single rotary Rimak tablet compression machine.
Fig. 6.19: Tablet manufacturing flow chart
Prior to compression the prepared granules were evaluated for pre-compression parameters
(flow properties) viz. Angle of repose, Bulk density, Tapped density, Hausner’s ratio and
Compressibility index as per the procedure mentioned.
Appearance
Tablets were examined for texture, any surface flaws like cracks and chips.
Table: Characteristics of Batches
Sr. No.
Batch No.
Characteristic/observation
Appearance
Color
Taste
Thickness
Dimensions
1
I01
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
26 mm
2
I02
White color, Caplet shape,
smooth, free from cracks
white
Bitter
5.7 mm
25 mm
3
I03
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
27 mm
4
I04
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.8 mm
28 mm
5
I05
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.8 mm
26 mm
6
I06
White color, Caplet shape,
smooth, free from cracks
white
Bitter
5.8 mm
25 mm
7
I07
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.8 mm
27 mm

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Dimensions
Dimensions such as thickness of the tablets were measured using digital Vernier caliper.
Weight variation
20 tablets of each formulation batch were weighed individually using an electronic balance.
The average weight was calculated and individual tablet weight was then compared with
average value and the deviation was recorded.[51]
Friability
Where, F = friability Wo = initial weight of the ten tablets W = final weight of the ten tablets
Disintegration time (in vitro)
The disintegration time was determined by using USP tablet disintegration test apparatus
using 900 ml of deionised water without disk. For this, 6 tablets of each formulation were
used and the disintegration test was conducted at following test conditions.
Hardness
Drug content
Two tablets of each formulation were used. The tablets were weighed and crushed. A
quantity of powder equivalent to 650 mg of Ibuprofen was accurately weighed and
transferred to 100 ml volumetric flask to which small volume of Phosphate buffer pH 7.2 was
added to disperse the contents. Final volume was adjusted to 100 ml using Phosphate buffer
8
I08
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.8 mm
28 mm
9
I09
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.8 mm
26 mm
10
I10
White color, Caplet shape,
smooth, free from cracks
white
Bitter
5.8 mm
25 mm
11
I11
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
27 mm
12
I12
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
28 mm
13
I13
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
25 mm
14
I14
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.7 mm
27 mm
15
WG1
White color, Caplet shape,
smooth, free from cracks
White
Bitter
5.9 mm
28 mm
% F = (Wo – W) / Wo x 100

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7.2. The dispersion was stirred for 2 hr using magnetic stirrer and then allowed to settle.
Solution was filtered through Whatman filter paper (No.41). Appropriate dilution of filtrate
was made using Phosphate buffer pH 7.2 and the UV absorbance was recorded.[55]
Drug release study (in-vitro)
i) Drug release of Ibuprofen in phosphate buffer pH 7.2
Table 6.14: Drug release of Ibuprofen in phosphate buffer pH 7.2
Batch
no.
WEIGHT
VERIATION
HARDNESS
Disintegration
time
Drug
content
Drug
release
FRIABILITY
I01
0.651±5
111
64
95.30
80.30
0.1
I02
0.652±5
112
72
96.45
85.60
0.2
I03
0.645±5
90
78
96.22
95.60
0.3
I04
0.653±5
86
65
98.00
96.30
0.1
I05
0.655±5
72
63
97.38
88.30
0.4
I06
0.650±5
69
68
90.23
89.30
0.3
I07
0.651±5
48
78
96.45
89.36
0.2
I08
0.640±5
50
70
88.68
90.36
0.4
I09
0.643±5
70
65
95.40
92.36
0.3
I10
0.646±5
96
60
89.30
96.30
0.2
I11
0.650±5
110
55
99.20
99.30
0.1
I12
0.651±5
90
50
98.30
96.78
0.2
I13
0.653±5
97
20
86.40
92.33
0.3
I14
0.651±5
30
78
87.46
91.40
0.5
WG1
0.652±5
67
180
85.30
78.60
0.2
Fig: Drug release of Ibuprofen tablet (MADG Vs WG)

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Fig 6.13: X- ray diffraction spectrum of Ibuprofen
The analysis of XRD pattern reveals sharp intensity of the crystallinity peaks of the pure
drug, but when it was incorporated into the excipients the intensities of the peaks were
decreased due to decreased crystallinity of the drug. The formulation containing MCC and
Lactose DC showed maximum amorphisity. XRD analysis showed that there was little
reduction in the crystallinity of drug when formulate these polymers
Differential Scanning Calorimeter
Fig. 6.14: DSC formulation graph
The thermo gram of pure Ibuprofen showed sharp endothermic with melting peak at 77.31ºC.
Thermo gram of In optimized formulation showed peak at 77.11ºC. Slight shift in of
endothermic peaks on left hand with decreased in its intensity indicates little amorphization
of drug shown in Figure.
This may attributed to presence of moisture which may cause drug in crystallization form and
hence reduces drug dissolution which may results in decreased release of Ibuprofen.

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FTIR
Fig. : FTIR formulation graph
FTIR spectrum of Ibuprofen showed peaks at 945.94 due to O-H bending, 1258.72 due to C-
O stretching, 1378.69 due to CH2 and CH3,1417.65 due to Ar C-C stretching and 1700.98
due to C=O stretching. The optimize formulation showed more intense and prominent peaks.
SEM Analysis
Scanning electron microscopy was performed to study the effect of mixing time on the
morphology of particles. Figure shows the scanning electron micrograph of initial blend of
Ibuprofen and binders. Result was determine as per procedure and SEM of drug, placebo and
formulation show following
C:Batch F4
Fig: SEM formulation and placebo graph
DISCUSSION
Rheumatoid arthritis, osteorthritis and other musculoskeletal major disorder in India.
Ibuprofen has a local action in larg intestine as it is used in the treatment of Rheumatoid

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arthritis, osteorthritis and other musculoskeletal disorder. Ibuprofen primarily absorbed from
lower part of gastrointestinal tract. The main objective of the study was to develop, evaluate
and optimization of tablets containing poorly water soluble drug by moisture activated dry
granulation method, thereby reducing the production cost of tablet.
Appearance, melting points, loss on drying, λmax, IR study and DSC study of drug Ibuprofen
were carryout as per the specification of B.P. It was observed that the obtained sample of
Ibuprofen complies with the standard of quality mentioned in B.P. Standard calibration curve
of Ibuprofen (absorbance Vs concentration) was found to be linear and obeyed Beer
Lambert’s law in the range of 0-10µg/ml. SSG and povidone were evaluated for their
standard. It was observed that they complies with the standard of quality as per prescribe
official books.
Preliminary batches of Ibuprofen tablets were prepared by moisture activated dry granulation
method using sodium starch glycolate as Superdisintegrant and povidone as binder polymer
in various concentrations. From the results of preliminary batches, it was observed that
polymer concentration is important parameter in the formulation of tablets. As the SSG
concentration was increased from 12 mg to 20 mg, and concentration of povidone were
increased from 10 mg to 16 mg disintegration time, % drug release from tablets were
increased. The disintegration time was decreased with the decrease in the quantity of sodium
starch glycolate in tablets by moisture activated dry granulation process
CONCLUSION
Ibuprofen tablets were successfully developed using moisture activated dry granulation
method. Concentration of sodium starch glycolate 2.8% and concentration of povidone 0.8%
was taken then resultant tablets were given drug release (85.60±0.36) in 15 minutes. The in-
vitro results indicated that the tablets were potentially useful. The moisture activated dry
granulation method was found to be simple, reproducible, easily controllable, economical,
and continues process. Additionally, the excipients used for the formulation of tablets were
cheap and easily available. Other drugs for the use in moisture activated dry granulation
method can be incorporated in the formulation of tablets. Therefore, these types of moisture
activated dry granulation method for tablets can be commercially processed easily and
potentially better other than wet granulation method for formulation of tablets.

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ACKNOWLEDGEMENT
The authors are thankful to ZIM Laboratories Ltd, Nagpur, Maharashtra. India for providing
the free gift sample of drug Ibuprofen. Authors wish to thank the Principal of Kamla Nehru
College of Pharmacy, Nagpur for providing necessary facilities to carry out this work.
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