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International Journal of Pharmaceutics 455 (2013) 1– 4

Contents lists available at ScienceDirect

International Journal of Pharmaceutics

j o ur nal ho me page: www.elsev ier .com/ locate / i jpharm

ield strength of microcrystalline cellulose: Experimental evidence byielectric spectroscopy

ailas S. Khomane, Arvind K. Bansal ∗

epartment of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali, Punjab, India

r t i c l e i n f o

rticle history:eceived 4 May 2013eceived in revised form 30 July 2013ccepted 4 August 2013vailable online xxx

eywords:

a b s t r a c t

The water-induced ionic charge transport in compacted microcrystalline cellulose (MCC) has beenreported to be governed by the densification behaviour. Hence, mechanical properties were expected tocorrelate with conductivity behaviour of MCC compacts. Both in-die and out-of-die compaction behaviourof MCC powder was investigated using a fully instrumented rotary tablet press. The dielectric mea-surements were carried out using a Novocontrol Concept 40 broadband dielectric spectrometer and dcconductivity (�dc) was extracted from the low frequency conductivity data at room temperature. As

ield strengtheckel analysisonductivityCC

ompactionlastic deformation

postulated, compaction pressure corresponding to maximum conductivity (�dc max) was observed to cor-relate with yield strength of MCC, determined using in-die and out-of-die Heckel analysis. AlthoughHeckel transformation is most commonly used in pharmaceutical technology, its general use to char-acterise the mechanical properties of organic pharmaceutical materials has been criticized. The presentstudy has provided experimental evidence that Heckel equation is practically useful to describe plasticdeformation of organic pharmaceutical powders.

. Introduction

Materials are usually classified into three categories, plastic,lastic and brittle based on their deformation behaviour. However,harmaceutical powders are viscoelastic in nature and predom-

nantly show a particular type of deformation behaviour (Patelt al., 2006). Plastic deformation is a prerequisite for pharma-eutical compaction. In pharmaceuticals, plasticity of the materials characterized in terms of its yield strength. Yield strength isefined as stress (compaction pressure) at which material startso deform plastically. Heckel transformation is most commonlysed to determine the yield strength of pharmaceutical materialsHeckel, 1961a,b).

Microcrystalline cellulose (MCC) is a valuable tableting excipi-nt. It is a predominantly plastically deforming material and itsechanical behaviour has been studied extensively in pharmaceu-

ical arena (Amidon and Houghton, 1995; Khan et al., 1988; Patelnd Bansal, 2011; Patel et al., 2011; Sun, 2008). Water induced-

harge transport in compacted MCC has also been reported (Ekt al., 1997; Nilsson et al., 2003, 2006; Strömme et al., 2003). It was

∗ Corresponding author at: Department of Pharmaceutics, National Institute ofharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab 16062, India. Tel.: +91 172 2214682 2126; fax: +91 172 2214692.

E-mail address: akbansal@niper.ac.in (A.K. Bansal).

378-5173/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2013.08.003

© 2013 Elsevier B.V. All rights reserved.

observed that charge transport mechanism in MCC was governedby compact densification behaviour.

Measurable water-induced charge transport through the com-pact requires a continuous pathway for the ions to move betweenthe particles. It was reported that at a given moisture content, theconnectedness of the interparticulate bonds and the mesopores,determined the magnitude of the conductivity in MCC compacts(Nilsson et al., 2003, 2006; Strömme et al., 2003). The densificationdependent dc-conductivity (�dc) of the MCC compacts can provideinsight into mechanistic aspects of particle rearrangement andplastic deformation. Particle rearrangement facilitates interpartic-ulate contacts that may lead to creation of continuous pathwaysrequired for conductivity and results in an increased �dc. However,as compaction pressure increases further and particle deformationcommences, continuous conductivity pathway may be disturbedand consequently, �dc may decline. Thus, the compaction pressurecorresponding to the �dc max is expected to correlate with yieldstrength of the material.

In the present work, dielectric and compaction properties ofMCC have been investigated to test the above hypothesis. Thedielectric measurements have been carried out using a broadbanddielectric spectrometer (Novocontrol GmbH Concept 40, Novo-control Technology, Germany). The �dc was extracted from the

low frequency conductivity data at room temperature. Mechani-cal properties of MCC powder have been investigated using a fullyinstrumented rotary tablet press. Both in-die and out-of-die com-paction data were analyzed using Heckel analysis.

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K.S. Khomane, A.K. Bansal / Internati

. Materials and methods

Prior to compaction, MCC (Avicel PH 112, FMC Biopolymer,hiladelphia, PA) was conditioned for at least one week in a desic-ator at room temperature at 75% RH created using saturated NaClalt solution. MCC gained a moisture content of 7.5% after this treat-ent. The powder was taken out of the desiccator and immediately

ubjected to compaction at various pressures.

.1. Thermogravimetric analysis (TGA)

Moisture content of preconditioned MCC was determined usingGA (851e TGA, Mettler Toledo, Switzerland) operating with STARe

oftware (version 9.0). About 4–5 mg of MCC was weighed accu-ately in open alumina crucibles and subjected to thermal scanf 25–300 ◦C at the heating rate of 10 ◦C min−1. Prior to analysis,nstrument was calibrated using high purity (>99.999%) aluminiumcalibration standards, Mettler-Toledo AG, Switzerland) (Khomanet al., 2011).

.2. Powder compaction

A rotary tablet press (Mini II, Rimek, Ahmedabad, India) wasquipped at one of the 8 stations with 15 mm D-tooling with a flatunch tip. A feed frame was used for uniform die filling and blindies were used at all other positions. Pre-compression rollers wereet out of function. Pretreated MCC powder was compacted at dif-erent compaction pressures ranging from around 0 to 100 MPa. Theableting speed was kept constant at 14.0 rpm. The tablet weightas varied so as to produce compacts of ∼2 mm thickness. After

ompaction, the compacts were again stored over a saturated NaCl

olution for approximately one week to ensure equilibrium.

Compaction data was acquired by Portable Press AnalyzerTM

version 1.2, revision D, Data acquisition and analyzing system,uuMan Oy, Kuopio, Finland), through an infrared (IR) telemetric

10-3 10-2 10-1 100 10 1 1

Frequen

100

101

102

103

104

105

Perm

ittivi

ty'

dc-like imperfe

w

Fig. 1. Real part of the permittivity for M

urnal of Pharmaceutics 455 (2013) 1– 4

device with 16-bit analog-to-digital converter (6 kHz). Force wasmeasured by strain gauges at upper and lower punches (350×,full Wheatstone bridge; I. Holland Tableting Science, Nottingham,UK), which were coupled with displacement transducers (linearpotentiometer, 1000×). Upper and lower punch data were recordedand transmitted on separate channels by individual amplifiers(“Boomerangs”). The amplifiers truncated the raw data from 16bit to 12 bit after measuring to check IR transmission (data trans-mission rate – 50 kbaud; internal data buffer – 1024 measurementpoints). Analysis of compaction data was carried out by PPA analy-sis software (version 1.2, revision D, PuuMan Oy, Kuopio, Finland).Accuracy of force and displacement transducers was 1% and 0.02%,respectively. The suitability of the data acquisition system has beenreported in the literature (Khomane et al., 2012, 2013; Matz et al.,1999).

2.3. Dielectric spectroscopy measurements

Dielectric measurements were carried out using a broadbanddielectric spectrometer (Novocontrol GmbH Concept 40, Novocon-trol Technology, Germany) in the frequency range of 10−2 to 106 Hz.Relative humidity and temperature were controlled by purgingcompressed gas connected to Quadro system, initialized for drygas option. Temperature was controlled within ±0.05 K for isother-mal measurements. The compacts were placed into a dielectric celldesigned for powder compact and were subsequently subjected todielectric measurements. A constant force on the upper electrodeensured good contact between the sensor and compact throughoutexperiments (Dantuluri et al., 2011).

The �dc is extracted from the low frequency conductivity dataaccording to previously described method (Mattsson et al., 1999;

Nilsson et al., 2003). Briefly, the real part of the conductivity wasplotted versus its derivative with respect to the logarithm of theangular frequency and �dc was then extracted from a linear fit ofthe data.

02 10 3 10 4 10 5 10 6 10 7

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CC tablet equilibrated at 75% RH.

K.S. Khomane, A.K. Bansal / International Jo

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ig. 2. Conductivity as a function of tablet density. The presented values are averagesf five measurements and error bars represent their standard deviations.

. Results and discussion

.1. Permittivity spectra

Fig. 1 shows a representative dielectric permittivity spectrumf MCC tablet. A dipolar loss process, also called as ˇwet relaxationssociated with the collective motions of a water-cellulose mixedhase (Einfeldt et al., 2000, 2001; Nilsson et al., 2006), was observedround 100 Hz. At low frequencies (below 1 Hz) the permittivityncreased with decreasing frequency and was observed to followower-law behaviour. This behaviour is characteristic for dc-like

mperfect charge transport and has already been reported for MCCNilsson et al., 2003, 2006).

.2. Density dependence of conductivity

Fig. 2 shows the �dc of MCC as a function of tablet density. Con-uctivity values were extracted from the dc-like imperfect chargeransport region of permittivity spectra (Fig. 1). There was initialapid increase in the conductivity with increasing tablet density.owever, it started decreasing above 0.9 g/cm3. This behaviour ofCC is consistent with the previous reports (Nilsson et al., 2003,

006; Strömme et al., 2003), wherein this density dependent con-uctivity behaviour of MCC was attributed to its densification andeformation behaviour. The previous works have investigated con-uctivity behaviour at low (Strömme et al., 2003) and high (Nilssont al., 2003) tablet density, separately in two different publications.ence determination of �dc max was not possible from the reportedata. Moreover, conductivity as a function of compaction pressure

as also not reported previously.

Conductivity values of MCC compacts were plotted as a func-ion of compaction pressure to gain some mechanistic insightsFig. 3). Initially, �dc increased with the compaction pressure,

ig. 3. Effect of compaction pressure on conductivity of MCC. The presented val-es are averages of five measurements and error bars represent their standardeviations.

urnal of Pharmaceutics 455 (2013) 1– 4 3

however, as the pressure exceeded 16.85 MPa, conductivity valuesstarted decreasing and attained a plateau at higher compactionpressures. This can be explained by the mechanical events i.e.particle rearrangement and plastic deformation that occur duringcompaction.

As discussed earlier, a continuous conduction pathway is a pre-requisite of water-induced charge transport in the MCC compacts.MCC is a semicrystalline material and water is associated with theavailable anhydroglucose units (AGUs) in the amorphous domains(Zografi et al., 1984). Water binds to the amorphous fibrils at thesurface of the MCC particles during storage under humid con-ditions (Nilsson et al., 2003). Thus, interparticulate contacts arerequired for the ions to move between the particles. Under lowcompaction pressures (<16.85 MPa), particle rearrangement tookplace that facilitated interparticulate contacts. This was observed asan increase in conductivity up to a compaction pressure of ∼16 MPa.Increase in compaction pressure beyond this resulted in particledeformation that led to decrease in surface sites available for theion binding. Reduction in surface sites decreases the number ofpossible routes for the ions to take. Hence, a decrease in the con-ductivity was observed at compaction pressures beyond 16.85 MPa.Therefore, it was postulated that compaction pressure correspond-ing to �dc max corresponds to the yield strength. This was furtherconfirmed by employing Heckel analysis to the compaction data.

3.3. Heckel analysis

The Heckel equation (Eq. (1)), one of the most popular mathe-matical models, provides a method for transforming a parametricview of the force and displacement data to a linear relationship forthe materials undergoing compaction (Heckel, 1961a,b). It is basedon assumption that densification of the bulk powder under forcefollows first-order kinetics

ln[

11 − D

]= KP + A (1)

where D is the relative density of the tablet (the ratio of tabletdensity to true density of powder) at applied pressure P and K isthe slope of straight line portion of the Heckel plot. The reciprocaltransformation of the slope gives mean yield pressure, Py. The ini-tial curve portion of Heckel plot arises from particle rearrangementbefore plastic deformation takes place. Constant A gives densifica-tion of the powder due to initial particle rearrangement. Heckelalso proposed a relationship between the constant K and the yieldstrength (Y) for plastically deforming materials.

Y = 13K

(2)

Since, Py is inversely related to K, yield strength of the materialwas found to be one third of the Py (Hersey and Rees, 1971; Sunand Grant, 2001).

Two method of data collection have been reported for Heckeltransformation, namely, “zero pressure” or “out-of-die” and “at-pressure” or “in-die” Heckel analysis (Khomane et al., 2012; Patelet al., 2006). In the first method, D is measured on the compactsafter relaxation following ejection from the die and Py derived fromthis method is called as “true mean yield pressure”. In the secondmethod, the relationship between D and P is established from a sin-gle compression cycle (Khomane and Bansal, 2013). Py derived fromthis method is called as “apparent mean yield pressure”. Both in-dieand out-of-die Heckel analysis were carried out in the present study

(Fig. 4). Heckel parameters were determined from linear portion ofthe curves and are summarized in Table 1. Yield strength givenby in-die and out-of-die Heckel analysis correlated well with thecompaction pressure corresponds to �dc max. This confirmed the

4 K.S. Khomane, A.K. Bansal / International Journal of Pharmaceutics 455 (2013) 1– 4

Compaction Pressure (MPa)

ln (1

/1-D

)

0 2 0 4 0 6 0 8 0 1 0 00

1

2

3

4

Compaction Pressure (MPa)

ln (1

/1-D

)

0 2 0 4 0 6 0 8 0 1 0 00

1

2

3(a) (b)

Fig. 4. In-die (a) and out-of-die (b) Heckel plot for MCC.

Table 1In-die and out-of-die Heckel parameters for MCC.

Method Slope (K) Mean yield pressure (Py) Yield strength (Y) Regression coefficient (R2)

hc

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A

D

E

E

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Out-of-die 0.02172 46.04 MPa

In-die 0.02013 49.68 MPa

ypothesis that yield strength of MCC is the compaction pressureorresponding to �dc max.

. Conclusion

As hypothesized, the compaction pressure corresponding todc max has been observed to correlate with yield strength ofCC determined using Heckel transformation. This correlationship

nables us to capture the mechanical events occurred during theompaction of MCC. The initial non linear portion of the Heckelurve (Fig. 4) was attributed to the particle rearrangement. This islso evidenced from the conductivity–pressure curve (Fig. 3).

Although Heckel transformation is most commonly used inharmaceutical technology, its general use to characterise theechanical properties of organic pharmaceutical materials has

een criticized. This primarily due to lack of evidence between theathematical parameters derived from Heckel equation (Py or Y)

nd plastic deformation of the pharmaceutical materials (Paronennd Ilkka, 1996; Sonnergaard, 1999). In the present study, excel-ent correlationship between compaction pressure correspondingo �dc max and yield strength derived from Heckle plot providedxperimental evidence that Heckel equation is equally useful toescribe plastic deformation of organic pharmaceutical powders.

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