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Isolation and Characterization of Microcrystalline Cellulose Derived from
Plants as Excipient in Tablet: A Review
Nagina Belali
1,2,*
, Anis Y. Chaerunisaa
2
, Taofik Rusdiana
2
1. Department of Pharmaceutics, Faculty of Pharmacy, Kabul University, Jamal Mena, 1006, Kabul,
Afghanistan
2. Department of Pharmaceutics, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Jatinangor KM
21.5 Bandung-Sumedang, 45363
Received: 9 May 2019/Revised: 15 May 2019/Accepted: 17 May 2019/ Published: 13 Jun 2019
ABSTRACT
Microcrystalline cellulose (MCC) is a versatile and frequently used material in different industries such as
pharmaceuticals production, medical, cosmetics, and food industry. Its qualities of being inert, economic,
compatibility, compatibility, non-toxicity, biodegradability, good mechanical properties, high surface area,
variety and availability of different grades and biocompatibility has made it very popular. Many research
has been done on MCC to isolate it from different plant sources that are economical and eco-friendly. MCC
is extracted from α cellulose that is abundant in nature as most of MCC is produced from wood. However,
new eco-friendly sources with changes in methods of isolation have been applied for the production of
MCC. In this review MCC isolated from different plant-based resources, extraction process parameters, the
origin of raw material and its influence on critical material attributes of MCC has been outlined and
discussed thoroughly. Since these critical material attributes have a significant effect on tablet making
process parameters (compressibility, compatibility and etc) and its post-compression characters.
Keywords: Microcrystalline cellulose, isolation, characterization, raw material, tabletability
1. Introduction
Microcrystalline cellulose (MCC) is a partially
depolymerized purified derivative of α-cellulose
that has alpha bonds and cannot be digested and
absorbed in the human body because humans do not
have the enzyme to break those bonds.
Microcrystalline cellulose is a white, crystalline
powder that does not have any taste or odor. This
makes it a good choice to be applied in different
industries such as pharmaceutical, food, and
cosmetics [1]. It has marked characteristics of good
strength, fibrous nature, crystallinity, light in
weight, biocompatibility, water insolubility, and
biodegradability that makes it a choice excipient in
today’s era of renewables with diverse applications.
In the modern era, environmental issues are of
significance, and most materials are expected to be
green that won’t harm our environment and are
degradable from natural sources, however, most of
MCC is produced from wood pulp and purified
cotton that is harmful to the ecosystem. Therefore,
through last two decade efforts has been done to
isolate MCC from natural sources and wastes of
plants that are either eco-friendly and economical,
as it can be isolated from any material that has high
cellulose concentration [2]. Many studies have
reported different cheap sources that would be
discussed and their properties in sense of how good
they are along with results of their characterization
would be presented.
MCC was first discovered by Battista and Smith
in 1955 and was commercialized by the name of
Avicel. In 1964 it was introduced as a direct
compression tableting excipient under name of
Avicel PH that was later registered in the National
formulary, in 1966 until now it is produced by more
than 10 suppliers around the world [3]. MCC is of
significance in regards to its unique characteristics
that make it an optimum excipient such as self-
disintegrating properties, water retaining
properties, good binding agent, compactibility at
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N. Belali et al / Indo J Pharm 2 (2019) 23-29
24
low pressures, compatible to most of APIs and even
has suspension stabilizing effects [4] [5]. MCC is
generally used as a filler due to its binding
properties and is preferred as one of the best filler
and binder for direct compression, because of its
good compactibility and compressibility properties
[6][7]. Its properties have been further enhanced by
combining it with other excipients or co-processing
it with other excipients to increase the functionality
of MCC. A study done by Nagin K. Patel in 1992
reveals that a combination of lactose with 50% of
microcrystalline cellulose give very good
compressible properties to tablets [8].
Rowe et al. reported that the compactability
index among five different brands of MCC was
different, also most important is crystallinity of
MCC that can significantly affect the dissolution of
API [9]. Another study by Suzuki et al reported the
effects of crystallinity on the dissolution of tablets,
where tablets of acetaminophen were produced
with MCC that was pulverized to decrease its
crystallinity. Tablets of acetaminophen with MCC
having crystallinity between 25-12% showed a
significant increase in dissolution of the drug [3].
Kimie et al also reported how the presence of MCC
even in small amounts can affect the stability of
acetylsalicylic acid by hydrolysis since MCC is
very hygroscopic. Also, the decrease in crystallinity
of MCC was depicted intentionally to see its effects
on the hydrolysis of API, as it tends to absorb more
moisture and water when crystallinity is decreased
[10].
As mentioned above a variety of sources have
been employed for isolation of MCC that have
different compactability and different attributes as
their raw materials and manufacturing conditions
are different. Significant differences in lignin
content, hemicellulose sugars, and composition,
particle size, and flow properties were analyzed
among four brands of MCC from Finland, India,
Ireland, and Japan by M. Landin et al, that
correlated with water-cellulose interaction and
particle size with flow properties [11]. A different
source of woods and fibers have variability of
chemical composition in terms of hemicelluloses,
lignin, and proportions of cellulose, and structural
organizations [12] that’s why MCC isolated from
the different source even on the basis of region,
would have different characteristics that we aim to
study and explain well in the present study.
2. Discussion
Microcrystalline Cellulose (MCC) isolation has
been done by a variety of techniques the general
process has been presented in figure I. Foremost the
number of lignocellulose compounds should be
evaluated in plant as it is made of cellulose,
hemicellulose, and lignin, lignin is the most
difficult to be separated from cellulose and is done
by physical, biological, chemical and combined
processes. After delignification and bleaching,
MCC is usually produced by acid hydrolysis with a
mineral acid that cleaves the paracrystalline or
amorphous regions while crystal domains having
high resistance would be maintained, and slurry
obtained is spray dried, type of acid used, time of
Figure 1. MCC manufacturing steps
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application and temperature play an important role
in particle size, crystallinity, and morphology of
MCC. Drying step is a critical step that will affect
the particle size distribution and moisture content
of MCC that are critical attributes for excipients,
MCC can be dried by Fluidized bed dryer, freeze
drying, microwaves and static oven after which
MCC is grinded to desired particle size [13].
On industrial scale cellulose is produced mostly
from cotton, wood pulp and lignocellulosic that
requires steps of delignification and bleaching but
Olevira et al prepared MCC from Bacterial
cellulose, Acetobacter xylinus (is the only known
species capable of producing cellulose on
commercial level) where these steps are not needed,
and thus have different properties such as lower
thermal stability [14]. MCC isolated from Jute by
Jahan et al concluded that high acid concentration
method produced MCC with better properties than
low acid concentration, as their MCC had good
thermal stability and crystallinity of 74%, which in
our point of view is because of using organic acid
as they had applied formic acid but in high
concentration [15]. MCC produced by different
methods of acid hydrolysis from different raw
material with resulting crystallinities has been
presented in table 1.
Lower crystallinity index shows that the
amorphous regions were removed with
hydrothermal treatment [13]. The total amount of
Table 1. Processing conditions and raw materials of MCC
Raw material
Acid Hydrolysis
Reference
Wood pulp cellulose
Sulphuric acid
[16]
Esparto grass fibers
Hydrochloric acid
[17]
Oil palm empty fruit bunch
Sulphuric Acid
[18]
Cellulose produced in the culture medium of
static Acetobacter xylinum
Sulphuric Acid
[14]
Rice straw and Banana plant waste
Alkaline acid pulping (10% NaOH,
H
2
SO
4
), acid-alkaline (5% H
2
SO
4,
10%
NaOH)
[19]
Cotton fabrics waste
Hydrochloric acid at 110-170˚C
[20]
Jute fiber
Formic acid 90%
[15]
Cotton silver
Sulphuric acid 55%
[21]
Roselle fibers
Hydrochloric acid
[22]
Pomelo Peel
Hydrochloric acid
[23]
Olong Tea waste
Hydrochloric acid
[24]
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water sorbed by MCC is proportional to its
amorphous material, thus MCC that has lower
crystallinity would have more sorbed water
compared to those with high crystallinity, that can
have a significant impact on the stability of water
sensitive APIs and would degrade [7]. However,
dissolution rates of acetaminophen tablets reduced
with decrease in crystallinity to about 37%, because
water penetration into tablets is increased Another
study done by Awa et al, effect of MCC
crystallinity on Acetylsalicylic acid tablets showed
that MCC with low crystallinity can hydrolyze
ASA to salicylic acid, that affects stability of
dosage form that is a much more important aspect,
that reveals the importance of MCC crystallinity on
pharmaceutical properties of tablets [10].
Moisture content is also critical property as it
has been seen that it can influence compaction
properties, tensile strength, and viscoelastic
properties of MCC in tablets. When the moisture
level is lower than 3% it won’t affect compaction
properties of MCC, however, increase in moisture
content to an optimum level will eventually
increase the strength of the tablet, that might be
because of decrease in interparticular distance and
increase in intermolecular attraction forces [25].
More than 3% of water content in microcrystalline
cellulose would disrupt hydrogen bonds that cross-
link hydroxyl groups on the cellulose chain,
resulting in a strength decrease [5].
Moisture content, particle size, tapped density,
conductivity, and pH have a significant effect on
tabletability of MCC, although conductivity and pH
have not been incorporated in Critical Material
Attributes (CMA) of MCC. Thoorens et al reported
that tapped density might be critical to tabletability
in addition to particle size and moisture content of
MCC, thus concluded that formulators should
identify CMAs to improve quality of the product
[26]. Particle size has minimum effects on
tabletability, however, variability in particle size
can impact on flowability which will, in turn, affect
tablet hardness, weight uniformity, content
uniformity. Using fine MCC would promote tablet
strength however it would affect flowability
because it increases cohesiveness [27]. A technical
note by Gamble et al on particle size distribution
and its effects on flow properties on conventional
MCC was elucidated that the proportion of
agglomerates of MCC particles in MCC especially
in avicel PH200 can improve its flowability,
because of increase in particle size but it can
promote segregation of particles on basis of their
size that would eventually affect the content
uniformity [28].
Another property that was reported to have a
significant impact on tabletability is particle
morphology, that is explained in terms of particles
length and diameter, as particles with higher L/D
ratio had better tablet strengths and another study
reported MCC morphology can influence the
dissolution of the drug [29]. Hydrolysis treatment
affects the size and surface morphology of MCC
and level of smoothness of particles, fewer
researches had used TEM to examine the surface
morphology of MCC but results of SEM presented
in most of the researches presented morphology of
MCC particles and no significant difference was
seen in their morphology presented in the table.
Trache et al and Adel et al reported that the
diameter of MCC from the market had large
diameter than MCC isolated from lignocellulosic
raw materials [17][30].
MCC is usually spray-dried that promotes
porous structure and gives it a low bulk density that
would facilitate compressibility that is one of the
attributes that makes MCC so popular, thus this
result can be drawn that low bulk density can
improve tabletability, although it would negatively
affect flowability [8]. This finding is inconsistence
with study by Dolker in 1993, that mentioned MCC
has high intraparticle porosity of 90-95% of the
surface area being internal, this high porosity
promotes swelling and disintegration of MCC
tablets, that is related to water penetration in the
hydrophilic matrix of tablet by disruption in
hydrogen bonds, at the same time if compaction
force is increased it would decrease water
penetration into the tablet and hence increasing
disintegration time [8] [26].
Nowadays, MCC is a commercial excipient that
is available since last 60 years with a price of
almost 4 dollars per kilogram, which is comparable
to or less than some other engineering fillers. It is
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produced worldwide by more than 10 companies,
several methods have been used for isolation of
pure MCC, physicochemical properties and
mechanical characteristics of MCC is variable on
the basis of the origin of raw materials and the
extraction process that has been discussed in detail
here and also presented by Thoorens et al.
3. Conclusion
Microcrystalline Cellulose is a diverse excipient
with widespread application that is considered one
of the best diluent. MCC is a cellulose derivative
that is abundant in nature thus can be isolated from
a number of raw materials, and a number of eco-
friendly, cheap, waste managing methods have
been applied for production of MCC. MCC has
widespread application in different industries and
as seen above it has been produced from different
raw materials with variability in parameters of
manufacturing process that has an impact on
Critical Material Attributes, and because of this
variability use of MCC from different suppliers
with different sources and different methods of
isolation should be validated, when used on
industrial scale. CMAs of MCC such as particle
size, moisture content, surface area, surface
morphology do impact the tabletability of MCC as
they influence flow properties of MCC. Since such
critical attributes are confirmed when applied in
specific formulations thus its control in different
batches, by different suppliers and the different raw
material is a difficult task. Thus policymakers, drug
manufacturers and suppliers of excipients should
synchronize their work so excipients processes and
functionality can be understood well.
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