Delivered by

THANK YOU FOR YOUR ORDER

Thank you for your recent purchase. If you need further assistance, please contact Customer Service at
customerservice@copyright.com. Please include the Request ID, so we can better assist you.

This is not an invoice.

CUSTOMER INFORMATION ORDER INFORMATION

Ordered For: Kasturi Request ID: 17852061
Company: Exelixis Ordered For: Kasturi
Client ID: 2503 Ordered For Email: kpawar@exelixis.com
Address: 1851 Harbor Bay Parkway Ordered: 8/7/2022 11:26 AM
Deliver Via: Email (PDF)

Alameda, CA 94502 Delivery Address: kpawar@exelixis.com

Country: United States Tracking Info.: NONPROJ
Phone:
Fax:
Email: kpawar@exelixis.com

DOCUMENT INFORMATION
Std. Num.: 03639045 Type: Doc Del (Journal Article)
Publication: Drug Development and Industrial Pharmacy Copies: 1
Publisher: Taylor & Francis Urgency: Normal
Vol(Iss) Pg: 44 (9) p.1512-1519 Genre: Journal Article
Date 9/2/2018 Total Fee: $73.89

Title: Evaluation of non-crystalline cellulose as a novel excipient in solid dose products

Author(s): Pawar, Kasturi; Render, Diane; Rangari, Vijaya; Lee, Yoon; Babu, R. Jayachandra

Usage: Ordering 1 copy for the following stated purpose: "Internal General Business Use"

The contents of the attached document are copyrighted works. You have secured permission to use this document for the following
purpose: Ordering 1 copy for the following stated purpose: "Internal General Business Use"
You have not secured permission through Copyright Clearance Center, Inc. for any other purpose but may have other rights pursuant to
other arrangements you may have with the copyright owner or an authorized licensing body. To the extent that a publisher or other
appropriate rights-holder has placed additional terms and conditions on your use of this document, such terms and conditions are
specified herein under “Copyright Terms”. If you need to secure additional permission with respect to this content, please
purchase the appropriate permission via RightFind.

Copyright Terms: This document has been provided for the use of the individual receiving the document, as authorized in the Copyright
Notice.<br><br>

*<strong>IMPORTANT NOTE</strong>*: For documents delivered in an electronic format, unless authorized under a
separate license from the rightsholder or an authorized intermediary like Copyright Clearance Center, Inc., the person
or end-user ordering the document is authorized to: (a) store the document for personal viewing and for no other
(800) 422-4633 Toll Free Email:
(203) 423-2175 Direct
purpose; and (b) make a single print copy of the document. Any additional uses (such ascustomerservice@copyright.com
the distribution of copies for
marketing or promotional purposes) are not authorized and require separate permission.<br><br>
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
2018, VOL. 44, NO. 9, 1512–1519
https://doi.org/10.1080/03639045.2018.1472276

RESEARCH ARTICLE

Evaluation of non-crystalline cellulose as a novel excipient in solid dose products

Kasturi Pawara, Diane Renderb, Vijaya Rangarib, Yoon Leec and R. Jayachandra Babua
a
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, USA; bDepartment of Materials
Science, Tuskegee University, Tuskegee, AL, USA; cDepartment of Chemical Engineering, Auburn University, Auburn, AL, USA

ABSTRACT ARTICLE HISTORY

Objective: The objective of this study was to evaluate non-crystalline cellulose (NCC) as a novel tablet Received 11 June 2017
excipient in solid oral dosage forms in comparison with microcrystalline cellulose (MCC) and silicified Revised 24 March 2018
microcrystalline cellulose (ProsolvV
R , SMCC). Accepted 23 April 2018
Significance: MCC, although a widely used tablet excipient, has diasdvantages in terms of its low dilution
KEYWORDS
potential for potent drugs, and sensitivity to lubricant and moisture. SMCC, a modified version of MCC, has Tablets; microcrystalline
improved tablet compression properties. However, SMCC is expensive and also affects the moisture sorp- cellulose; excipient; Heckel
tion and particle deformation during compression leading to increased tensile strength and tablet hard- analysis; Kawakita analysis
ness. NCC was found to be similar to SMCC in its performance as a tablet excipient and thus can serve as
a cheaper alternative to SMCC.
Methods: Scanning electron microscopy (SEM), X-ray diffrectometry (XRD), and differential scanning calor-
imetry (DSC) analyses were performed on NCC, MCC, and SMCC. Further, out-of-the die Heckel, Kawakita
compact densification and stress-strain analyses were performed to evaluate their compaction and com-
pressibility properties. Various compendial and non-compendial tests were performed to to determine the
flow properties of materials. Dissolution studies were performed using amlodipine besylate as a
marker drug.
Results: It was found that NCC has similar or even better flow properties and compactibility than MCC
due to its porous and amorphous structure whereas it had similar properties as SMCC.
Conclusions: Based on the data, it can be concluded that NCC can serve as a cheaper and better alterna-
tive to MCC as excipient in solid dosage forms.

Introduction
The choice of excipients remains a critical factor in pharmaceutical
formulations as they determine the quality and performance of
the final formulation. Microcrystalline cellulose (MCC) is a versatile
pharmaceutical excipient used in solid dosage forms. It is a widely
used diluent for direct compression but is also reported to be
used as binder, disintegrant, lubricant and glidant [1].
Traditionally, MCC is synthesized by acid hydrolysis of wood pulp,
cotton, corn-stalk etc [2]. However, despite of its wide use, MCC
suffers from few shortcomings. The fibrous nature of MCC contrib-
utes to its poor flow and low compactibilty properties [3]. This
restricts its applications for direct compression of poorly flowing
and low compactibility drugs. Further, MCC has a low dilution
potential for potent drugs, and sensitivity to lubricant and mois-
ture [4]. To overcome these limitations, attempts have been made
to create new grades of existing excipients by manipulating the
fundamental properties of materials such as morphology, particle
size and shape, surface area, porosity, and density [5]. For
example, silicon-di-oxide has been co-processed with MCC to give
silicified MCC (SMCC, ProSolvV R ) resulting in improved compressi-
unpleasant gritty sensation in the mouth [8]. Cellulose and its
derivatives are generally recognized as safe and most acceptable
materials for use in food and pharmaceutical products. Several cel-
lulosic polymers have been reported as exipients in the tablet
compression such as UICEL (a proprietary cellulose based tablet
excipient) [9], cellulose nanofibers (CNF) [10], and low crystallinity
powdered cellulose (LCPC) [11]. These materials differ in the man-
ufacturing process and micromeritic properties. The structural
organization of cellulose at various levels influences the morpho-
logical properties of the material and their compactible or com-
pressible properties. Non-crystalline celluose (NCC) in the present
study was produced by simple process and is practically non-
crystalline and has free flowing characteristics for its use in solid
dosage forms. It has distinct advantages over MCC in terms of
morphology, physical properties, reactivity, and water absorption
[12]. Thus, NCC can serve as an alternate, novel excipient for solid
oral dosage forms in comparison to existing tablet excipients such
a MCC and SMCC. The paper, thus, describes the studies that were
performed to compare NCC with MCC and SMCC in terms of its
tabletting properties.

bilty, flowability, better dilution potential and reduced lubricant

and moisture sensitivity for MCC [6]. An increase in tensile Materials and methods
strength and tablet hardness due to silicification has been
Materials
reported in literature [7]. However, co-processing steps involved in
MCC (AvicelV PH 101) was obtained from FMC Biopolymer (Newar,
R
SMCC production can be complex and, SMCC if used in orally dis-
DE). SMCC (ProSolvV SMCC 50) and Sodium starch glycolate
R
integrating dosage forms, at higher concentrations, leaves an

CONTACT R. Jayachandra Babu rjbabu68@gmail.com Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University,
Auburn, AL, USA
ß 2018 Informa UK Limited, trading as Taylor & Francis Group

(ExplotabV) were obtained from JRS Pharma (Patterson, NY).
R
Lactose (ForemostV #316 Fat Flo) was obtained from Foremost
R
farms (Baraboo, WI). Magnesium stearate was obatined from Fisher
scientific (Pittsburgh, PA). Amlodipine besylate was obtained from
Alembic Pharma (Gujarat, India). All materials were passed through
US standard sieve# 325 and dried at 50
C for 8 h to normalize
their particle size and moisture content, respectively.
Synthesis of NCC
Synthesis of NCC has been reported elsewhere by one of the
coauthors in this manuscript [12]. This is a single-step process
without excessive temperature or pressure and carbohydrate
decomposition. In brief, alpha cellulose was treated with concen-
trated sulfuric acid to form slurry. The mixture was then left at
ambient temperature to sit for about 120 min. sufficient to form a
viscous fluid. This was followed by addition of water to reduce the
acid concentration. The slurry was then dewatered, neutralized,
and re-precipitated in purified water. During this process, the cel-
lulose particles agglomerate. Since the hydrogen bonds which
hold the crystalline structure of cellulose are broken, the crystallin-
ity of the material was essentially removed. The resulting NCC was
more homogenous morphologically, more porous and has high
surface area per unit weight than parent alpha cellulose.
Micromeritics of NCC in comparison to MCC and SMCC
The micromeritics were evaluated in terms of true density, bulk
density, tapped density and percent porosity. Flow properties
included angle of repose, angle of spatula, compressibility index,
and Hausner’s ratio. True density (qtrue) of the materials was deter-
mined using Helium displacement pycnometer (Accupyc 1330,
Micromeritics, Norcross, GA).
Bulk density (qbulk) was obtained directly from the ratio of 20 g
of powder to its volume measured in a 100 ml graduated cylinder.
Tap density (qtap) was determined using a U.S. Pharmacopoeia
(USP) method-II using USP Model 12 Tap Density Tester (Pharma
Alliance Group, Valencia, CA) by measuring the powder volume
after 1200 taps. Compressibility index and Hausner’s ratio were
calculated using the standard formulae as given in USP. Porosity
(e) of the powder was determined as per equation:

forces up to 48.3 MPa. Each tablet contained 8% Amlodipine
e ð%Þ ¼ 1  qbulk = qtrue  100 (1)
Angle of repose was determined according to standard proce-
dures as described in the USP34/NF29. Briefly, angle of repose was
measured for the heap of powder formed by passing the samples
through a funnel at a height of 2 cm from the horizontal surface.
Angle of repose (h) was estimated from the following equation:
tan h ¼ a=b (2)
Where [a/b] is the ratio of the length of the side opposite the
angle to the length of the side adjacent to the angle. Angle of
spatula was measured using a protractor and a steel spatula with
an approximately 6-inch blade. In this method, the spatula was
inserted to the bottom of the heap that is carefully built by drop-
ping the sample through a funnel at a height of 2 cm from the
horizontal surface. The spatula was then withdrawn vertically and
the angle of the heap formed on the spatula was measured.
Surface area analysis of NCC, MCC, and SMCC
The specific surface area of all the powder samples were deter-
mined using a Nova 3000 surface area analyzer (Quantachrome
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1513
Corporation, Boynton Beach, FL) to measure nitrogen sorption.
The surface area per unit powder mass was calculated according
to the Brunauer–Emmet–Teller (BET) equation (Equation (3)) using
multi-point analysis [13]. The specific surface area Sw in m2/g is
calculated as:
Sw ¼ 4:37  Vm (3)
where Vm is the volume of nitrogen needed to form a monolayer
in cm3/g.
Morphology of the materials
Surface morphologies of MCC, NCC, and SMCC were studied using
a scanning electron microscope (JEOL-5800). The samples were
spread onto double-sided adhesive conductive carbon tape and
coated with a thin layer of gold/palladium mixture (Au/Pd) using a
sputter coater Hummer 6.2 to prevent charge buildup by the elec-
tron absorption of the specimen. A 20 kV accelerating voltage was
applied to perform needed magnification.
Solid state characterization of the materials
The powder materials were characterized using differential scan-
ning calorimetry (DSC) using Q1000 (TA Instruments, New Castle,
DE). Temperature and cell constant were calibrated using indium
and sapphire samples, respectively. DSC samples were scanned at
a rate of 10
C/min. over a temperature range of room tempera-
ture to 380
C under nitrogen purging. X-ray powder diffraction
(XRD) patterns of solid-state forms of MCC, NCC, and SMCC were
measured using a Rigaku D/MAX 2200 X-Ray diffractometer to
investigate the crystal structure. Radiations generated from CuKa
source with a wavelength of 0.154 nm at 30 mA and 40 kV were
used to study the X-ray diffraction patterns. The instrument was
operated over the 2h range of 5–65
.
Preparation of amlodipine besylate tablets using MCC, NCC and
SMCC as diluents
The tablets were compressed on a hydraulic Carver press
model-B (Carver Inc. Wabash, IN) at different compression
besylate, 48% NCC/MCC/SMCC, 39.5% lactose, 4% sodium starch
glycolate, and 0.5% magnesium stearate. The tablets were com-
pressed using B-tooling flat-faced 6.5 mm punch and die set
(Natoli Engineering, Saint Charles, MO). Diameter and thickness
of the tablets were measured using a pair of digital Vernier
calipers. Hardness of the tablets was determined using digital
hardness tester (Pharma Alliance Group, Valencia, CA). The vol-
ume (v) of tablets was determined from the dimensions
obtained from tablet tool drawing. The apparent density of the
tablets, qc, was calculated from the weight and volume of the
tablet (qc ¼ w/v).
Compressibility analysis
The elastic deformation and volume reduction mechanisms on the
compacts were studied using out-of-die Heckel analysis and
Kawakita analyses whereas stress/strain analysis was performed to
determine the elastic moduli of the tablets under various poros-
ity conditions.
The densification of MCC, NCC, and SMCC blends was analyzed
by the ‘out-of-die’ Heckel equation. This equation is based on the
1514 K. PAWAR ET AL.
assumption that the dependence of densification on pressure fol-
lows first order:
Lne ¼ K  P þ D (4)
where P is the compaction pressure; e is the porosity of the com-
pact; K is the slope of the linear portion of the Heckel plot that
describes the influence of pressure in reducing the void fraction
(i.e. increasing the density of the tablet); and D is the intercept of
the Heckel plot and it represents the powder densification by die
filling and particle rearrangement before deformation and bonding
of the individual particles takes place [14,15]. The brittle fracture
point was determined from the hardness (kPa) versus compression
force (MPa) plots with the point of decline in kPa with increase in
MPa. Porosity [e] of the compacts was calculated by the following
equation:
 lets made from NCC. The rest of the tablet composition was same
e ¼ 1 qc = qt  (5)
The percent porosity [%e] of the compacts was calculated by
the following equation:
 
%e ¼ 100 1 qc = qt Þ (6)
The Kawakita model illustrates the relationship between the
degree of volume reduction of the powder and the applied pres-
sure [16]. The Kawakita equation was employed to study powder
compression using the degree of volume reduction, C, a parameter
equivalent to the engineering strain of the particle bed and is
expressed as:
P=C ¼ P=a þ 1=ab (7)
Equation (7) can be rearranged in a linear form as:
C ¼ 1 q0=qa (8)
where q0, qa, C, and P, are the tablet apparent density, powder
bulk density, degree of volume reduction and compression force,
respectively. The constant ‘a’ is the compressibility index, which is
related to the total volume reduction for the powder bed, and the
constant ‘b’ is related to the resistant forces (friction/cohesion) to
compression.
Stress/strain analysis was performed on texture analyzer (Model
TA-HD, Surrey, UK) using tablets of different porosity values
(approximately 2, 5, 10, and 15%) compressed at various compres-
sion forces. Tensile strength measurement was carried out using
Fell and Newton method [17]. The diameter of both the platen
and the probe was 50 mm. The tablet was placed at the center of
the lower flat platen operating with a 500 N load cell. The dimen-
sions of the compacts were measured before exposing them to a
fracture force test. The fracture force was measured by compress-
ing diametrically (n ¼ 3) in rupture test using pretest speed, test
speed, post-test speed, and rupture distance of 1, 0.1, 2 mm/s, and
4 mm, respectively. Peak force obtained in the force–displacement
profile was taken to represent the fracture force. The tensile
strength can be directly correlated to the tablet strength and was
calculated from the diameter, thickness of the compact, and the
force required for fracturing the tablet using the following equa-
tion:
rt ¼ 2F= p dt (9)
where rt denotes the tensile strength, F is the diametric crushing
force, d and t are the diameter and thickness of the compacts.
Lubricant sensitivity
The lubricant sensitivity of the materials was determined by pre-
paring the tablet blends (as described in the tablets
manufacturing section) with various amounts of magnesium stear-
ate (0, 0.5, 1, and 2% w/w). The blending time was kept constant
to maintain the uniformity. Tablet compacts of 125 mg were made
at 27.6 MPa compression force. Lubricant sensitivity ratio (LSR) was
calculated as a ratio according to the relationship:
LSR ¼ ðH0 –Hlub Þ=H0 (10)
where H0 and Hlub are the hardness values for tablets prepared
without and with lubricant, respectively.
Dissolution studies
Amlodipine besylate (solubility of 7.40  103 g/l) was used as a
model drug at 8% w/w to study the dissolution properties of tab-
as that described in Section 2.7. The dissolution study was per-
formed as per USP34/NF28 using USP-II dissolution apparatus
(Hansen Research, Chatsworth, CA) at 75 rpm in 500 ml of 0.01 N
hydrochloric acid). The drug content of the dissolution samples
was determined using UV spectrophotometer (Jasco V-630, Easton
MD) set at a kmax of 238 nm. A calibration curve was plotted in a
concentration range of 1–40 mg/mL, and the R2 value obtained
was 0.9997.
Results and discussion
Chemical characterization of NCC
The DSC thermograms of MCC and SMCC indicate melting endo-
therms at 338
C and 340
C, respectively. In case of NCC, the dis-
appearance of the melting endotherm around 340
C and
appearance of a new endothermic peak at 260
C indicates a dif-
ferent solid state for this material (Figure 1). The non-crystalline
nature of NCC is clearly evident from the XRD patterns where the
2h peak representing crystallinity at 22
is significantly diminished
as compared to MCC or SMCC. Additional minor peaks at 33
and
37
indicate different lattice structure, pointing towards the fact
that NCC is devoid of any crystalline nature (Figure 2).
Physical characterization of NCC
Morphology
Surface area analysis using BET equation showed that NCC has a
larger surface area than MCC (Table 1). This might be due to the
reduced crystallinity, surface roughness, and even particle shape.
Further, the largest surface area for SMCC is attributed to the
NCC
← Heat Flow
MCC
SMCC
25 100 200 300 380
o
Temperature ( C)
Figure 1. SEM pictures of MCC, NCC, and SMCC.
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1515

presence of SiO2 in the structure providing the finest particle size properties. This might be due to the amorphous nature of NCC
of this material. The homogenous distribution of SiO2 also pro- that prevents entanglement facilitating better flow. On the other
vides improved flow properties. The SEM micrographs in Figure 3 hand, presence of SiO2 in SMCC imparts higher surface area and
show porous structure of NCC as compared to MCC and SMCC. glidant effect that enables superior flow properties. The lower
The regular and evenly distributed particles provide improved angle of repose (below 35) and angle of spatula for SMCC and
compactibility and flow properties to NCC as compared to MCC. NCC further confirmed that flowability of these materials is better
than MCC (Table 1). Similar observations on the flow properties of
Micromeritic properties of NCC in comparison to MCC and SMCC. SMCC were reported [18].
The micromeritic and flow properties of NCC, in comparison to
MCC and SMCC are given in Table 1. All the materials have com-
parable true densities. The higher bulk and tap densities of NCC
indicate its better compacting particles than MCC. This may be
due to the lack of crystal lattice and regular shape of particles
resulting in close inter-particulate interaction and compaction. The
higher bulk and tap densities of SMCC than other materials are
due to the presence of SiO2 which imparts surface modification
that helps in better packing. Superior mechanical and compaction
properties of silicified MCC over MCC have been reported [18por].
Rojas and Kumar [18] have attributed the superior compaction
properties to the higher bulk and tap densities for silicified MCC
over non-silicified form. The lower compressibility index and
Hausner’s ratio for NCC over MCC indicates its better flow MCC

MCC

NCC

SMCC

NCC

0 10 20 30 40 50 60 70
2-Theta SMCC
Figure 2. DSC thermograms of MCC, NCC, and SMCC. Figure 3. XRD patterns of MCC, NCC, and SMCC.

Table 1. Micromeritic properties of MCC, NCC, and SMCC.

Material Tapped density (g/ml) Bulk density (g/ml) Compressibility index (%) Hausner’s ratio Angle of repose (h) Angle of spatula (h) Surface area (m2/g)
MCC 0.32 0.49 34.6 1.53 61.04 ± 0.28 85.60 ± 1.20 0.87
NCC 0.42 0.56 25.0 1.33 35.12 ± 0.31 79.60 ± 1.90, 1.08
SMCC 0.38 0.50 24.0 1.32 21.64 ± 0.69 74.80 ± 1.50 6.80
All the experiments were conducted in there replicates.
p < 0.001 versus MCC and SMCC.
p < 0.01 versus MCC.
p < 0.05 versus SMCC.
1516 K. PAWAR ET AL.
Table 2. Heckel analysis for tablets made with MCC, NCC, and SMCC.
Material Py (MPa) A D0 DB DA
MCC 41.64 3.63 0.32 0.65 0.97
NCC 31.60 3.68 0.42 0.55 0.97
SMCC 38.93 2.78 0.38 0.56 0.94
Py: powder yield pressure; A: degree of densification due to particle rearrangement; D0: relative density due to die filling at zero pressure; DB: Relative density due to
particle rearrangement/fragmentation; DA: Total powder relative density due to die filling at zero pressure and particle rearrangement/fragmentation at low compres-
sion pressure.
Tableting properties of NCC in comparison to MCC and SMCC
Heckel analysis was performed in order to evaluate the effect of
applied pressure on the elastic deformation and various parame-
ters of the analysis are presented in Table 2. The linear portion in
the Heckel plot is the characteristic for materials that undergo
plastic deformation during compression. The slope of the linear
region (K) indicates the extent of the plastic deformation of mater-
ial. Yield pressure value (Py) is the inverse of slope K and it refers
to the pressure at which the material begins to deform plastically.
The intercept (A) of the plot gives information about the degree
of densification due to die filling and particle rearrangement.
D0 is the relative density of the powder bed at the point when
the applied pressure equals zero and it describes the initial
rearrangement phase of particles as a result of die filing. The DB
parameter represents the extent of powder bed arrangement due
to particle fragmentation/rearrangement at low pressures. DA rep-
resents the total degree of densification due to die filling at zero
pressure, and rearrangement and fragmentation at low compres-
sion force. NCC showed lower Py value than MCC indicating that
although the plasticity of NCC is reduced due to its amorphous
conversion, the larger free volume and lack of crystal lattice leads
to greater inter-particulate contact and less compression pressure
is required to deform it than MCC. On the other hand, for MCC,
highest Py is indicative of higher yield strength, requiring a higher
compression force to initiate deformation. Similar results are
reported by Joshi et al for amorphous celecoxib as compared to
its crystalline form [21]. SMCC showed similar Py value as NCC.
This might be due to the silicification of MCC particles that
increases brittleness of the material and thus low pressure is
required for deformation. Rojas et al reported a lower Py value for
silicified MCC over non silicified MCC [20]. MCC showed lowest D0
value indicating that the particles at zero pressure did not pack
well. This is due to the elongated (fiber-like) and irregular shape
of the particles that could form bridges and arches, preventing
the close packing of powder in bulk state On the other hand,
higher D0 value for NCC indicate that the regular shape of par-
ticles and close inter-particulate contact helped in better packing.
Further, SMCC also gave similar D0 value as NCC indicating that
the regular-shaped particles packed well. Upon application of low
compression force, MCC showed the highest densification as evi-
dent from highest DB value. This is because the pressure facilitates
packing of irregular particles that are otherwise elongated and do
not accommodate well. Once the pressure is applied, the fibrous
particles can rearrange, deform and bend extensively. NCC showed
little lesser DB value than MCC as the regular and porous nature
of the particles do not bend or fragment as extensively as MCC.
Furthermore, porous nature of particles along with the increased
brittleness due to silicification resulted in a lower DB value for
SMCC. However, the total densification (DA) values indicate that
MCC and NCC underwent similar densification whereas SMCC
showed lower densification than the former materials. These
results indicate that where MCC undergoes densification mainly by
particle rearrangement and less by die filling whereas NCC and
Mechanical properties of the compacts
Pressure range (MPa) (R )2
E' (MPa) Maximum stress (MPa) Maximum strain (%)
11.1–88.5 (0.9507) 0.62 2.06 2.97
11.1–66.4 (0.9583) 0.70 2.06 2.75
11.1–44.3 (0.9991) 0.71 2.08 2.70
30
Hardness (kPa)
25
20
MCC
15 NCC
10 SMCC
5
0
0 10 20 30 40 50 60
Compression force (MPa)
Figure 4. Effect of compression force on hardness of tablets made with MCC,
NCC, and SMCC. Values represent the mean and standard deviation of
six replicates.
SMCC particles undergo densification primarily by die filling and
the role of particle rearrangement and plastic deformation is lesser
than MCC.
Figure 4 shows the effect of compression force on the hardness
of tablets. NCC provided harder tablets than MCC and SMCC at all
compression forces. The brittle fracture point for NCC was
27.6 MPa, whereas MCC and SMCC, it was greater than 48.3 MPa.
Around the brittle fracture point, the hardness of MCC, NCC, and
SMCC tablets were 28, 25 or 24 kPa, respectively. The amorphous
nature of NCC offers strong intermolecular and inter-particulate
bonds, which helps in better cohesion leading to harder tablets
[22]. Further, it is reported that the amorphous materials can dem-
onstrate higher surface energies leading to stronger inter-particu-
lar bonding [7]. Higher surface energy of amorphous NCC may
lead to higher potential for the particles to fuze together and
cohere forming stronger bridges during compression. Similar
results were reported for the difference in tensile strengths for
amorphous and crystalline lactose [23].
Figure 5 shows the percent porosity with respect to compres-
sion force. MCC showed high porosity values than NCC at low
compression forces (p < 0.05). The dominant linear region in the
Heckel curve is characteristic for materials that undergo plastic
deformation during the compression. Further, the steeper the
slope, the more ductile the material is considered. A steeper curve
for MCC indicated that it is more ductile than NCC. This plastic
deformation of MCC during compression results in a close contact
between the particles and possible hydrogen bond formation [24].
At low compression pressures, lesser particle interaction between
the elongated fibers of MCC lead to an initial high volume. As the
compression pressure increased, the particle interaction and sub-
sequent rearrangement of elongated fibers greatly increased lead-
ing to a greater reduction in porosity. However, at 27.6 MPa, the
particle rearrangement and deformation were at the maximum
extent, beyond which there cannot be any more deformation or
particle arrangement, hence the porosity reduction reached a plat-
eau. Since densification of NCC was mainly due to die filling and
less by particle rearrangement and plastic deformation, the
 DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1517

8 Table 3. Kawakita analysis for tablets made with MCC, NCC,

0.15
*P < 0.05 and **P < 0.01 vs NCC and SMCC.

Slope of 1/ln
R2

Porosity
*
0.10
Material a b ab 1/b
**
ln 1/Porosity 6 0.05
MCC 0.79 0.53 0.42 1.89 1.0
0.00 NCC 0.72 0.56 0.40 1.77 1.0
SMCC 0.75 0.60 0.45 1.66 1.0

C
C

C
C
M

SM
N
4 All the data are the average of three experiments. a, compress-
ibility index; b: degree of forces opposing the compression
force; ab: Constant measuring the extent of particle rearrange-
2 ment during compression; 1/b: Inverse measure of the extent
of plastic deformation during compression.
NCC M CC SM CC
0
0 10 20 30 40 50 60 3000 *** P < 0.001 versus MCC

Tensile strength
Compression force (MPa) *** *** ***
2000 *** ***

(kPa)
***
***
20
***
Porosity (%)

1000
15 NCC MCC SMCC
SMCC NCC MCC
10 0
0 10 20 30 40 50
5 Compression force (MPa)
Figure 6. Stress-strain analysis for tablets made with MCC, NCC, and SMCC.
0 Values represent the mean of six replicates.
0 10 20 30 40 50 60
Compression force (MPa) 0.30
* P<0.5; **P<0.01; ***P<0.001 versus MCC
Lubricant sensitivity ratio

Figure 5. ‘Out of die’ Heckel analysis of MCC, NCC, and SMCC. Values represent
the mean and standard deviation of six replicates.
reduction in porosity was not as great as with MCC. SMCC showed
high porosity values owing to the presence of SiO2 on its surface.
The porosity values obtained at 3.4 MPa for MCC, NCC, and SMCC
were 13.84, 12.99, and 16.69%, respectively, whereas at 48.3 MPa it
was 1.88, 1.81, and 4.32% for MCC, NCC, and SMCC, respectively.
The percent reduction in porosity after compression at 48.3 MPa
was 13.6, 13.9, and 25.9% for MCC, NCC, and SMCC, respectively.
This indicates that SMCC was the most compressible of all fol-
lowed by NCC and MCC.
Table 3 indicates the Kawakita parameters calculated for MCC,
NCC, and SMCC. A linear relationship between P/C vs. P was estab-
lished with correlation coefficient (R2) value of 1.0 for all the mate-
rials. Values for slope and intercept were obtained from the plots.
Further, Kawakita constants such as a, b, ab, and 1/b were calcu-
lated from the slope and intercept values. Constant ‘a’ obtained
by calculating the inverse of the slope of the Kawakita plot, repre-
sents the volume reduction on compression or compressibility of
the material. Constant ‘b’ is obtained by the product of ‘a’ and
intercept of the Kawakita plot and it is indicative of the degree of
forces opposing the compression force due to cohesion between
the particles. Constant ‘1/b’ is the inverse measure of the extent of
plastic deformation of the material during compression [25]. MCC
showed highest ‘a’ value indicating the high compressibility and
degree of volume reduction owing to its excellent plasticity and
deformation ability. On the other hand, NCC and SMCC showed
similar compressibility and lower ‘a’ values than MCC. This might
be because of the reduced plasticity of the materials due to
amorphous conversion and silicification, respectively. These results
substantiate the compressibility index data shown in Table 1.
Further lower ‘1/b’ values for NCC and SMCC confirm the reduced
plasticity as low pressures were required to reduce the half of the
original volume, as compared to MCC. These results are in par
0.25
0.5%
0.20 1.0%
2.0%
0.15
***
*** *
0.10 **
0.05
0.00
MCC NCC SMCC
Figure 7. Lubricant sensitivity ratios for tablets made with MCC, NCC, and SMCC.
Magnesium stearate was used at 0.5, 1.0, and 2.0% concentration. Values repre-
sent the mean and standard deviation of four replicates.
with low Py values for NCC and SMCC, indicating the low yield
pressure for their deformation.
Tensile strengths were determined for tablets of MCC, NCC,
and SMCC, using force required for fracturing the tablet, and plot-
ted against various compression forces as shown in Figure 6.
Significant differences were observed for the tensile strength val-
ues for MCC, NCC, and SMCC at all studied forces. NCC and SMCC
showed higher tensile strength at all compression forces than
MCC. This may be due to the high inter-particulate interaction and
bonding due to amorphous nature and modified structure due to
silicification in case of NCC and SMCC, respectively. This also sub-
stantiates the low yield pressure value in Heckel analysis, indicat-
ing the ease of deformation as compared to MCC. The high
number of binding sites and contact points in NCC and SMCC
resulted in better compaction and thus improved mechan-
ical properties.
The sensitivity of MCC, NCC, and SMCC towards the lubricant,
magnesium stearate was tested at different concentrations
(Figure 7). NCC showed the lowest lubricant sensitivity followed
1518 K. PAWAR ET AL.
125
Percent released (%) 100
75 MCC
NCC
50 SMCC
25
0 ation of microcrystalline cellulose: a critical review. Eur J
0 25 50 75 100 125 150
Time (min.)
Figure 8. Dissolution rate of amlodipine besylate from the tablets made with
MCC, NCC, and SMCC. Values represent the mean and standard deviation of
three replicates.
by SMCC and MCC at all concentrations of magnesium stearate. In
case of NCC, the amorphous conversion improved the lubricant
sensitivity of the material. This may be because of the rupture of
the lubricant film due to extensive deformation of particles during
compression [26]. Further, the highly porous nature of NCC con-
tributed to its lower sensitivity towards lubricants as observed for
hollow inulin particles [27,28]. In case of SMCC, the SiO2 coating
competes with magnesium stearate upon compression to cover
the cellulose surface reducing its sensitivity to magnesium stear-
ate [20].
Dissolution profiles in Figure 8 indicate that the tablets made
with MCC, NCC and SMCC demonstrated similar dissolution pro-
files for Amlodipine besylate. All materials achieved 100% dissol-
ution within 15 min. This indicates that NCC can provide a similar
dissolution profile as that of MCC and SMCC. Though NCC pro-
vided harder tablets, it has higher water absorption capacity,
which facilitated quick water penetration and subsequent dissol-
ution of drug in the tablets.
Conclusions
Non-crystalline cellulose (NCC) was evaluated as a novel excipient
in solid oral dosage forms. For this, it was compared with the
widely used tableting excipients such as MCC and SMCC.
Analysis of micromeritic properties indicates that NCC has higher
bulk density, better flow properties and high surface area as
compared to MCC. SEM data confirmed that NCC is porous
whereas DSC and XRD data indicated that it is a practically non-
crystalline material, as compared to MCC. Overall, NCC showed
similar compressibility, dissolution profile but lesser lubricant sen-
sitivity and better flow properties than MCC. Hence, NCC can be
considered a viable alternative excipient to MCC and SMCC for
solid dose products. As the manufacture process is simple, the
cost may be reduced.
Acknowledgements
The authors acknowledge the financial support provided by NSF
award, 1137682. Authors also acknowledge FMC Biopharma, JRS
Pharma, Foremost Farms, Alembic Pharma for providing samples
for this research.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
[1] Saigal N, Baboota S, Ahuja A, et al. Microcrystalline cellulose
as a versatile excipient in drug research. J Young
Pharmacists. 2009;1:6–12.
[2] Rojas J, Lopez A, Guisao S, et al. Evaluation of several
microcrystalline celluloses obtained from agricultural by-
products. J Adv Pharm Tech Res. 2011;2:144–150.
[3] Duki103/2 A, Thommes M, Remon JP, et al. Production of
pellets via extrusion3spheronisation without the incorpor-
Pharm Biopharm. 2009;71:38–46.
[4] Tobyn MJ, McCarthy GP, Staniforth JN, et al.
Physicochemical comparison between microcrystalline cellu-
lose and silicified microcrystalline cellulose. Int J Pharm.
1998;169:183–194.
[5] Block LH, Moreton RC, Apte SP, et al. Co-processed exci-
pients. Pharm Forum. 2009;35:1026–1028.
[6] Buckton G, Yonemochi E. Near IR spectroscopy to quantify
the silica content and difference between silicified micro-
crystalline cellulose and physical mixtures of microcrystal-
line cellulose and silica. Eur J Pharm Sci. 2000;10:77–80.
[7] Kachrimanis K, Nikolakakis I, Malamataris S. Tensile strength
and disintegration of tableted silicified microcrystalline cel-
lulose: influences of interparticle bonding. J Pharm Sci.
2003;92:1489–1501.
[8] Rojas J, Buckner I, Kumar V. Co-proccessed excipients with
enhanced direct compression functionality for improved
tableting performance. Drug Dev Ind Pharm. 2012;38:
1159–1170.
[9] Kumar V, Reus-Medina M, Yang D. Preparation, characteriza-
tion, and tabletting properties of a new cellulose-based
pharmaceutical aid. Int J Pharm. 2002;235:129–140.
[10] Kolakovic R, Peltonen L, Laaksonen T, et al. Spray-dried cel-
lulose nanofibers as novel tablet excipient. AAPS
PharmSciTech. 2011;12:1366–1373.
[11] Kothari SH, Kumar V, Banker GS. Comparative evaluations of
powder and mechanical properties of low crystallinity cellu-
loses, microcrystalline celluloses, and powdered celluloses.
Int J Pharm. 2002;232:69–80.
[12] Lee YY. inventor; Auburn University, assignee. Use of non
crystalline cellulose as a medicine tablet medium. United
States patent US 7,977,473 B1. 2011 Jul 12.
[13] Adamson AW, Gast AP. Adsorption of gases and vapors on
solids. New York (NY):Wiley-Interscience; 1997.
[14] Heckel RW. An Analysis of Powder Compaction Phenomena.
Trans. Metall. Soc. AIME 1961a;221:1001–1008.
[15] Heckel RW. DensityMetall. Soc. AIME paction Pheno-
menamed/11790. Trans. Metall. Soc. AIME 1961b;221:
671–675.
[16] Kawakita K, Ludde KH. Some considerations on powder
compression equations. Powder Technol. 1971;4:61–68.
[17] Fell JT, Newton JM. Determination of tablet strength by the
diametralcompression test. J Pharm Sci. 1970;5:688–691.
[18] Rojas J, Kumar V. Comparative evaluation of silicified micro-
crystalline cellulose II as a direct compression vehicle. Int J
Pharm. 2011;416:120–128.
[19] Edge S, Steele DF, Chen A, et al. The mechanical properties
of compacts of microcrystalline cellulose and silicified
microcrystalline cellulose. Int J Pharm. 2000;200:67–72.
[20] Rojas J, Kumar V. Effect of silicification on the tableting per-
formance of cellulose ii: a novel multifunctional excipient.
Chem Pharm Bull. 2012;60:603–611.

[21] Joshi AB, Patel S, Kaushal AM, et al. Compaction studies of
alternate solid forms of celecoxib. Adv. Powder Technol.
2010;21:452–460.
[22] Johansson B, Alderborn G. The effect of shape and porosity
on the compression behaviour and tablet forming ability of
granular materials formed from microcrystalline cellulose.
Eur J Pharm Biopharm. 2001;52:347–357.
[23] Sebhatu T, Alderborn G. Relationships between the effective
interparticulate contact area and the tensile strength of tab-
lets of amorphous and crystalline lactose of varying particle
size. Eur J Pharm Sci. 1999;8:235–242.
[24] Reier GE, Shangraw RF. Microcrystalline cellulose in tablet-
ing. J Pharm Sci. 1966;55:510–514.
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY 1519
[25] Zhang Y, Law Y, Chakrabarti S. Physical properties and com-
pact analysis of commonly used direct compression binders.
AAPS PharmSciTech. 2003;4:489–499.
[26] Nicklasson F, Johansson B, Alderborn G. Tabletting behav-
iour of pellets of a series of porosities - a comparison
between pellets of two different compositions. Eur J Pharm
Sci. 1999;8:11–17.
[27] Eissens AC, Bolhuis GK, Hinrichs WL, et al. Inulin as filler-
binder for tablets prepared by direct compaction. Eur J
Pharm Sci. 2002;15:31–38.
[28] Bolhuis GK, Eissens AC, Adrichem TP, et al. Hollow filler-
binders as excipients for direct compaction. Pharm Res.
2003;20:515–518.