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International Journal of Pharmaceutics 441 (2013) 527– 534

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

jo ur nal homep a ge: www.elsev ier .com/ locate / i jpharm

low and compaction behaviour of ultrafine coated ibuprofen

arth K. More, Kailas 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 23 August 2012eceived in revised form 30 October 2012ccepted 31 October 2012vailable online 8 November 2012

eywords:ompactionry coating

buprofenabletingechanical properties

uper plasticityompressionrushing strength

a b s t r a c t

Good flow and compaction properties are prerequisites for successful compaction process. Apart frominitial profile, mechanical properties of pharmaceutical powders can get modified during unit processeslike milling. Milled powders can exhibit a wide range of particle size distribution. Further downstreamprocessing steps like compaction can be affected by this differential particle size distribution. This hasgreatest implications for formulations like high dose drugs wherein the active pharmaceutical ingredient(API) contributes the maximum bulk in the final formulation. The present study assesses the impact ofdry coating with ultrafine particles of same material, on the flow and compaction properties of the corematerial. Ibuprofen was selected as model drug as it has been reported to have poor mechanical prop-erties. Ultrafine ibuprofen (average size 1.75 �m) was generated by Dyno® milling and was dry coatedonto the core ibuprofen particles (average size 180 �m). Compaction studies were performed using afully instrumented rotary tablet press. Compaction data was analyzed for compressibility, tabletability,compactibility profiles and Heckel plot. Dry coating of the ibuprofen exhibited greater compressibil-ity and tabletability, at lower compaction pressure. However, at compaction pressure above 220 MPa,

compressibility and tabletability of coated as well as uncoated materials were found to be similar. Heckelanalysis also supported the above findings, as Py value of uncoated ibuprofen was found to be 229.49 MPaand for 2.0% ultrafine coated ibuprofen was found to be 158.53 MPa. Lower Py value of ultrafine coatedibuprofen indicated ease of plastic deformation. Superior compressibility and deformation behaviour ofultrafine coated ibuprofen attributed to increased interparticulate bonding area. This strategy can alsobe explored for improving tabletability of high dose poorly compressible drugs.

. Introduction

Tablet is the most preferred dosage form to orally deliver drugs,s it offers numerous technical and economical advantages (Hant al., 2008; Patel et al., 2006). However, poor mechanical propertiesecome a hurdle in successful development of tablet formulation.his becomes severe in case of high dose poorly compressible drugsike ibuprofen. Moreover, mechanical properties of pharmaceuticalowders can modify during unit processes like milling. Milling canenerate ultrafine or nano particles that can get coated onto theigger core particles and affect the mechanical properties like flownd compressibility. This may have profound impact in case of highose poorly compressible drug. Hence it is imperative to study theffect of ultrafine coating on the mechanical properties of high dose

oorly compressible drug.

Various approaches have been reported to improve the mechan-cal properties of the material. Crystal habit modification by

∗ 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 © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2012.10.048

© 2012 Elsevier B.V. All rights reserved.

crystallization from different solvents was reported as an aid toimprove the densification behaviour of nitrofurantoin (Marshalland York, 1991). Bacher et al., showed improved compactibilityand compressibility of calcium carbonate and sorbitol using wetgranulation (Bacher et al., 2008). The effect of particle size and com-paction force on the compaction behaviour of paracetamol was alsostudied (Patel et al., 2007). Co-crystallization of caffeine also led toimprovement in the mechanical properties (Sun and Hou, 2008).Recently, modification of the surface by coating, has been reportedto improve the flow (Hou and Sun, 2008; Jallo et al., 2011; Yanget al., 2005) and compaction properties (Shi and Sun, 2011) of amaterial. When the materials blended, differ largely in their particlesizes, the smaller material tend to coat on the coarser material. Theadhering material tends to form a percolating network which gov-erns the compaction properties of the material (Barra et al., 1999).Mechanical properties of the guest material critically contributeto these changes. It was demonstrated that poorly bonding guestmaterial improves the flow properties, but deteriorates the com-paction properties (Sun, 2011). For example, dry coating of colloidal

silica (Cab-O-Sil) on the MCC particles improved flow property butreduced the tabletability (Chattoraj et al., 2011). Improvement inthe flow property was attributed to reduced interaction/bondingbetween the particles and ‘ball bearing’ effect. However,

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study of IBU and UIBU. Tablets of the materials were prepared by

28 P.K. More et al. / International Journ

eterioration of the compaction properties was attributed to reduc-ion in the bonding strength of the material due to presence ofoorly bonding silica on the surface of MCC.

It has also been reported that coating of an API with highly bond-ng polymers like PVP improved tableting properties (Shi and Sun,999). All the reported examples employed coating of a differentuest material on the core material and bonding strength played

crucial role in governing the compaction behaviour. However, aeport dealing with coating of the ultrafine particles (particles hav-ng size below 15 �m) of the same material and its impact on flownd compaction is still lacking.

Present study assesses impact of coating of ultrafine particlesf same material on the flow and compaction properties of theore material. Ibuprofen was selected as model drug. Ultrafine par-icles of ibuprofen (average size 1.75 �m) were generated usingyno® mill and coated onto core material of average particle sizef 180 �m, by dry coating method. Compaction behaviour wasssessed using a fully instrumented rotary tablet press and dataas analyzed for compressibility, tabletability, compactibility pro-le (CTC profile) and Heckel plot. This science based approach helpso understand the effect of material properties on the processabilityf tablets in the perspective of QbD principles (Yu, 2008).

. Experimental

.1. Materials

.1.1. IbuprofenIbuprofen was kindly gifted by Arbro Pharmaceuticals Ltd., New

elhi, India. Sample exhibited plate shaped crystal habit. It wasassed through set of sieves and the fraction BSS # 60–80 was useds ibuprofen core/bulk material (IBU).

.2. Methods

.2.1. Generation of ultrafine ibuprofen (UIBU)Wet milling process was used to generate ultrafine IBU. 10 g of

BU and 100 ml of distilled water was introduced into the millinghamber. Twice volume (200 ml) of glass beads of 0.75–1 mm sizeas added to it. IBU was subjected to wet milling using Dyno® mill

Willy A. Bachofen AG Maschinenfabrik, Basel, Switzerland) for 1 h.emperature of the milling chamber was maintained at 4.0 ± 0.2 ◦Curing the milling process. Average particle size of IBU ultrafineuspension was determined using Zeta sizer® (Nano ZS, Malvern,

orcestershire, UK). Ultrafine suspension obtained by the millingrocess was dried overnight at 60 ◦C in a vacuum oven (Narang Sci-ntific Works Pvt Ltd., New Delhi, India). The agglomerated materialbtained upon drying was milled using mortar pestle and passedhrough BSS # 200 to get loose aggregates of ultrafine IBU (UIBU).

.2.2. Coating of UIBU on core particles (IBU)Initially, UIBU and IBU were geometrically mixed. The mix-

ure (10 g) was poured into a plastic bottle and 20 g of glasseads (4–5 mm size) were added to it. The method was optimizedor the ratio of glass beads to IBU (1:1, 2:1, 3:1) and processingime (10 min, 20 min, 30 min). The bottle was attached to horizon-ally mounted shaft of Kalweka® instrument (HD 410 E, Kalweka,ujarat, India) and rotated at 150 rpm. Different percentages ofltrafine coatings were applied to obtain ultrafine coated IBUUCIBU). A control (DCC) sample was generated by processing IBUnder similar conditions of amount of glass beads and processingime, but without adding UIBU.

.2.3. Solid state characterizationPXRD patterns of IBU, UIBU and 2.0% UCIBU were recorded at

oom temperature on Bruker’s D8 Advance diffractometer (Bruker

harmaceutics 441 (2013) 527– 534

AXS, Karlsruhe, West Germany) with Cu K� radiation (1.54 A), at40 kV, 40 mA passing through nickel filter. Analysis was performedin a continuous mode with a step size of 0.01◦ and step time of 1 sover an angular range of 3–40◦ 2�. Obtained diffractograms wereanalyzed using DIFFRACplus EVA (Version 9.0) diffraction software(Bruker AXS, Karlsruhe, West Germany).

Differential scanning calorimetry (DSC) of IBU, UIBU and 2.0%UCIBU was conducted using DSC, Model Q2000 (TA Instruments,New Castle, USA). Prior to analysis, the instrument was calibratedusing high purity standard of Indium for temperature and heat flowmeasurement, respectively. DSC cell was purged with 50 ml/mindry nitrogen. Accurately weighed samples (1–2 mg) were heated instandard aluminium pans in the temperature range of 25 to 100 ◦C,using a heating rate of 10 ◦C/min. Low temperature DSC of UIBU wascarried out in the temperature range of −60 to 25 ◦C to rule outthe possibility amorphization during milling. Obtained data wasanalyzed using the software Universal Analysis® (TA Instruments,New Castle, USA).

Hot stage microscopy (HSM) of IBU, UIBU and 2.0% UCIBUwas carried out using Leica DMLP polarized microscope (LeicaMicrosystems, Wetzlar, Germany) equipped with Linkam LTS350 hot stage (Leica Microsystems, Wetzlar, Germany). Sam-ples were mounted on the glass slide and heated from 25 to80 ◦C at the heating rate of 5 ◦C. Photographs were taken usingJVS colour video camera and analyzed using Linksys32 software.Additionally, optical and polarized microscopy of IBU, UIBU and2.0% UCIBU were performed by mounting them on glass slidesand observing them under optical as well as polarized lightmode.

Particle size distribution of DCC and UCIBU samples wasdetermined microscopically by measuring diameter along thelongest axis (DMLP polarized microscope, Leica Microsys-tems, Wetzlar, Germany). Moisture content (n = 3) of DCC andUCIBU samples was determined by Karl Fischer (KF) titration(Metrohm 794 Basic Titrino, Herisau, Switzerland). Instrumentwas calibrated with disodium tartrate dihydrate for accu-rate moisture determination. Sample size of approximately200 mg was utilized for the moisture content determina-tion.

Scanning electron microscopy (SEM) of UIBU, DCC and 2.0%UCIBU was performed using a scanning electron microscope (S-3400, Hitachi Ltd., Tokyo, Japan) operated at an excitation voltageof 10 kV at different magnifications. Powders were mounted ontosteel stage using double sided adhesive tape and coated with goldusing ion sputter (E-1010, Hitachi Ltd., Tokyo, Japan).

2.2.4. True density and flow propertiesTrue density (n = 3) of IBU was determined by helium pycnome-

ter/true density metre (Pycno 30, Smart Instruments, Mumbai,India). Bulk density (n = 3) of DCC and UCIBU samples was deter-mined using a 100 ml measuring cylinder. Bulk density of UIBU(n = 3) was determined using a 10 ml measuring cylinder. Tappeddensity (n = 3) of the samples was determined by bulk density appa-ratus (ETD 1020, Electrolab, Mumbai, India) using USP method I.Flow properties of the materials were determined by calculatingHausner ratio and Carr’s index.

2.2.5. Compaction properties2.2.5.1. Hydraulic press. Hydraulic press (Hydraulic Unit Model3912, Carver Inc., Wabash, USA) was used to perform compaction

compacting 400 mg of materials up to 35 MPa compaction pressurein a hydraulic press with a dwell time of 2 s using 13 mm punch dieset. The tablets were further characterized for weight, thicknessand hardness.

al of Pharmaceutics 441 (2013) 527– 534 529

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taining 0.5, 1 and 2.0% of UIBU coating, respectively, were generatedusing this optimized method.

P.K. More et al. / International Journ

.2.5.2. Instrumented rotary tablet press. Rotary tablet press (MiniI, Rimek, Ahmedabad, India) was equipped at one of the 8 stations

ith 8 mm D-tooling with flat punch tip. Feed frame was used forniform die filling and blind dies were used at all other positions.re-compression rollers were set out of function. Tablets of eachaterial were compressed at constant volume. The weight of the

ablet was adjusted to 250 ± 5 mg. The applied compaction forceas controlled by the pressure roller with a hand wheel. Com-action force was initially adjusted to low and increased graduallyo collect data at different compaction pressure. Tableting was per-ormed at the constant speed of 14 rpm. Compaction data werecquired by portable press analyzerTM (PPA) Version 1.2, Revision

(Data Acquisition and Analyzing System, PuuMan Oy, Kuopio,inland), through an infrared (IR) telemetric device with 16-bitnalogue-to-digital converter (6 kHZ). Analysis of compaction dataas carried out by PPA Analyze software (Version 1.2, Revision D,

uuMan Oy, Kuopio, Finland) (Khomane et al., 2012).

.2.6. Determination of tablet tensile strength and porosityDiameter and thickness of the tablets were measured using

alliper (Mitutoyo America Corporation, Chicago, USA) and theireights were measured using a digital balance (PM480, Mettler

oledo AG, Greitensee, Switzerland). The hardness of the tabletsas measured using tablet hardness tester (Erweka, Connecticut,SA). The tensile strength (�) of the tablets was calculated by usingq. (1).

= 2F

�dt(1)

Here, F is the hardness (N) of the tablet obtained by hardnessester, d is the diameter and t is the thickness of the tablet. Theensity of the tablet was calculated from the weight and volume ofhe tablet. The solid fraction of the tablet was calculated by dividingensity of the tablet with true density of IBU. The porosity of theablet was calculated from the solid fraction using Eq. (2).

orosity = 1 − solid fraction (2)

Compaction pressure was calculated from the punch face areand compaction force. The data obtained was interpreted to obtainTC profile and Heckle plot. Tabletability is represented by the plotf tablet tensile strength against compaction pressure (Joiris et al.,998). Compressibility is represented by the plot of tablet poros-

ty against compaction pressure (Joiris et al., 1998). Compactibilitys represented by the plot of tablet tensile strength against tabletorosity (Joiris et al., 1998). Heckel plot is the linear transforma-ion of the parametric force and displacement relationship (Patelt al., 2010). It is represented by the Plot of ln [1/1−D] against com-action pressure where D is the relative density of tablet (tabletensity/true density of powder). Reciprocal transformation of thelope of the linear portion of the Heckel plot gives mean yield pres-ure (Py) (Heckel, 1961).

. Results and discussion

.1. Generation of UIBU

Temperature of the milling chamber was maintained at.0 ± 0.2 ◦C to prevent melting or degradation of IBU during the wetilling process. Average particle size of the ultrafine suspensionas found to be 1063 nm (PDI 0.469) by Zetasizer®. No stabilizer(s)as included as it may have altered the compaction properties

f IBU. Drying of ultrafine suspension produced aggregates whichere milled using mortar pestle and passed through BSS # 200.

his gave a powder of mean diameter of 1.75 �m and a range of.5–3.1 �m.

Fig. 1. Plot of particle size distribution of IBU against glass beads/IBU ratio forprocessing time of (a) 10 min, (b) 20 min and (c) 30 min.

3.2. Coating of UIBU on core particles

Dry coating involved breaking down the aggregates of UIBUand coating them onto IBU. However, the process may also reducethe initial particle size of IBU. Therefore, process was optimizedwith respect to (i) ratio of glass beads: IBU (ii) and processingtime. Particle size distribution of IBU after different processing wasdetermined using optical microscopy and plotted against the threedifferent ratios of glass beads: IBU and three different time points,as shown in Fig. 1.

The maximum ratio and processing time that did not signifi-cantly affect the initial particle size of IBU were selected for drycoating of UIBU on IBU. Accordingly, glass beads: IBU ratio of 2:1and 20 min processing time were selected (Fig. 1b). Three differentdry coated batches 0.5% UCIBU, 1.0% UCIBU and 2.0% UCIBU, con-

Fig. 2. PXRD overlay of IBU, UIBU and 2.0% UCIBU.

530 P.K. More et al. / International Journal of Pharmaceutics 441 (2013) 527– 534

Table 1Particle size distribution and moisture content of samples.

Parameter DCC 0.5% UCIBU 1.0% UCIBU 2.0% UCIBU

Particle size distribution (�m) D50 180 168 175 178D90 230 214 212 216

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.3. Solid state characterization

Particle size distribution and moisture content of DCC and UCIBUre shown in Table 1. Particle size distribution of control (DCC)nd coated materials was found similar. Moisture content of theaterials was found <0.1% (Table 1).PXRD pattern for IBU, UIBU and 2.0% UCIBU (Fig. 2) showed sharp

eaks and compared well with the reported pattern (Plakkot et al.,011). PXRD pattern of UIBU was found similar to IBU indicating nohange in the solid form during wet milling process. However, thentensity of the peaks decreased probably due to reduced preferredrientation (Koradia et al., 2004; Roberts et al., 2002; Varasteh et al.,009). PXRD pattern of 2.0% UCIBU also compared well with IBU,hus ruling out any solid form change during the coating process.

DSC traces of IBU, UIBU and 2.0% UCIBU showed sharp melt-ng endotherms that correlated well with its reported values inhe literature (Fig. 3) (Kocbek et al., 2006). IBU showed meltingndotherm at 74.75 ◦C (onset temperature) with an enthalpy ofusion of 127.9 J/g. UIBU showed melting endotherm at 67.71 ◦Conset temperature) with an enthalpy of fusion of 106.5 J/g. UIBUhowed lowering of the melting point and enthalpy of fusion.owering of the enthalpy of fusion may be attributed to amor-hization during milling. The low temperature DSC (−60 to 25 ◦C)as carried out to characterize the glass transition temperature of

morphous UIBU. DSC thermogram showed no endothermic eventround reported glass transition temperature i.e. −42.3 ◦C indicat-ng absence of amorphous content in the given sample (Fig. 4).ence in absence of amorphous content, lowering of the meltingoint and enthalpy of fusion was attributed to the reduction inhe particle size (Alavi and Thompson, 2006; Eckert et al., 1993;uri and Yang, 2007). The 2.0% UCIBU showed melting endotherm73.37 ◦C) at a position, almost similar to IBU, with an enthalpy ofusion of 129.3 J/g.

Thermal events of IBU, UIBU and 2.0% UCIBU were also visual-zed using HSM and they corroborated findings of DSC. However,SM of 2.0% UCIBU revealed interesting information. As shown inig. 5, ultrafine particles showed melting at 73.3 ◦C (Fig. 5c and d),

Fig. 3. DSC overlay of IBU, UIBU and 2.0% UCIBU.

0.08 (0.010) 0.09 (0.017) 0.076 (0.005)

followed by melting of the core IBU particles at 78.5 ◦C (Fig. 5e andf). This further confirmed coating of UIBU over the surface of IBU.

Optical and polarized microscopy of IBU, UIBU and UCIBU wereperformed and polarized microscopy showed birefringence in allthe cases.

SEM images of DCC, 2.0% UCIBU and UIBU were captured at dif-ferent magnifications. DCC crystals exhibited irregular plate shapehabit (Fig. 6a). Surface of the DCC particles was found rough atthe magnification of 1000× (Fig. 6c) and 10,000× (Fig. 6e). The2.0% UCIBU crystals also exhibited plate shaped habit (Fig. 6b) andshowed presence of ultrafine particles on the surface (Fig. 6d andf). SEM images of UIBU showed particles in the ultrafine range(0.5–5 �m) (Fig. 6g and h). Particle size of the ultrafine particlespresent on the surface of the IBU particles also determined usingSEM (n = 25). Particle size was found in the range of 0.4–2.4 �m.

3.4. True density and flow properties

True density of IBU was found to be 1.1174 ± 0.0006 g/ml whichcorrelated well with its reported value (Patel and Bansal, 2011).UCIBU (0.5, 1.0 and 2.0%) showed marginally lower, while UIBUshowed significantly lower bulk density, as compared to DCC. Asimilar trend was also seen in case of tapped density. Carr’s indexand Hausner ratio were evaluated as marker of flow properties.UIBU showed significant increase, whereas 0.5, 1.0, 2.0% UCIBUshowed marginal increase in that order (Table 2). Poor flow prop-erty of UIBU could be attributed to increased cohesivity, due tomilling.

3.5. Compaction properties

3.5.1. Hydraulic pressHydraulic press was used to perform compaction study of UIBU

as its poor flow property and limited quantity, prevented study on

a fully instrumented rotary tablet press. CTC and Heckel analysis ofIBU and UIBU were performed using the data obtained after char-acterization of the tablets. Tabletability of UIBU was found superiorover IBU at all compaction pressures as shown in Fig. 7.

Fig. 4. DSC thermogram of UIBU at low temperature (−60 to 25 ◦C).

P.K. More et al. / International Journal of Pharmaceutics 441 (2013) 527– 534 531

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ig. 5. HSM of 2.0% UCIBU (a) 32.1 ◦C normal mode, (b) 33.1 ◦C polarized mode, (c)

olarized mode.

Compressibility of UIBU was also found greater than IBU at allompaction pressure (Fig. 8). Compactibility profile of both theaterials was found similar. Py values of IBU and UIBU were found

o be 50.54 MPa and 18.98 MPa, respectively.

.5.2. Instrumented rotary tablet pressCTC analysis of DCC, 0.5% UCIBU, 1.0% UCIBU and 2.0% UCIBU was

arried out using the compaction data obtained by instrumentedotary tablet press. Tabletability is the ability of the material toe transformed into tablets of sufficient strength upon applica-ion of compaction pressure (Joiris et al., 1998). Increasing trend inhe tabletability was obtained upon increasing coating with ultra-ne particles of IBU (Fig. 9a). Tabletability of DCC and 2.0% UCIBUas significantly different (P = 0.004). Better tabletability of UCIBUas achieved due to improved compressibility over DCC at all the

ompaction pressures (Fig. 9b). Higher compressibility indicatesreater tendency of volume reduction upon application of com-action pressure (Joiris et al., 1998). However, above compactionressure of 220 MPa, the compressibility and tabletability of DCCnd 2.0% UCIBU were found to be almost similar. Compactibilitys the ability of the material to form tablets of sufficient tensiletrength under the effect of densification (Joiris et al., 1998). Com-

actibility of DCC and UCIBU were found similar at all compactionressure (Fig. 9c). Heckel analysis was also performed using theompaction data (Fig. 9d). Py value for DCC, 0.5%, 1.0%, and 2.0%CIBU was found to be 229.49, 194.12, 168.00 and 158.53 MPa.

able 2ulk and flow properties of materials.

Material Bulk density Tapped densi

DCC 0.534 (0.003) 0.682 (0.005)UIBU 0.308 (0.002) 0.495 (0.004)0.5% UCIBU 0.509 (0.007) 0.678 (0.005)1.0% UCIBU 0.491 (0.005) 0.678 (0.003)2.0% UCIBU 0.467 (0.003) 0.662 (0.013)

tandard deviations are given in parentheses.

normal mode, (d) 74.0 ◦C polarized mode, (e) 78.5 ◦C normal mode and (f) 78.8 ◦C

UCIBU showed significantly lower Py value than DCC and fur-ther a decreasing trend was observed with higher percentage ofcoating.

3.6. Impact on flow behaviour

Present work demonstrated significant impact of ultrafine coat-ing i.e. coating with ultrafine particles (average size 1.75 �m), onthe coarser particles (average size 180 �m) of the same materialon the mechanical properties of IBU including its flow behaviour.Flow properties of the coated materials were found different thancontrol material. Ultrafine particles tend to coat on the surface ofbulk particles, as they possess high surface energy (as evident fromthe SEM images). Ultrafine particles present on the surface formeda percolating network that enhanced interactions between the par-ticles. This led to increase in the cohesivity of the material (Fig. 10).Increased Carr’s index and Hausner ratio of UCIBU over IBU indi-cated deterioration of the flow properties that was attributed toincrease in the cohesivity of the material. Moreover, an increas-ing trend was observed (in both the cases) upon increasing coatingload. This indicated worsening of flow properties upon increasingcoating load, due to formation of a more cohesive and strong per-

colating network. Cohesive materials tend to form aggregates anddemonstrate poor flow. Such materials are difficult to pack than freeflowing materials (Luo et al., 2008). This explains the decreasingtrend of bulk and tapped density of UCIBU, upon increasing % of

ty Carr’s index Hausner ratio

21.621 (0.136) 1.275 (0.008) 37.823 (0.181) 1.608 (0.005) 24.989 (1.120) 1.333 (0.020) 27.500 (0.562) 1.379 (0.006)

29.365 (1.375) 1.416 (0.028)

532 P.K. More et al. / International Journal of Pharmaceutics 441 (2013) 527– 534

Fig. 6. SEM images (a) DCC 300× magnification, (b) 2.0% UCIBU 300× magnification, (c) DCC 1000× magnification, (d) 2.0% UCIBU 1000× magnification, (e) DCC 10,000×magnification, (f) 2.0% UCIBU 10,000× magnification, (g) UIBU 6000× magnification and (h) UIBU 15,000× magnification.

Fig. 7. Tabletability of IBU and UIBU.

Fig. 8. Compressibility of IBU and UIBU.

P.K. More et al. / International Journal of Pharmaceutics 441 (2013) 527– 534 533

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ig. 9. Compaction data analysis of DCC, 0.5% UCIBU, 1.0% UCIBU and 2.0% UCIBU (a

oating. Hence, dry coating with ultrafine particles, slightly deteri-rated the flow properties of IBU.

.7. Impact on compaction behaviour

Tabletability of the material is governed by its compressibilitynd compactibility. Compressibility is dependent on the availableonding area, while compactibility is dependent on the bondingtrength of the material (Sun, 2011). Modification of the surface,ike coating, may change any of the above property (Shi and Sun,011; Yang et al., 2005). Tabletability of UIBU was found to beuperior over IBU, due to its better compressibility. Ultrafine par-icles enhanced the overall bonding area thus facilitating plastic

eformation and compressibility. Findings from Heckel analysislso supported this behaviour, where in UIBU demonstrated lowery value than IBU. This indicated ease of plastic deformation andence better compressibility of UIBU. It may be postulated that the

Fig. 10. Schematic diagram depicting impact of ultrafine coa

etability plot, (b) compressibility plot, (c) compactibility plot and (d) heckel plot.

compaction properties might have altered due to modification ofthe solid form of the drug. However, this possibility was ruled outby performing solid state characterization of UIBU.

Tabletability of the UCIBU was found higher than DCC at allcompaction pressures and an increasing trend was observed withincreasing percentage of coatings. This was attributed to theimproved compressibility of UCIBU over DCC. As discussed ear-lier, it was an outcome of the formation of percolating network ofUIBU. Significant improvement in the tabletability was observedin case of 2.0% UCIBU (P = 0.004). Presence of ultrafine particleson the surface of UCIBU particles, increased the bonding area thatled to better plastic deformation and hence improved tabletabil-ity. However, at higher compaction pressure, the compressibility

(and hence tabletability) of DCC and UCIBU was found to be almostsimilar. As the particle size of IBU and UCIBU was found almostsimilar, the effect of particle size on the compaction propertieswas not expected. Compactibility of both the materials was found

ting on flow and compaction behaviour of ibuprofen.

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34 P.K. More et al. / International Journ

imilar, as coating with the same material did not alter the bondingtrength. Compressibility data was also supported by the Heckelnalysis where in the Py values of UCIBU were found lower thanCC and a decreasing trend was observed with increasing % ofoating. Py value indicates the pressure required to undergo plas-ic deformation. Lower Py value of UCIBU indicated ease of plasticeformation over DCC. As evident from Fig. 9a, 2.0% UCIBU requiredround 21 MPa compaction pressure to form tablets of 0.85 MPaensile strength. However, DCC required 104 MPa to prepare tabletsf almost similar tensile strength (0.88 MPa).

Thus, up to 2% of coating with ultrafine particles can improve theompressibility and hence tabletability with slight reduction in theow properties. However, beyond 2% coating load, the flow prop-rties may worsen. Hence, it is recommended to control the unitperations so as to control generation of ultrafine particles within%. Hence, this work has highlighted the “pros and cons” associ-ted with generation of ultrafine particles during the industrial unitperations. Moreover, this approach can be further explored andracticed to improve compaction properties of high dose poorlyompressible drugs.

. Conclusion

Present study reveals the changes in the mechanical behaviourf the material upon coating of the ultrafine particles over theurface of the core material. This increased bonding area and cohe-ivity of the material. Flow property of the ultrafine coated materialeteriorated slightly. However, the compressibility of the material

mproved and led to better tabletability. This study highlighted thaturface coating with the ultrafine particles of the same materialignificantly affected bonding area rather than bonding strengthhat ultimately governed the compaction behaviour of the mate-ial. This work has implications in manufacturing process of tabletsnvolving micronization and subsequent compaction. This strategyan also be explored for improving tabletability of high dose poorlyompressible drugs.

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