Vol 2, Issue 2, 2020 (43-54)
http://journal.unpad.ac.id/idjp
*Corresponding author,
e-mail : margaretha17003@mail.unpad.ac.id (M. E. Putri)
https://doi.org/10.24198/idjp.v2i2.26422
2020 M. E. Putri et al
Preparation of Cellulose Nanocrystals and Compliance as Pharmaceutical
Excipient: a review
Margaretha Efa Putri
1
, Anis Y. Chaerunisaa
1
, Marline Abdassah
1
, Iman Rahayu
2
1
Department of Pharmaceutics, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang 45363,
indonesia
2
Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjajaran,
Sumedang 45363, Indonesia
Received : 21 Feb 2020/Revised : 23 Feb 2020/Accepted : 2 Maret 2020/Published : 23 June 2020
ABSTRACT
Cellulose nanocrystals is a cellulose derivates which has been widely researched and observed
as an chemical agent. Different with cellulose that has been widely used as pharmaceutical
excipient especially in solid dosage form, cellulose in nanocrystals form is not available in
pharmaceutical grade. Cellulose nanocrystals have different characteristics and quality which
are depend on its preparation including sourcing, isolation procedure, and hydrolysis reaction
involved. This difference is very important to deeply observed its impact in pharmaceutical
dosage form with different active ingredients. In addition, cellulose nanocrystals should meet
FDA requirement as pharmaceutical excipient. This review describe cellulose nanocrystals
preparation and its characteristics, its application to active pharmaceutical ingredients, and its
properties in order to meet FDA requirement.
Keywords: Cellulose, nanocrystals, pharmaceutical excipient
1. Introduction
Cellulose is widely used as a pharmaceutical
excipient, such as powdered cellulose,
microcrystalline cellulose, carboxymethyl
cellulose salt, cellulose acetate, cellulose acetate
phthalate, methyl-, ethyl-cellulose,
hydroxymethyl-, hydroxyethyl methyl-,
hydroxypropyl-, hydroxypropyl methyl-
(hypromellose), modified hypromellose. These
cellulose derivatives are commonly applied in
every pharmaceutical dosage form as polymeric
agents (1). These derivates have many weaknesses
that lead researchers to explore new excipient. A
new type of cellulose-derived excipient that has
been developed is cellulose nanocrystal. This
cellulose nanocrystals was first developed by
Ranby in 1951. He hydrolyzed wood cellulose
fibers with sulfuric acid and found that the
amorphous part disintegrated leaving highly
crystallinity nanoparticles (2).
Cellulose nanocrystal is cellulose crystals with
high crystallinity degree which are produced by
hydrolysis of cellulose polymer from plant, some
animals, or other resources (3). Cellulose is a
polymer that is composed of d-glucose unit which
is linked at carbon atom number 1 and number 4,
or 14, d-glucose monomer (4). Cellulose
polymer in nature usually in 500 of polymerization
degree with 243.000 molecular weight (1).
Cellulose is the main compound of the stem
system in plant (4) that supports the plant body.
Powder cellulose, microcrystalline cellulose, and
modified cellulose have been used widely in
pharmaceutical as excipient not only in solid
dosage form but also in semisolid dosage forms
(1). Although cellulose nanocrystal has not been
used yet, many researches were conducted to
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
44
describe cellulose nanocrystal and character as a
pharmaceutical excipient.
Cellulose sources
In the starting phase in plant growth, cellulose
is synthesised by merenkim cell and is transferred
from the cytoplasm into the plant cell wall. The
synthesis is catalyzed by cellulose sintase enzyme
to form the main microfibril in plant cell wall
besides matrix phase. Beside that noncrystalline
matrix phase contains pectin, lignin, and
hemicellulose (5). Cellulose is continuously
produced into the cell walls, and increasing its
polymerization degree and is found to more
elongated and thickened. Then, the thickened
cellulose squeezing organelles, likes cell nuclei,
mitochondria until cell death (6). This means, the
higher the body of plant, the longer the cellulose in
the form of fiber. Then, cellulose often calls with
plant fiber.
Based on the sources, cellulose is divided into
natural and synthesis cellulose (7). Natural
cellulose usually get from woody plant or herbs,
not only from the stem but also can be found in
fruit (coconut fiber), seed (cotton), and (sisal).
Moreover, the first synthesis cellulose has been
conduct without a biosynthetic pathway, using
glycosyl fluoride substrate in the cellulase enzyme
(8).
Cellulose also can be found in animal especially
in their fur, like hemp, llama, and camel,
moreover in bacteria, algae, and marine biota.
Waste from wood, agriculture, oil, sugar, fruit and
nut, textile, and conservation waste also contain
cellulose (3).
Cellulose isolation
The main production of world cellulose mostly
use wood form high plant include cellulose
production for pharmaceutical ingredient (1). In
nature form, cellulose fiber in woods (2-3 mm in
diameter) composed of 3 levels of fiber. First, a
thin fiber is in 50-100 µm, main fiber (10-20 µm)
which is composed of 70-75% cellulose, 15-20%
hemicellulose, 3% pectin, and 3% lignin, and the
smallest part is microfibril in 4-10 nm or 6000-
9000 degree of polymerization (6). To obtain high
purity cellulose, its necessary to remove lignin,
pectin, and hemicellulose.
Lignin in the unit phenylpropane from
precursor p-coumaryl alcohol (H), coniferyl
alcohol (G), dan sinapyl alcohol (S). Lignin has
alcohol, carbonyl, carboxylate, methoxyl, and
sulfonic acid. Lignin structure is usually different
based on sources, for example, lignin in grass that
contains nitrogen element (9). Lignin soluble in
water (in form lignosulfonate), soluble in ethanol,
methanol, and dioxane (solvent lignin), insoluble
in water and organic solvent (kraft lignin dan
hydrolyzed lignin) with glass temperature around
127-227°C (9). The main methods of the
extraction of lignin and cellulose from different
sources historically explored are hydrothermal,
acidic, alkaline, wet oxidation, ammonia fiber
explosion, organosolvent, and, most recently, ionic
liquid pretreatment methods (10).
Pectin can be completely removed when the
alkaline boiling process is integrated into fiber
bast. However, acid scouring does not help to
remove pectin molecular chains so that more
residual pectin is evident in the sample after acid
scouring (11).
Hemicelluloses chemically are a class of
polymers of sugars, including the six-carbon
sugars mannose, galactose, glucose, and 4-O-
methyl-D-glucuronic acid and the
five
-carbon
sugars xylose and arabinose. The number average
DP is about 100-200 sugar units for each
hemicellulose molecule. Hemicelluloses are much
more soluble and labile, that is, susceptible to
chemical degradation, than is cellulose. They are
soluble in 18.5% NaOH. The low molecular
weight hemicelluloses become soluble in dilute
alkali at elevated temperatures, such as in kraft
cooking (12).
In synthesis cellulose process, pectin, lignin,
and hemicellulose is removed from fiber and
cellulose trough acid treatment, alkali boiling
treatment, and bleaching (13,14). an alkaline
process solubilizes most of pectins and
hemicelluloses. A standard procedure would be the
treatment of the pulp free of extractives in 2-5
wt.% NaOH or KOH with a solid to liquid ratio of
1:20, stirring the solution at 80°C for 2 hours.
After washing until neutral pH, several bleaching
cycles are performed to remove lignin. Bleaching
agents break down phenolic molecules present in
the lignin and remove the by-products of this
reaction, thus bleaching the material, usually use
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
45
chlorine agent, hydrogen peroxide, acetic acid, or
sulphuric acid . After several washing and cleaning
steps, the pulp is ready to hydrolyze (13,15).
Chemical properties of cellulose
Cellulose consists of D-glucopyranose ring
units in the 4C1-chair con
figuration, which
exhibits the lowest energy conformation. Such
units are linked by β-1,4-glycosidic bonds that
result in an alternate turning of the cellulose chain
axis by 180°C. Cellobiose with a length of 1.3 nm
can be considered the repeating unit of cellulose
(4).
Figure 1. Structure of cellulose (16)
Changes in the molecular structure originate
from reactions leading to hydrolysis or oxidation
of the cellulose chain. Such reactions mainly occur
on the surface of the
fibrils or in amorphous
regions. The DP of native cellulose of various
origins is in the range of 1,000–30,000, which
corresponds to chain lengths of 500–15,000 nm.
The cellulose samples that are obtained by
isolation methods possess DP values ranging
between 800 and 3,000 (4).
From this cellulose, cellulose nanocrystals can
be prepared through a hydrolysis reaction which
can then be used as a pharmaceutical excipient.
This review is describing the preparation of
nanocrystals cellulose and how important its role
in the pharmaceutical dosage forms.
2. Methodology
This article review uses 9 articles about
isolation and preparation of nanocrystals cellulose
(CNC), 10 research international articles from
2019-2020 about the application of CNC in
pharmaceutical and drug delivery, and 3 more
from 2015-2019 about the toxicology of CNC.
However, for support argument, this articles use
more either research and review article about
cellulose sourching, isolation, and other cellulose
properties.
Table 1. Using CNC in pharmaceutical dosage form and drug delivery system
Cellulose
sources
CNC preparation
method
Research outcome
Cotton
(Whatman
filter paper)
63% sulfuric acid at
50C for 30 min
Cholesterol was successfully covalently
anchored to cellulose nanocrystals (CNCs)
surfaces. Modified cellulose nanocrystals with
cholesterol exhibit potential as drug release
excipients and nano-reinforcing agents within
hydrophobic polymer matrices.
Purchased
Cellulose
nanocrystals
CNC rod shape; degree
of polymerization 137;
half sulfate ester 254
mmol/kg, diameter 4-5
nm, length 300-400 nm
Using of 0.6 % (w/v) CNCs improved
significantly the Anti-stx2B-Ab immobilization
and the level of signal detection of Escherichia
coli O157:H7. The formulation could be used
for the preparation of antibody immobilization
support for pathogens detection
roots of
Dorema
kopetdaghens
Sulfuric acid
cellulose I with the crystallinity index of
83.20% and size of 4.95 nm. The cytotoxicity of
CNCs against A549 cell line has not exhibited
any cytotoxic effects. The analysis of labeling
efficiency in regards to
99m
Tc-CNCs has been
observed to be above 98%, while the
biodistribution of radioactivity has displayed a
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
46
high uptake by the kidneys and blood
circulation.
Cotton filter
paper
64% Sulphuric acid 45C
for 60 min.
cetyltrimethylammonium bromide (CTAB)
modi
fied nanocrystalline cellulose has the best
performance in terms of loading and release of
paclitaxel at pH 5.8 and 7.4. Sodium dodecyl
sulfate (SDS) modi
fied nanocrystalline cellulose
has the lowest loading of paclitaxel which is
43.61 mg/g, with the highest cumulative release
of 95% at pH 7.4 and 65% at pH5.8 for 16h.
Tween20 modi
fied nanocrystalline cellulose can
sustain the release until 19 h for around 80% at
pH 5.8 and 7.4.
Kenaf bast
fiber
Pretreatment: NaOH
4% at 80C for 3 hours,
bleaching with NaClO
in acetate buffer at 80C
for 4 hours.
Treatment: 64% H2SO4
at 45C for 40 min
Yield nanocrystalline cellulose is 41% with 8,03
nm diameter, 107,68 nm length, and aspect ratio
13,4. The surface modification of NCC with the
cationic surfactant of the CTAB increased the
thermal degradation of the nanoparticle. The
prepared CTAB– NCC nanoparticles were able
to bind significant quantities of hydrophobic
curcumin with a range of 80% to 96%. The
FTIR and elemental analysis shows that the
optimum modification of NCC was at 4 mM of
CTAB with DS value of 0.12, as well as the
highest binding efficiency with 96% up to 100
µg curcumin added.
Not available
Sulphuric acid
the chalcone hydrosolubilization was achieved
through these β-CD/CNCs/chalcone complexes.
Loading ratio was around 20% for the two
complexes. Then, β-CD/CNCs/chalcone
complexes demonstrated in vitro
antiproliferative effect against colorectal and
prostatic cancer cell lines. As β-CD/CNCs alone
were shown to have no effect on cell
proliferation, the antiproliferative activity.
Banana fiber
Oxalic acid
The nanoparticles of rifampisin loaded alginate-
CNC exhibited pH dependent swelling and in
vitro drug release properties. Only 15% of the
RIF was released in 2h, showing that the
nanoparticles could e
ffectively protect the drug
from gastric conditions.
Wood
Not available
The CNC is used in astaxanthin nanoemulsion
inhibit cell poliferation thus it induces apoptosis
and was effective ROS against cancer cells.
Cotton lint
Sulphuric acid and
nitric acid
This research has evaluated CNC influence on
in situ gelation behavior and in vitro release of
pilocarpine hydrochloride from nanocomposites
formulation for ophthalmic drug delivery. The
CNC was found increasing gel strength and the
drug release kinetics of the sustained release of
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
47
pilocarpine hydrochloride.
Bacterial
cellulose
Sulphuric acid
This study bacterial nanocrystal cellulose
(BCN) was used in Pickering emulsion with
alginate and hydrophobic drug which is
alfacalcidol. The BCN has good colloidal
property formed by external gelation achieving
the loading and sustained release of alfacalcidol.
The alginate composite beads with BCN
exhibited low cytotoxicity and good capabilities
for osteoblast differentiation.
3. Discussion
Natural cellulose can be transformed into
micro- and nanoscale materials by applying
speci
fic top
-down approaches, yielding de
fined
products such as microcrystalline cellulose,
micro
fibrillar cellulose, and whiskers. The micro
-
and nanoscale materials mainly differ in DP and
crystallinity according to the disintegration
technique used and, consequently, differ in shape
(4).
The three main types of nanocellulose are
cellulose nanofibers (CNF), cellulose nanocrystals
(CNC), and bacterial cellulose (BC), that differ in
their dimensions, functions, and preparation
methods. Cellulose nanofiber has 5-60 nm
diameter and several micrometers in length, which
is produced by chemical, mechanical, or enzymatic
treatment. The preparation of cellulose nanofiber
uses high-pressure homogenization,
microfluidization, refining, grinding,
electrospinning, ultrasonication, cryo crushing,
and steam explosion. Cellulose nanocrystals or
nanocrystalline cellulose have 5-70 nm in diameter
and 100-250 nm (plant source) or 100 nm-several
micrometer (tunicates and algae) in length,
moreover it is can be obtained by hydrolyzing
cellulose with some acid catalyst. The bacterial
cellulose have 20-100 nm in diameter and is
produced through bacterial culture (28).
3.1 Nanocrystalline cellulose
Typically, to produce CNC, cellulose has to be
previously isolated to be directly attacked.
Therefore, new tendencies of CNC production are
focused on the isolation of CNC without a
previous cellulose purification. However, when
CNC is desired to be obtained from biomass,
including wood and agricultural residues, not only
cellulose is present but also different extractives,
hemicelluloses, lignin, or inorganic particles. In
these cases, different pretreatments might be
applied before the acid hydrolysis (28).
A standard recipe for the acid hydrolysis of a
pulp starts with the milling of the dry sample.
Then, a solution of 60-66 wt.% H
2
SO
4
at an acid to
pulp ratio between 8 and 20 mL/g (28). oxalic acid
at the concentrations between 50 and 70 wt.%
(28).
Table 2. Production of nanocrystalline cellulose
Source
Treatment
Pretreatment
Outcome
Reference
Eucalyptus
wood
Sulfuric acid
(56-64%, 45 or
60C) for 10-120
minute
Toluen/ethanol
extraction, acidified
NaClO2, KOH
Max. Yield 66,7%. CNC-I in
spindle-shape, CNC-II twisted
strip.
(29)
Cotton
(Whatman
filter paper)
63% sulfuric
acid at 50C for
30 min
Not available
good dispersion in water, Rod-like
particles, negative surface charge of
ζ = −52.5 ± 0.5mV at 0.1g/ mL
(17)
Brown, red,
and greed
seaweeds
51% sulfuric
acid at 45C for
30 min.
De-polymerization:
0,2 M HCl at 30c for
2 h and 4% NaOH at
75C for 3 hours.
Bleaching: 5% KOH
Amorphous ron were effectively
removed, Rodshape particles with
21-248 nm length and 4,8-41 nm
width. Aspect ratio 2,5-1,5.
Cellulose I with crystalline index
(30)
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
48
for 3 hours, 6-10%
NaClO. Then 30%
H2O2 at 80C for 70
min
66,97-98,89%, have thermal
stability.
Bamboo
Sulfuric acid 6,5
M, phosphoric
acid 6,5 M,
hydrochloric
acid 6,5 M, and
acetic acid 99%
: nitric acid 68%
(10:1) at 60C for
2 hours
Not available
HCl and acetic acid more be able to
broke the hydrogen bonding in
crystalline region by swelling with
low crystallinity. Sulfuric acid: rod
shape in 4-9 nm diameter and 6-200
length. Phosphoric acid: 20-85 nm
with particle size distribution
narrower than sulphuric acid.
Acetic acid/nitric acid: 6,5 -20 nm
length. HCl: nanocrystal particle
can aggregate due to no particle
charge. Crystallinity: sulfuric aci >
phosphoric acid > acetic acid/nitric
acid > hydrochloric acid. Thermal
stability HCl>sulphuric acid and
phosphoric acid.
(31)
Cotton
Hydrochloric
acid at 4N
concentration
and 100°C
temperature for
120 minute and
64% sulfuric
acid at 50°C for
45 minute.
Phosphoric acid
in room
temperature at
concentration
6,2; 7,8; 9; or
10,7 M then was
increased the
temperature to
100°C.
Not available
At 50C the cellulose still in pulp
form. At 7,8 M concentration of
phosphoric acid, the hydrolysis
reaction was not homogeous and
completely done. Cellulose
nanocrystal that was prepared by
phosphoric acid has very low
charge density, however very easily
dispersed in polar solvent.
Additionally, the thermal stability
of nanocrystalline cellulose with
phosphoric acid is higher than
sulfuric acid. The optimal condition
is 90 minute at 100C with 10,7 M
phosphoric acid. The particle size
has 31 nm width and 316 nm
length, and aspec ratio 11,
compared than H-CNC 20 nm and
S-CNC 22 nm, and aspec ratio
respectively 10 and 9. The
crystallinity respectively was 81,
81, 85, dan 79 %.
(32)
Cotton
62 % sulfuric
acid at 47C
Enzyme or chemical
pretreatment
Particle size 183 – 209 nm, DP:
173-210, PDI 0,17 – 0,20. NCC
dengan enzyme pretreatment can
resulting yield to 82% or 12%
higher than chemical degumming.
(33)
Cotton
Microcrystals
cellulose
6M HCl was
autoclaved 110C
for 3 jam, and
Not available
The highest yield rendemen
tertinggi was obtained at 2 hours of
reaction time in acid/cellulose ratio
(34)
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
49
sulfuric acid
64% at 50C for
1 hour
was 40 with particle size of 295
nm. Neutralizing with ammonia is
recommended to obtain the optimal
condition.
Microcrystall
ine cellulose
Sulfuric
acid/nitric acid
Not available
the surface hydroxyl groups on
CNCs could be converted into
carboxyl groups efficiently after
0.5
 h treatment. The degree of
oxidation could reach a maximum
value of 0.11 at the reaction
temperature of 80
 °C CCNCs
presented a rod–like morphology
with the length and diameter of
186
 ± 13 and 9
 ±
 3 nm, respectively.
More importantly, the CCNCs
showed excellent dispersibility in
water and some organic solvents
due to the existence of negative
carboxyl groups.
(35)
Banana fiber
Oxalic acid
Steam exploded
using a 2% NaOH at
pressure 15 lb for 2
hours, followed by
hydrogen peroxide
bleaching
Rodlike particles 10-20 diameter
and 100-200 nm length.
(23)
The application of sulfuric acid in nanocrystals
isolation can produce sulfate ester on the hydroxyl
group of cellulose, acetic acid can produce acetyl,
and hypochlorite can produce carboxylic acid
groups (36).
The drying of CNC can be done with air drying,
freeze-drying, supercritical drying, and spray
drying. The supercritical drying can obtain good
thermal stability and low crystallinity. Spray
drying may obtain the most stable with high
crystallinity, however, the yield obtained is low.
The drying process with dry air increases the
proportion of cellulose II crystalline compared to
the other methods. Therefore, freeze-drying is the
most suitable drying process with a high yield and
better thermal stability and crystallinity (37).
3.2 Nanocrystalline cellulose as excipient
Microcrystalline cellulose with molecule
(C
6
H
10
O
5
)n/2 (n=220), is usually used as
absorbent, anti-adherent, capsule or tablet filler,
binder, and disintegrant. Microcrystalline cellulose
slightly soluble in 5% NaOH, practically insoluble
in water, acids, and organic solvents. Besides, it is
stable despite being hygroscopic (1). The
disintegration mechanism of microcrystalline
cellulose is due to the hydrophilic and hygroscopic
nature of the molecule, resulting in a high water
uptake rate. This property triggers the breaking of
the hydrogen bonds between cellulose particles,
swelling, then expanding the volume of the solid
material. The combination of these mechanism can
trigger the penetration of solvents into solid drug
particles and dissolved them (38,39).
Nanocellulose can increase the amorphization
of derivates and nifedipine (biopharmaceutical
system class II drugs) thereby increasing their
solubility and bioavailability by testing the drug
release both in-vitro and in-vivo in mice (40,41).
Cellulose nanofiber can improve the intrinsic
dissolution of indomethacin (42).
Disintegration time and dissolution of CNC
continually resulting in fast disintegration and
dissolution and effective in low concentration of
CNC (43). CNC has mucoadhesive properties in
the gastrointestinal tract based on CNC interaction
with mucin molecule and changes the mucin-CNC
complex surface charge (44). Moreover, CNC may
interact with intestine membrane cell
M. E. Putri et al / Indo J Pharm 1 (2020) 43-54
50
phospholipids and disrupt the membrane cell
integrity (45), thus increase drug permeability
(46).
3.3 Cellulose nanocrystals to meet
pharmaceutical excipient requirement
Based on IPEC-European safety test guidelines
(De Jong, 1999), an oral excipient should meet the
requirements for fulfilling some various tests. The
zero phase is ADME (absorption, distribution,
metabolism, and excretion). The first phase must
require the basic data including the oral acute
toxicity, sensitization skin, chromosomal damage,
AMES test, micronucleus, and 28-days toxicity (2
species) intended route. Additional data for short
of medium repetition intake (multidose): 90-days
toxicity (most appropriate species), teratology (rat
and rabbit), genotoxicity assays. As for IPEC-
America acute dermal toxicity, eye irritation, and
first-generation reproduction testing for chronic
use.
Table 3. Cellulose nanocrystals testing to fullfill IPEC requirement
Cellulose
sources
CNC preparation
method
Research outcome
Reference
Wheat bran
Sulfuric acid
Zeta potential values of the CNC suspensions
ranged from −36.5 to −39.8 mV, high crystallinity
(70.32%). The thermal stability of CNC shifted to
lower temperature with increasing hydrolysis time.
In addition, the obtained CNC exhibited
interesting physicochemical properties (the
water/oil retention capacities and the adsorption
capacities to heavy metals) and good
biocompatibility. CNC showed no obvious
cytotoxicity to Caco-2 cells at 1000 μg/mL.
(47)
Microcrystals
cellulose
Sulphuric acid
Nanocrystals cellulose was not able to induce
micronuclei in BEAS 2B cells in 2.5-100 μg/mL
for 48 hours treatment and not induce interleukin
1β (IL-1β) and pro-inflammatory cytokines tumor
necrosis factor-α (TNF-α). Thus, CNC is not
genotoxic and immunotoxic
(48)
Wood
Not available
Nano cellulose induced cytotoxicity to HaCaT
cells (>156 μg/mL) and HDF-α cells (>313
μg/mL) but did not induce the skin and eye
irritation on 3D models.
(49)
4. Conclusion
CNC has been widely used as
apharmaceutical excipient in the research world.
However, CNC has not provided yet in the
pharmaceutical industry, especially in a
pharmaceutical grade. This review has explained
how important CNC in solid dosage form not
only for improving drug oral bioavailability but
also in the drug delivery system. CNC also has
meet some of IPEC requirement and has high
potential as new as pharmaceutical ingredients.
Thus, the research about the CNC oral acute and
chronic toxicity has not well evaluated which is
important to prepare the CNC in pharmaceutical
grade. Besides, the research about CNC function
an effect in solid dosage form has not widely
observed in various drugs. Also, more research
about the effect of catalyst residue of CNC not
only in its compatibility with drugs but also in
chronic toxicology testing.
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