Advanced Powder Technology 28 (2017) 1270–1280

Contents lists available at ScienceDirect

Advanced Powder Technology

journal homepage: www.elsevier.com/locate/apt

Original Research Paper

Application of moisture activated dry granulation (MADG) process to

develop high dose immediate release (IR) formulations
Kailas K. Moravkar ⇑, Tariq M. Ali, Jaywant N. Pawar, Purnima D. Amin 1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, UGC-CAS (Elite Status), N. P. Marg, Matunga (E), Mumbai 400019, India

a r t i c l e i n f o a b s t r a c t

Article history: Moisture activated dry granulation (MADG) method was used to develop IR tablets with cohesive, fluffy
Received 6 January 2016 and high dose drugs. To evaluate this approach, three drugs: metformin hydrochloride, acetaminophen
Received in revised form 10 February 2017 and ferrous ascorbate were selected as model compound along with three binders: maltodextrin DE16,
Accepted 14 February 2017
PVP K 12 and HPC. The granules were generated using MADG method and tablets were prepared using
Available online 3 March 2017
rotary tablet press. The granules and tablets were characterized for particle size analysis, flow properties,
tablet hardness, friability, moisture content, dissolution study, disintegration time and stability study. All
Keywords:
results were found to be within acceptable limits. Development of all formulation tablets were found as
Moisture activated dry granulation
Low viscosity grade polymer
best fitted for an immediate release of Metformin hydrochloride, acetaminophen and ferrous ascorbate.
High drug loading MADG delivered a robust manufacturing process for generation of granules with excellent flowability.
AeroperlÒ 300 pharma The tablets prepared using this method were found to show better content uniformity, good compactabil-
ity and low friability. Use of this approach aids to lower the amount of excipients used to overcome phys-
iochemical limitation of the drug substances and there side effects. Both drying and milling steps in wet
granulation were not required for MADG process. MADG became a cost effective process which could lead
to reduced total tablet size and also save time.
Ó 2017 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder
Technology Japan. All rights reserved.

1. Introduction size as well as a growing interest in fixed dose combination prod-

Optimizing the formulation of solid oral dosage forms requires
fundamental knowledge and mechanistic understanding of the
inter-relationship among process variables and excipient proper-
ties to overcome various physicochemical limitations of the drug
substances such as poor powder flow, powder compatibility, disso-
lution, and stability [1,2]. Generally active pharmaceutical ingredi-
ent (API) powders have relatively small particle sizes (<100 mm)
with non-spherical particle shape. They usually possess high cohe-
sivity and poor flowability. Granulation techniques play a key role
in improving the physicochemical properties of active ingredient
by blend prepared with other excipients.
Excipients with beneficial physicochemical properties can be
used to overcome the less desirable properties of drug substance
[3,4]. High drug loading formulations have recently been drawing
increased attention due to patient preferences for smaller dosage
⇑ Corresponding author.
E-mail addresses: php12kk.moravkar@pg.ictmumbai.edu.in (K.K. Moravkar), pd.
amin@ictmumbai.edu.in (P.D. Amin).
1
Address: Department of Pharmaceutical Science and Technology, Institute of
Chemical Technology, Matunga, Mumbai 400019, Maharashtra, India.
ucts. Maximization of drug loading can effectively decrease dosage
form sizes as well as reduce manufacturing batch sizes to provide
cost savings [5].
In many cases direct compression of drug with the binder are
unsuitable for tableting due to poor compactibility properties.
Roller compaction dry granulation has its own issues such as loss
of compactibility and wet granulation of drug substances are diffi-
cult; especially when compounds with poor solubility, wettability
and small particle size at drug loading is above 70%. [6]. To over-
come these problems, a novel continuous granulation method
called moisture-activated dry granulation (MADG) was developed
by Ullah et al. [8]. MADG is a 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. The whole process can ideally be
performed within a conventional high shear granulator, hence this
process is called as ‘‘one-pot process”. All components and func-
tional excipients required for granulation and compression are
blended in same pot; so that there is no need to transfer of granule
intermediates to other equipment; Thus MADG process is the ideal
granulation process for the manufacture of solid dosage forms con-
taining high dose drug substances. MADG has very few variables,

http://dx.doi.org/10.1016/j.apt.2017.02.015
0921-8831/Ó 2017 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.
 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280
resulting in lesser need for expensive PAT technology. For
hydrophobic drugs- a small amount of water used to make the bin-
der evenly tacky in the mixture which helps to granulate the
hydrophobic material. The MADG process can be divided into
two different stages: the agglomeration stage and the moisture
absorption stage. During agglomeration, a major portion of the for-
mulation containing the drug is agglomerated. The drug is blended
with filler and binder in the powder form. A small amount (1–4%)
of water is sprayed in the form of small droplets onto the blend
while blending. Water moistens the blend and this moisture makes
the binder to become tacky, resulting in formation of moist
agglomerate particles. It is known that size of granules depends
on the quantity of water used in process of granulation. Process
of milling is required, if the size of granule is more than the
desired. However, MADG requires a little water, so that it requires
neither milling nor heat drying. Another advantage of this process
is that there is no issue of end point sensitivity as it is major con-
cern in wet granulation. In the second stage following agglomera-
tion an absorbent powder i.e. water insoluble filler component is
added while blending. It absorb most of the excess water, resulting
in the formation of dry and free flowing granules. After this, a
disintegrant can be added and blended, followed by the lubricant
[6–10].
Literature addresses MADG granulation process; however for-
mulation of high dose drug loaded IR tablet preparation with lim-
ited excipients was not observed. A comparison, using a sematilide
hydrochloride formulation, of moisture-activated dry granulation
in a planetary mixer was performed vs. traditional wet granulation
in a planetary mixer, roller compaction, and direct compression
[11]. The moist granulation technique was also compared to wet
granulation and direct compression using an acetaminophen for-
mulation [12]. Effect of formulation factor on moist granulation
techniques was studied to develop controlled release tablet [13].
Excipient – excipient interaction also studied by using MADG pro-
cess [14].
The goal of present study is to develop a new green process
methodology which utilizes less energy applicable to number of
formulations containing water soluble or insoluble high drug load-
ing drugs. The significant feature of this new methodology is that
an excipient is added to the formulation only when performance
improvement of the finished product is required. The study was
conducted with three different binders: PVP K 12, maltodextrin
DE 16 and HPC for granule formation and comparative study of
their performance was also studied.
Metformin HCl, is an oral hypoglycemic agent of the bigua-
nide class used in the treatment of non-insulin dependent dia-
betes mellitus (NIDDM), Metformin HCl is highly water soluble
(>300 mg/ml at 25 °C), hygroscopic and presents stability prob-
lems. It is highly crystalline and has poor compaction properties,
difficult to form tablets by direct compression and wet granula-
tion. There is a pharmaceutical challenge to develop the high dose
formulation of metformin used clinically [15,16]. Ferrous
ascorbate is indicated in the treatment of iron deficiency anemia.
It is hygroscopic, highly water soluble, dark violet poorly com-
pressible fine powder [17]. Acetaminophen is an analgesic,
shows elastic deformation and produces weak compact with
roller compaction. Also it gives too many fines or too many coarse
particle with wet granulation due to poor solubility and com-
pressibility [18,19]. These three drugs were selected as model
API’s to carry out these studies. The intent of MADG process is
to bind the drug with excipients to create free flowing, compati-
ble, and nonaggregating granules. The prepared granules were
characterized for granule size distribution, flowability, dissolution
and compactibility. Resultant granulations were compressed into
tablets. Tablet performance were evaluated by in vitro dissolution
and other tests. This paper summarizes the results obtained in
1271
development of this study and discusses technical and economic
benefits of the proposed methodology.
2. Material
Acetaminophen (APAP) USP and Ferrous ascorbate were
obtained from Bajaj Healthcare Pvt Ltd., Mumbai, India. Metformin
HCl was purchased from Shweta Pharma, Mumbai, India. Plas-
doneÒ K 12 (Polyvinylpyrrolidone, PVP USP) was gifted by ISP,
Wayne, NJ and AeroperlÒ 300 pharma was provided as gift sample
by Evonik Degussa India Pvt Ltd, Mumbai, India. MaltodextrinDE16
(SUNMALTÒ) was purchased from Gujarat Export Limited, India;
Hydroxypropylcellulose (HPC-SSLÒ) was procured from NIPPON
SODA, Mumbai, India; Magnesium stearate was purchased from
Nitika Pharmaceutical Specialties Pvt. Ltd., INDIA.
3. Methods
3.1. Formulation composition for moisture activated dry granulation
(MADG)
A batch size of 240 g was considered for formulation trials as
shown in Table 3. Drugs were sifted through 16 mesh screen and
blended with the low viscosity grade binders [20]: Povidone K12,
Maltodextrin DE16 and Nisso HPC SSL and granulated by spraying
2% w/w water for 15 s in the granulation bowl at 700 rpm impeller
speed for 5 min. Followed by Aeroperl Ò300 Pharma was added as a
moisture absorbent at 700 rpm impeller speed for next 2 min. Pre-
sieved lubricant magnesium stearate was added to the above blend
in the granulator and blending was continued for 0.5 min at
300 rpm [21].
3.2. Measurements of physical properties of granules
3.2.1. Particle size distribution
Sieve analysis was carried out using 25 g of granules and a ser-
ies of U.S. standard sieves of mesh size corresponding to 850 mm,
600 mm, 300 mm, 250 mm, 180 mm, 150 mm, 75 mm. The granules
were placed on the top sieve and mechanically shaken for 10 min
using Electromagnetic sieve shaker (Electrolab Pvt Ltd.). The frac-
tion retained on each screen was weighed and the particle size dis-
tribution was determined.
3.2.2. Scanning electron microscope
Scanning electron microscopy (SEM) was performed to observe
granule growth and shape development as a function of polymeric
binder. Microscopic images of granules were taken using XL 30
Model, JEOL 5400, Japan.
3.2.3. Compressibility
Flow properties of the granules were evaluated by determining
the compressibility index and angle of repose. The bulk and tapped
densities of the final blends were determined by applying 1250
taps to 10 g of sample in a 1000 mL measuring cylinder using pow-
der tester (PT-R, Hosokawa micron). The % compressibility was
determined using the formula defined as [(DT
DB)/DT], where DT
is the tapped density and DB is the bulk density [22]. The hausner
ratio was calculated by formula as the ratio of tapped and bulk
density: [DT/DB]. The flowability was classified according to US
pharmacopeial convention benchmarks from excellent to passable.
3.2.4. Angle of repose
Angle of repose was measured by the fixed-funnel and free-
standing cone method [22]. 10 g of sample was placed in funnel
and allowed to fall from fixed height of 2 cm till a powder heap
1272 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280
was formed at the base. The diameter and radius of the powder
heap was measured. The angle of repose was calculated using
the formula.
tan h ¼ h=r
where
h = angle of repose,
h = height of the heap from the base funnel stem,
r = radius of the heap.
3.2.5. Moisture content of the granules
The moisture content of the granules for each batch was deter-
mined on a Citizen MB-50 moisture balance (Citizen Scale (I) Pvt.
Ltd, address.). 4 g of - sample was - placed onto the sample pan,
and the heating cycle was started (0–4 min). The percentage mois-
ture content was calculated from the weight loss of the sample on
heating. The experiment was performed in triplicate. The instru-
ment was allowed to cool between the tests.
3.2.6. Granule growth
Particle size was measured by using a Mastersizer 2000 MU
(Malvern Instruments Ltd., Malvern, UK) based on integrated light
scattering principle. Particle size was determined for plain drugs
and other ingredients used in MADG formulations. The particle-
size distribution of granules prepared by MADG was determined
by electromagnetic sieve shaker (Electrolab Pvt Ltd.) using follow-
ing sieves: 850 lm, 600 lm, 300 lm, 250 lm, 180 lm, 150 lm,
75 lm. Results were presented as particle-size distribution and
as the particle size at which 50% (lm) of particles were below
the given size denoted as the median particle diameter, or d50.
3.2.7. Granule strength
The granule strength of all compound granulated with various
binders was measured. To evaluate the breakage behavior of gran-
ules, a repeated impact test was used. In this test, about 200 gran-
ules of each sample were fed into 100 particle-wall impacts per
second with controlled impact velocity. The fracture fraction was
calculated using the following formula [10,23].
Fracture fraction ¼ ðsample weight

weight retainedÞ=sample weight
3.3. Preparation and evaluation of tablets
Granules were compressed into tablets, and evaluated for
parameters affecting tabletting behavior. Tablets were punched
using CadmachÒ rotary tablet press machine equipped with
9/18 in diameter, standard concave punch to a final tablet weight
of 600 mg. Tablets were compressed at different compression
forces 2.5 kN, 5.0 kN, 7.5 kN, 10.0 kN and 15.0 kN and 25 rpm. Con-
tent uniformity, weight variation, thickness and hardness of the
tablets was determined for 10 representative samples for each
formulation.
3.3.1. Tablet hardness and thickness
Hardness of the tablets (kg/cm square) was measured using -
Electrolab hardness tester model: EH01. Tablet thickness (microm-
eter) was measured by Vernier calliper (Electrolab Pvt Ltd.). Ten
tablets were subjected to use for evaluation of each parameter.
Tensile strength was calculated as 2F/(p⁄ D⁄ T): where F is the
hardness, and D and T are diameter and thickness of the tablets.
3.3.2. Tablet disintegration time
The disintegration time was determined (n = 6) using 2 station
disintegration tester ED-2L (Electrolab Pvt Ltd.) (n = 6). Tests were
performed in distilled water at 37 ± 2 °C using disk’s method.
3.3.3. Friability
Tablet friability was determined by Duel drum friability tester
with weighing scale interface (EF-2 W, Electrolab Pvt. Ltd.). This
consist of a plastic chamber that revolves at 25 rpm, dropping
the tablets through a distance of six inches in the friabilator, which
was operated for 100 revolutions. The tablets were reweighed.
Compressed tablets that lose less than 0.5–1.0% of the weight were
considered as acceptable. The friability of the tablet was calculated
as a percentage according to the following equation:
½ðInitial weight
Final weightÞ=Initial weight  100 ¼ Friability
3.3.4. Tablet weight variation
Individual tablets were weighed (n = 10) and average tablet
weight was determined. The Tablet weight variation was calcu-
lated by the differences observed in the weight of tablet when
compared to average tablet weight. The variability was determined
as % RSD for 10 tablets.
3.3.5. Content uniformity
Tablets sampled from beginning, middle, and end of a compres-
sion run were individually assayed by UV spectrophotometer and
the variability (%RSD) in assay was calculated as percentage of
average assay.
3.4. In vitro drug dissolution study for IR tablet formulation
Drug release from formulated and commercially available
tablets of respective drugs, was performed using USP < 711 > Dis-
solution apparatus II at 50 rpm and 37 °C ± 0.5 °C by dissolution
tester (Electrolab Pvt Ltd.). Withdrawn sample quantity was 5 ml
at sampling time point. The average of the results was considered.
Table 1 lists the dissolution parameter of all three drugs.
3.5. Stability studies
Accelerated stability studies were conducted for all the formu-
lations as per ICH guidelines (40 ± 2 °C and 75 ± 5% RH) for the per-
iod of 6 months in a stability chamber (Thermolab, Mumbai, India).
The samples were placed in vials with bromobutyl rubber plugs
sealed with aluminum caps. Aliquots were withdrawn at 30, 60,
90 and 180 days and evaluated for the drug content and in vitro
drug release.
4. Result and discussion
4.1. Physical attributes
Table 2 shows the physical attributes of these three drugs.
4.2. Granule formation and particle size distribution by sieve analysis
Granulations with different binders were found to be desirable
as no wall adhesions or big lump formation was observed. MADG
process has many advantages like it does not require drying,
milling of granules. Aeroperl Ò300 Pharma (granulated colloidal
silicon dioxide) was added as a moisture absorbent. It is a part of
formulation (Table 3). This moisture absorbent come into contact
with moist agglomerates, they picks up moisture from the agglom-
erates and redistribute moisture within the mixture. The entire
 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280 1273

Table 1
Dissolution parameter of given API’s.

Sr. no. API Disso. Medium (900 ml) Sampling time point (min) UV absorbance (nm)
1 Metformin HCl Phosphate buffer (pH 6.8) 15,30 233
2 Acetaminophen Phosphate buffer (pH 5.8) 15,30 243
3 Ferrous ascorbate 0.1 N HCl 15,30,45 535

Table 2
Physical attributes of given API’s.

Attributes Metformin HCl Acetaminophen Ferrous ascorbate

Physical structure

Particle size (lm) 34–128 27–68 14–73

Water solubility (mg/ml) >100 0.07 98
Contact angle (°) 29 134 65

Metformin HCl
Maltodextrin PVP K 12 HPC SSL

100
% RETAINED

80
60
40
20
0
850 600 300 250 180 150 75 PAN
PARTICLE SIZE (µM)
1.1
Acetaminophen
Maltodextrin PVP K 12 HPC SSL

100
% RETAINED

80
60
40
20
0
850 600 300 250 180 150 75 PAN
PARTICLE SIZE (µM)
1.2
Ferrous ascorbate
Maltodextrin PVP K 12 HPC SSL

100
% RETAINED

80
60
40
20
0
850 600 300 250 180 150 75 PAN
PARTICLE SIZE (µM)
1.3

Fig. 1. Schematic representation of particle size distribution showing by given API’s. 1.1. Metformin HCl, 1.2. Acetaminophen, 1.3. Ferrous ascorbate.
1274 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280

2.1

2.2

2.3
Fig. 2. SEM images of granules formed by different polymeric binders. 2.1. Maltodextrin DE16, 2.2. PVP K12, 2.3. HPC SSL.

Table 3
Percent composition of MADG formulation.

Ingredients Formulations
A B C D E F G H I
Active 83.33 83.33 83.33 83.33 83.33 83.33 83.33 83.33 83.33
Maltodextrin 12.67 – – 12.67 – – 12.67 – –
PVP K 12 – 12.67 – – 12.67 – – 12.67 –
HPC – – 12.67 – – 12.67 – – 12.67
Aeroperl 300 Pharma 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
Water 2 2 2 2 2 2 2 2 2
Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Total 100 100 100 100 100 100 100 100 100

Actives – A,B,C-Metformin HCl; D,E,F -Ferrous ascorbate; G,H,I –Acetaminophen.

mixture thus becomes relatively dry. Although some of the mois-
ture is removed from the wet agglomerates, the larger particles,
may break up. but most of these agglomerates remain almost
intact. This process results in a granulation with uniform particle
size distribution.
AeroperlÒ 300 Pharma is used in MADG to absorb and distribute
the small amount of water that is used to make the binder evenly
tacky in the mixture. The amount of AeroperlÒ 300 Pharma used in
the process depends on the necessary binder and therefore water
concentration used in the formulation. Usually 1.5 wt.% of Aerop-
erlÒ 300 Pharma is sufficient if the water used is up to 2 wt.%
[24,25].
The particle size of the granules was in the 600–250 lm range.
Particle size distribution of granules of each formulation is shown
 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280 1275

Table 4
Primary particle size data.

Ingredient d10a (lm) d50a (lm) d90a (lm) f (d90/d10) Bulk density (g/mL
1) Tap density (g/mL
1)
Metformin 19.1 69.5 123.2 6.45 0.45 0.67
Acetaminophen 11.6 44.7 68.1 5.87 0.43 0.68
Ferrous ascorbate 22.7 40.2 72.9 3.21 0.46 0.68
Maltodextrin 17.7 52.5 114.2 6.45 0.43 0.63
PVP K12 18.6 41.8 108.9 5.85 0.44 0.63
HPC SSL 6.1 39.3 110.4 18.09 0.45 0.65
Aeroperl Ò300 Pharma 15.6 32.8 62.1 3.98 0.56 0.67
Magnesium stearate 4.5 7.9 14.2 3.15 0.42 0.71
a
d20, d50 and d90 – particle sizes at which 20, 50 and 90% (lm) of the sample is below this given size.

Table 5
Particle size distribution of granules prepared by MADG.

Formulation granules using d10a (lm) d50a (lm) d90* (lm) f (d90/d10) Bulk density (g/mL
1) Tap density (g/mL
1)
Maltodextrin 211 356 678 3.21 0.596 0.664
PVP 196 290 590 3.01 0.523 0.601
HPC 110 220 327 2.97 0.500 0.594
a
d20, d50 and d90 – particle sizes at which 20, 50 and 90% (lm) of the sample is below this given size.

Metformin HCl
50
% weight loss

40
30
20
10
0
0 5 10 15 20 25 30 35 40 45 50
Impact speed (m/s)
Maltodextrin PVP HPC
3.1
Acetaminophen
50
% weight loss

40
30
20
10
0
0 5 10 15 20 25 30 35 40 45 50
Impact speed (m/s)
Maltodextrin PVP HPC
3.2
Ferrous ascorbate
50
% weight loss

40
30
20
10
0
0 10 20 30 40 50
Impact speed (m/s)
Maltodextrin PVP HPC
3.3
Fig. 3. Schematic representation of granule strength of given API’s. 3.1. Metformin HCl, 3.2. Acetaminophen, 3.3. Ferrous ascorbate.

in Fig. 1. These plots demonstrate that granulated powder blends to be maximum for maltodextrin, intermediate for PVP binder
containing same binder but different drugs, shows some common and minimum for HPC (Fig. 2). This phenomenon is due to differ-
features in the particle size distribution. Granule growth is found ence in viscosity of these binder. It is known that micromechanical
1276 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280

Table 6
Physical properties of the granules.

Drug Binder Bulk density (g/mL
1) Tap density (g/mL
1) Carr’s index (%) Hausenr’s ratio Moisture content (%) Angle of repose (°)
Metformin Maltodextrin 0.625 0.675 7.5 1.08 2.23 22.9
PVP K 12 0.625 0.675 7.5 1.08 2.21 23
HPC 0.55 0.625 11.1 1.13 2.8 26.5
Acetaminophen Maltodextrin 0.56 0.625 13.6 1.17 2 26.8
PVP K 12 1 0.7 20.63 1.26 2.8 25.3
HPC 1 0.7 20.63 1.26 2.56 26.9
Ferrous ascorbate Maltodextrin 0.48 0.64 25 1.33 2.78 27.6
PVP K 12 0.51 0.62 18.36 1.22 2.56 24.4
HPC 0.44 0.59 25 1.35 2.89 30.6

Table 7
Tablet weight, thickness and hardness.

Drug Binder Weight (g) (avg.) Weight %RSD Thickness (mm) avg. Thickness % RSD Hardness (kg/cm2) Hardness % RSD
Metformin Maltodextrin 0.6 0.88 6.433 0.09 10.73 1.94
PVP K 12 0.595 0.59 6.436 0.09 10.57 0.55
HPC 0.551 0.91 6.436 0.09 9.73 2.14
Acetaaminophen Maltodextrin 0.596 0.86 5.123 0.00 10.83 1.07
PVP K 12 0.6 1.76 5.116 0.14 10.27 1.49
HPC 0.596 1.43 5.123 0.14 10.40 0.96
Ferrous ascorbate Maltodextrin 0.604 1.13 4.15 0.11 10.27 2.98
VP K 12 0.600 0.35 4.143 0.11 10.03 1.48
HPC 0.598 2.03 4.146 0.11 10.13 1.51

properties of interparticle bridges formed by different binder
depends on their viscosity. For example PVP has lower viscosity
than HPC, hence it promotes better granule nucleation process
[26–28]. This was supported by the results of the sieve analysis
of the granules. As shown in Fig. 2, the MADG method gave equiv-
alent intermediate size of granules with almost no fines.
4.3. Granule growth
The results for particle-size distribution and bulk and tapped
densities of mixtures are presented in Table (4 & 5). Factor (f) in
Tables 4 and 5 is a measure of particle-size distribution width
defined as the quotient between d10 and d90. The results for f indi-
cate broader particle-size distribution for a pre granulation mix-
ture compared to tableting mixture prepared using maltodextrin,
PVP and HPC, which is evident for formulation of granules by
MADG. Comparing the initial pre granulation mixtures with gran-
ules prepared by MADG, it can be seen that granules showed
higher densities in comparison with their initial mixture. This
could be elaborated as in a wide particle-size distribution, different
particle rearrangement can take place, in which the gaps between
larger particles were filled by smaller particles, which results in
denser packing [29].
4.4. Granule strength
The strength of granules was found to be varied significantly in
all formulations. Fig. 3 shows the results of attrition impact test for
all formulated granulations. HPC-containing granules showed lar-
ger weight loss at low impact. Maltodextrin containing granules,
were found to be much stronger at all conditions of the impact
speed. Whereas PVP showed intermediate results. The results of
the impact test indicate that granule strength of formulations with
a binder appears to be dominated by properties imposed by a bin-
der rather than constituent API. As previously reported, microme-
chanical properties of interparticle bridges formed by different
binders differ significantly. It could be concluded that for each
compound, granules formed with matodextrin were significantly
stronger during impact test than granules formed with PVP or
HPC [18].
4.5. Compressibility (% C)/compressibility index
The values of the compressibility factor for the batches are sum-
marized the data in Table 6. The compressibility factor is measure
the flow characteristics of a granulation. It is generally recognized
that the higher the percent compressibility of a material, the
poorer is its flowability and vice versa. It is generally desirable to
have values of 15% or lower. Compressibility index values of 25%
or higher indicating poor flow [30]. The data in Table 6 shows that
all the API’s had very good flow property with binders. In formula-
tion with PVP the flow property increases significantly because of
uniform size of granules.
4.6. Angle of repose
Angle of repose is a characteristic related to interparticulate
friction or resistant to movement of particle. It has been used to
characterize flow property of granule. Formulation of ferrous
ascorbate with maltodextrin and HPC was found to show highest
angle of repose (27° and 30° respectively), while other granules
of Metformin HCl and acetaminophen had repose angle in the
range of 20–25°. (It is generally desirable to have values of 30° or
lower. Values of 40° or higher indicates poor flow) [30].
4.7. Moisture content
Moisture plays a critical role in compression. One of the most
common causes of capping in tablets is inadequate moisture in
the blend ready for compression. Moisture may also affect the flow
characteristics of the powder. It should be noted that, moisture
absorbent AeroperlÒ 300 pharma is added while mixing in granu-
lation process. The moisture absorbent picks up moisture form
moist agglomerates resulting in moisture redistribution within
the mixture. When this happens, the entire mixture becomes rela-
tively dry. Result are shown in Table 6.
 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280 1277

Tensile strength (MPa)

Metformin HCl
5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20
Compression force (kN)
Maltodextrin PVP HPC
4.1
Acetaminophen
Tensile strength (MPa)

5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20
Compression force (kN)
Maltodextrin PVP HPC
4.2
Ferrous ascorbate
Tensile strength (MPa)

5
4
3
2
1
0
0 2 4 6 8 10 12 14 16 18 20
Compression force (kN)
Maltodextrin PVP HPC
4.3
Fig. 4. Schematic representation of tensile strength of given API’s. 4.1. Metformin HCl, 4.2. Acetaminophen, 4.3. Ferrous ascorbate.

Table 8 Table 9
Tablet content uniformity results. Tablet disintegration and friability.

Drug Binder Mean tablet Assay (%) % RSD Drug Binder Disintegration time (min) Friability (%)
Metformin Maltodextrin 98.23 0.79 Metformin Maltodextrin 3 0.1
PVP K 12 98.20 0.37 PVP K 12 4 0.12
HPC 97.67 0.70 HPC 5 0.15
ELCEPHASE-500Ò 5 0.3
Acetaaminophen Maltodextrin 99.73 1.21
PVP K 12 99.33 1.10 Acetaaminophen Maltodextrin 3 0.2
HPC 99.13 1.90 PVP K 12 5 0.26
HPC 4 0.24
Ferrous ascorbate Maltodextrin 98.37 0.74
CrocinÒ 3.5 0.36
PVP K 12 99.67 0.80
HPC 99.90 1.84 Ferrous ascorbate Maltodextrin 6.8 0.36
PVP K 12 6 0.15
HPC 7 0.29
Hemobest-XTÒ 8.5 0.45
4.8. Preparation and evaluation of tablets

4.8.1. Tablet weight, thickness and hardness

4.8.2. Tensile strength
As mentioned earlier, Hardness of the tablets (kg/cm square)
Tensile strength of tablets was evaluated as a function of the
was measured using - Electrolab hardness tester model: EH01.
compression force. The results are shown in Fig. 4. A desired tablet
Tablet thickness (micrometer) was measured by Vernier calliper
tensile strength profile should BE 2.0 MPa or higher at 10 kN com-
(Electrolab Pvt Ltd.). Ten tablets were subjected to use for evalua-
paction force. Granulated samples with all binders did not cap dur-
tion of each parameter. All Maltodextrin, PVP and HPC granulated
ing ejection and sticking was much less pronounced. The
samples did not show capping or sticking while tableting. No sig-
maximum tensile strength was relatively high, and the profile
nificant difference in thickness and hardness was observed for
had a desired slope. For both acetaminophen and ferrous ascorbate
tablets made from all binders (Table 7).
granules, PVP and especially maltodextrin improved the compress-
1278 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280

Table 10
In vitro dissolution profile for IR formulation.

Drug Binder % Release in time

15 min ± % RSD 30 min ± % RSD 45 min ± % RSD
Metformin Maltodextrin 85.87 ± 0.07 90.86 ± 0.14 –
PVP K 12 86.23 ± 0.13 91.88 ± 0.07 –
HPC 86.40 ± 0.23 89.89 ± 0.29 –
ELCEPHASE-500Ò 87.07 ± 0.24 89.95 ± 0.25 –
Acetaaminophen Maltodextrin 84.73 ± 0.18 85.62 ± 0.08 –
PVP K 12 85.28 ± 0.12 87.41 ± 0.07 –
HPC 85.29 ± 0.08 86.88 ± 0.03 –
CrocinÒ 85.87 ± 0.10 86.96 ± 0.05 –
Ferrous ascorbate Maltodextrin 27.81 ± 0.07 57.40 ± 0.30 78.13 ± 0.04
PVP K 12 27.50 ± 0.18 55.80 ± 0.05 77.86 ± 0.15
HPC 27.20 ± 0.28 54.94 ± 0.22 76.20 ± 0.06
Hemobest-XTÒ 29.80 ± 1.01 58.14 ± 0.23 79.93 ± 0.012

Metformin HCl
100

80
% released

60

40

20

0
0 15 30 45
Time in minute
Maltodextrin PVP K 12 HPC ELCEPHASE-500®
5.1.
Acetaminophen
100
% released

80
60
40
20
0
0 15 30 45
Time in minute
PVP K 12 HPC Maltodextrin Crocin®
5.2.
Ferrous ascorbate
100
80
% released

60
40
20
0
0 15 30 45
Time in minute
PVP K 12 HPC Maltodextrin Hemobest-XT®
5.3.
Fig. 5. Schematic representation of drug release profile of given API’s. 5.1. Metformin HCl, 5.2. Acetaminophen, 5.3. Ferrous ascorbate.

ibility (Fig. 4), For HPC containing granules, the slope of the com-
pactibility was relatively low, so that the desired tensile strength
could only be developed at relatively high compaction force. Unlike
acetaminophen and ferrous ascorbate, the tensile strength was rel-
atively high for metformin granules with all polymeric binders. The
results revealed that polymeric binders play a vital role in improv-
ing compactibility of granules, especially when compactibility of a
pure compound is low [18].
4.8.3. Tablet content uniformity
Tablets tested from each formulation met the USP Uniformity of
Dosage Units < 905 > criteria. This all the results were in the range
 K.K. Moravkar et al. / Advanced Powder Technology 28 (2017) 1270–1280 1279

Table 11
Stability study for IR formulation.a

Formulation 0 days 30 days 60 days 90 days 180 days

code
Drug Drug Drug Drug Drug Drug Drug Drug Drug Drug
content (%) release (%) content (%) release (%) content (%) release (%) content (%) release (%) content (%) release (%)
A 98.3 90.98 97.12 97.25 96.83 96.10 96.45 95.52 96.23 95.13
B 98.0 91.93 90.00 85.56 89.98 84.90 90.00 83.60 89.48 81.89
C 97.7 90.08 97.25 97.49 96.00 96.81 96.56 95.69 96.20 95.37
D 99.3 85.56 91.56 77.85 89.56 77.20 89.12 76.45 87.84 76.00
E 99.3 87.42 96.81 98.47 96.18 96.56 95.91 97.13 95.67 96.67
F 99.3 86.90 90.05 77.52 88.00 76.89 87.59 76.89 85.73 75.96
G 98.7 78.09 98.58 97.90 97.86 95.99 95.23 96.48 95.73 95.90
H 99.7 77.87 85.30 76.30 85.12 76.00 82.89 75.52 82.10 75.82
I 99.0 76.23 98.26 86.96 96.76 85.56 95.85 83.24 95.33 82.56
a
% Drug release determined at 30 min for metformin and acetaminophen formulations (A-F) and at 45 min for ferrous ascorbate formulations (G-I) as par USP guidelines.

of 85.0–115.0% with a relative standard deviation (RSD) of less
than or equal to 2.0%. The results are shown in Table 8.
4.8.4. Tablet disintegration time
The proposed formulation has no disintegrating agent.
Although, Tablets from each formulation processed by MADG dis-
integrated in less than 10 min. The composite range of disintegra-
tion time was 3–7 min. The result suggested that moisture
absorbent (Aeroperl 300 pharma) might have an effect on disinte-
gration time due to its high absorptivity to adhere to water. The
results are shown in Table 9.
granulation technique is successful in development of formula-
tions with high drug loading for three model drugs. MADG can
be easily explored as a granulation technique for drugs with differ-
ent properties. It minimizes the total number of excipients thus
decreasing the complexity of the formulation and increasing the
scalability of the formulation.
Acknowledgement
The authors are thankful to Evonik Degussa India Pvt. Ltd,
Mumbai for providing necessary facilities during research work.

4.8.5. Friability
Tablet friability of all the formulations was very low. The com-
posite range including all formulation was 0–0.5%. No cracked or
broken tablets were observed. The results are shown in Table 9.
4.8.6. In vitro dissolution profile for IR formulation
Invitro drug release profile were characterized. The results are
as shown in Table 10. All IR tablet formulations prepared by MADG
granulation techniques were found to show compliance with the U.
S. pharmacopoeia i.e. 80% release within 30 min for metformin,
acetaminophen and 75% release within 45 min for ferrous ascor-
bate drug. Formulations prepared with maltodextrin DE 16 showed
faster release than others. These results may be evaluated as
improvement of the wettability due to hydrophilic nature of mal-
todextrin more than others polymer binder used in the formula-
tions. Marketed product of respective drug tablets were also
compared with the prepared formulations, no significant differ-
ences were observed in drug release profiles (Fig. 5).
4.9. Stability study
The prepared formulations did not show any significant change
in drug content and in vitro drug release during stability study
(Table 11). MADG was found to give stable formulations for the
three drugs with three different polymer binders.
5. Conclusion
With the proposed methodology of MADG, it is possible to pro-
duce high drug loaded granules for drugs with significantly varying
properties and attributes. MADG is found to be a simple cost-
effective process yielding formulation with desirable pharmaceuti-
cal quality parameters. The study can conclude that the com-
pactibility and dissolution profiles of product made by this
method are satisfactory. A drug loading of >80% is possible using
MADG technique. MADG based formulations shows dissolution
performance comparable to commercial formulation. MADG as a
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