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International Journal of Biological Macromolecules 60 (2013) 148– 155

Contents lists available at SciVerse ScienceDirect

International Journal of Biological Macromolecules

jo ur nal home p age: www. elsev ier .com/ locate / i jb iomac

ffects of microcrystalline cellulose based comilled powder on theompression and dissolution of ibuprofen

ubrata Mallicka,∗, Saroj K. Pradhanb, Rajaram Mohapatraa

Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan University, Kalinganagar, Bhubaneswar 751003, Orissa, IndiaCollege of Pharmaceutical Sciences, Berhampur, Mohuda, Orissa, India

a r t i c l e i n f o

rticle history:eceived 3 April 2013eceived in revised form 17 May 2013ccepted 24 May 2013vailable online 31 May 2013

eywords:

a b s t r a c t

Ibuprofen is a poorly soluble and poorly compressible drug and is unsuitable for “direct tableting”.Microcrystalline cellulose (Avicel® PH 101) based ibuprofen powder formulations have been comilled inpresence of Aerosil® (colloidal silicon dioxide) as lubricant, and the total compression behavior was evalu-ated using the Cooper–Eaton equation. Scanning electron microscopy (SEM) revealed about the damage ofcrystal geometry of the crystalline drug after comilling. Differential scanning calorimetry (DSC) indicateddecrease of melting endotherm (partially) attributing to the decrease in crystalline intensity of ibuprofen

icrocrystalline cellulosebuprofenompressionrug dissolution

upon comilling. Small changes in the infrared spectra such as shift of characteristic bands, reduction inintensity, and appearance of new bands are mainly related to the possible physical interaction and/oramorphization of the drug in the comilled mixtures. Increased compaction can be achieved after millingof the microcrystalline cellulose based blends. Milling decreased particle size and improved wettabilityof the drug and increased dissolution. Microcrystalline cellulose based comilled ibuprofen powder with

nd dis

improved compression a

. Introduction

Ibuprofen, a nonsteroidal anti-inflammatory drug exhibits poorolubility and poor compressibility and is unsuitable for tabletingy direct compression method due to excessive elastic recovery1]. Cellulose is a most common and very attractive biological

acromolecule and can be modified for biomedical and phar-aceutical applications due to its properties like hydrophilicity,

iocompatibility, stereoregularity [2,3]. Avicel® PH 101 is a brandf microcrystalline cellulose, recommended as a potential directompression pharmaceutical excipient especially in the design andevelopment of tablets of poorly compressible and poorly solublerug [4]. Coprocessed silicified microcrystalline cellulose claimsetter flow ability and compressibility compared to Avicel® PH01 alone or physical mixture [5,6]. Compression behaviour of aowdered drug material can be influenced by its crystal habit [7,8].illing is a mechanical process, regularly used in the pharmaceuti-

al industry causes the crystal lattice disruption (defect formation)nd can lead to additional physicochemical changes in the crys-al structure of the drug particularly when comilled with some

pecific excipients [9,10]. Present work has been undertaken totudy compaction behavior and physicochemical characterizationf the formulated microcrystalline cellulose (Avicel® PH 101) based

∗ Corresponding author. Tel.: +91 674 2386209; fax: +91 674 2386271.E-mail addresses: s mallickin@yahoo.com, profsmallick@gmail.com (S. Mallick).

141-8130/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijbiomac.2013.05.021

solution may be taken as a future scope of scale up for “direct tableting”.© 2013 Elsevier B.V. All rights reserved.

ibuprofen powder after a brief comilling in presence of Aerosil®.Comilled Avicel based ibuprofen powder in presence of Aerosil®

supposed to improve compressibility as well as dissolution of drugcompared to the unmilled powder.

Compaction of pharmaceutical powder formulation into tabletcan be divided into two major steps. During initial compressionphase at low applied pressures rearrangement of particle occurswithout deformation or fracturing of the particles [11,12]. Thenext phase proceeds by elastic deformation, plastic flow or frag-mentation of the particles [13,14]. Kawakita and co-workers haveapplied the equation (Kawakita equation) in describing the volumereduction on tapping process as well as pressure [12,14]. Cooperand Eaton [15] introduced a biexponential equation describingthe compaction process of powders under applied pressure. Otherreported biexponential equations [16,17] based upon the relation-ships between the change of apparent density versus number oftapping and applied pressure utilized for the characterization ofcompaction process. The early stage of compaction process as afunction of pressure due to slippage of particles or rearrangementhas been explained in different ways in the literature although itis difficult to characterize and quantify [12,14]. The compactionprocess has been characterized here using newly reported biex-ponential equations [16,17] and compared with the Cooper–Eaton

equation. Physicochemical characterization of the status of the drugin the formulated powder was also carried out using analytical tech-niques such as, SEM, FTIR and DSC. In vitro drug release has alsobeen carried out.

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S. Mallick et al. / International Journal of

. Experimental

.1. Powder preparation by comilling

Ibuprofen (crystalline powder: IOL Chemicals and Pharmaceut-cals Ltd, India); Avicel® PH 101 (particle size ∼50 �m, mess size0/200: Lupin Pharmaceuticals, Mumbai, India) and Aerosil® (par-icle size ∼15 nm: Lupin Pharmaceuticals, Mumbai, India) was usedn this study. Different degrees of silicification (1, 2, 5 and 10%) wereone by physical blending of Avicel® PH 101 with Aerosil® (nameds: SMCC1, SMCC2, SMCC5, and SMCC10 respectively). Milling waserformed for a brief period of 1 h (Swastik Electrical and Scientificorks, Ambala cantt, India, ball to powder ratio, 5:1) at laboratory

mbient temperature (∼27 ◦C) with a rotational speed of 100 rpmhich allowed smooth cascading motion during milling. No signifi-

ant increase in temperature of the milled material was detected athe end of the process. Particle size distribution of bulk ibuprofen,hysical mixture and formulated milled powder was done by sievenalysis method using mesh: 30, 44, 60, 85, 100, 120 and 150.

.2. Density measurement

The bulk density was measured by pouring of powder samplesoosely into a graduated 250 ml cylinder. The volume of the powdered was determined by visual estimation. Six separate experimentserformed, and mean results were reported. The tap density waslso determined by tapping the same cylinder up to a 250 taps (or asong as no visual change in density found) using a bulk density mea-urement apparatus (Koshiash Instruments, India). The true densityf each powder material was determined by Helium pycnometerPycno 30, Smart Instruments, India) without replication.

.3. Preparation of compacts and measurement of apparentensities

Compacts of all powder materials were prepared on a Hydraulicellet press (Kimaya Engineers, India) over a compression pressureanging from 24.5 to 294.2 MPa, using a 10 mm diameter die andat faced punches. Powder materials for each compact of 400 mgere weighed accurately on an analytical balance and poured man-ally into the die and compacts for each load were prepared. Duringompression in the laboratory ambient condition (∼27 ◦C, ∼60%H) maximum upper punch pressure (with a dwelling time of 60 s)as recorded for each compact. The thickness of freshly produced

ablets was measured by a digital micrometer (Mitutoyo, Japan).hese data were used for calculation of apparent density, porositynd degree of volume reduction.

.4. Evaluation of particle rearrangement and compressionehaviour

.4.1. Application of Cooper–Eaton equationCooper and Eaton described the powder compaction process as

function of applied pressure using a biexponential equation as

1/Ro − 1/R

1/Ro − 1= a exp

(−Ka

P

)+ b exp

(−Kb

P

)(1)

here, Ro = relative density at zero pressure; R = relative density atressure P; a, b = constants. The magnitude of pressure at which theespective compaction process would occur with greatest proba-ility of density is described by Ka and Kb. Dense compacts wereroduced on a hydraulic pellet press, and the parameters of the

econd stage due to particle deformation were determined fromhe graphical presentation of Ln (1/Ro − 1/R)/(1/Ro − 1) versus 1/P,here the ordinate intercept of the linear region of second stage

ompaction measures (a + b) and Kb is the slope of that linear region.

ical Macromolecules 60 (2013) 148– 155 149

Particle rearrangement could be described by two major stepsbased on cohesiveness of the powdered material as (i) primaryrearrangements, and (ii) secondary rearrangements and Eq. (1) isrewritten replacing P by the tapping number N as [16–18]:

1/R′o − 1/R

′

1/R′o − 1

= a1 exp(−K1

N

)+ a2 exp

(−K2

N

)(2)

where, R′o = relative density before tapping obtained by the poured

density divided by the equilibrium tapped density. R′ = relativedensity at Nth tapped obtained by apparent density of a powdercolumn divided by the equilibrium tapped density. The coeffi-cient K1 represents the tapping required to induce densificationby primary particle rearrangements which has the greatest prob-ability of density, whereas K2 represents the tapping required toinduce densification through secondary particle rearrangements.a1, a2 = dimensionless constants. Above parameters were deter-mined from the graphical presentation of Ln(1/R

′o − 1/R)/(1/R

′o −

1) versus 1/N, where, a1 and (a1 + a2) were determined from theordinate intercepts of the linear regions of the initial and secondstage of tapping respectively, while K1 and K2 determined by slopesof the two linear regions respectively.

2.4.2. Apparent density as a function of number of tapping andapplied pressure

The packing of the powder bed by primary rearrangement andthe secondary rearrangement can also be expressed by followingbiexponential equation [16,17].

dt − dn = (dp − do) exp(−KpN) + (dt − dp) exp(−KaN) (3)

where, (dp − do) = density difference that indicates the primaryrearrangements of fine discrete particles. (dt − dp) = density dif-ference due to the secondary rearrangement only after achievingthe primary rearrangement. (dt − do) = density difference thatdescribes the total rearrangement phenomena that are the max-imal compaction achieved after the primary rearrangement andthe secondary rearrangement altogether. Kp and Ka = constantsrelated to packing rate during primary rearrangement and pack-ing rate during the secondary rearrangement respectively. Where,dp = apparent density that describes the extent of the primaryrearrangement of discrete particles. The above constants weredetermined by biphasic linear plots of Ln(dt − dn) versus N.

The above Eq. (3) is rewritten in describing the compaction phe-nomenon on applied pressure after replacing the tapping number,N by the pressure, P as [16,17]:

dT − d = (dT − dr) exp(−K′1P) + (dr − di) exp(−K

′2P) (4)

where, dT, the true density and d, apparent density at the spe-cific applied pressure P. (dT − d) = density difference that indicatesthe theoretical maximal compaction which could be achieved bydie filling and particle rearrangement. (dr − di) = density differencedue to plastic deformation and bond formation only. K

′1 and K

′2 =

constants related to packing rate during die filling and particlerearrangement and packing rate during plastic deformation respec-tively. (dr − di) and K

′2 were determined from the graphical plot of

dense compact of Ln(dT − d) versus P.

2.5. Characterization of powder samples by SEM, FTIR and DSC

The morphology of the powder samples was investigated usingscanning electron microscopy (SEM) (Instrument JSM-6390 Jeol,Japan) operated at accelerating voltage of 5 kV with a beam of cur-

rent as 40–100 nA. Samples were mounted on carbon sticky tabsand sputtered with gold coating (approximately 20 nm) prior toobservations. Fourier transform infrared (FTIR) spectroscopic mea-surements were performed using FTIR spectrometer (FTIR-4100

1 Biological Macromolecules 60 (2013) 148– 155

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IBSMM1 IBSMM 2 IBSMM 5

1/P

Ln(1

/Ro

–1

/R)

/ (1

/Ro

–1

)

1varied 0.722 (±0.071)–0.927 (±0.119) and the secondary densifi-cation fraction (a2) of total rearrangement varied between 0.065(±0.002) and 0.281 (±0.016) in the samples IBC, IBSMP5, IBSMM1,

-2.1

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IBC IBSMM1 IBSM M2

Ln(1

/R/ o

–1/ R

/ ) /

(1/R

/ o–

1)

1/N

50 S. Mallick et al. / International Journal of

ypeA, Jasco, Tokyo, Japan) employing potassium bromide pelletethod. The samples were scanned from 4000–400 cm−1. All spec-

ra were collected through scan of accumulations 80 at a resolutionf 4 cm−1 and scanning speed of 2 mm/s at ambient tempera-ure (16 ◦C). Spectral Manager for Windows software (Jasco, Tokyo,apan) was used for data acquisition and holding. A thermal anal-sis of the samples was performed with a differential scanningalorimeter (DSC Q10 V9.4 Build 287). Approximately 4 mg drugquivalent sample was weighed into the DSC pan, and the sealedan was placed in the sample side of the instrument. Scans werearried out at a rate of 10 ◦C/min at temperatures of between 20 ◦Cnd 170 ◦C, using a nitrogen gas purge at 50 ml/min.

.6. In vitro dissolution study

Dissolution studies were conducted using USP Apparatus II pad-le method (900 ml distilled water as dissolution medium, 37 ◦C,nd 50 rpm) with a Disso 2000 dissolution apparatus (Labindia,ndia). Dissolution was continued for 120 min. Samples (5 ml) were

ithdrawn at the predetermined intervals of 10, 15, 30, 45, 60,0 and 120 min and replaced by the fresh dissolution medium,o as to maintain sink condition and constant volume through-ut. Then, the solution was filtered through a 0.45 �m membranelter (WHATMAN, India) and absorbance data after suitable dilu-ion were recorded at 222 nm using UV visible SpectrophotometerJASCO V-630 spectrophotometer, Software: Spectra Manager). The

ean of four determinations was used to calculate the amount ofrug released from the samples using standard calibration curve.

. Results and discussion

.1. Particle size analysis

Particle size analysis of the bulk ibuprofen, physical mixture andormulated milled powders were carried out, and the respective D90nd D50 of all the samples have been tabulated in Table 1.

Average particle size has been decreased compared to purebuprofen crystalline powder and physical mixture after millingor a brief period of 1 h as understood by the decreased value of90 and D50 of the formulated samples. Moreover, a major differ-nce in average size has not been observed between SMCC1, SMCC2,MCC5, and SMCC10.

.2. Properties of particle applying Cooper–Eaton equation

Graphical representation of Cooper–Eaton equation of denseompact obtained for five representative milled powder mixturesIBSMM1, IBSMM2, IBSMM5, IBSMM10 and IBSMP5) is illustrated inig. 1. All the graphs remained practically linear and were found tot the linear relationship of the Cooper–Eaton equation (R2 > 0.93)o produce dense compact in the pressure range 24.5–294.2 MPahich could be claimed as the second stage of compaction. Atigher pressures (lower values of 1/P) particles begin to deformlastically and thereby fill the smaller voids. Table 2 lists the val-es of Cooper–Eaton parameters of the dense compact. Kb valuesetermined from the slope increased in all the milled samples andhysical mixture compared to the pure drug ibuprofen. That meanshe compressibility to induce densification by deformation [18] haseen improved during compression of the formulated powder intoablet than ibuprofen alone.

Cooper and Eaton described that when the sum of a and b isqual to unity, compaction can be completely explained by the

wo separate processes. This occurs by particle rearrangement andlastic flow or fragmentation. The summation (a + b) yielded here

value closer to unity [0.955 (±0.078) to 1.027 (±0.091)] in allhe cases which indicated that both the mechanisms are operating

-0.8 IBSMM 10 IBC IBSMP5

Fig. 1. Cooper–Eaton plots of dense compact of powder samples.

simultaneously and an almost nonporous compact (unity packingfraction) could be obtained from all these powder mix of ibuprofenin combination with SMCC or alone.

Plot of Ln (1/R′o − 1/R′)/(1/R′

o − 1) versus 1/N, of all samples hasbeen shown in the Fig. 2 to describe particle rearrangements totallybased upon tapping. Each profile clearly depicted the two distinctlinear regions and was also found to fit the biexponential Eq. (2) (R2

values 0.911–0.997). Rearrangement parameters under tapping ofall the samples are tabulated in the Table 3.

That means the compressibility to induce the densification byprimary particle rearrangement (K1) and by secondary particlerearrangement (K2) due to tapping is improved in milled pow-ders than IBC and physical mixture. Maximum improvement hasbeen seen in the primary rearrangement with IBSMM2 and sec-ondary rearrangement with IBSMM10. Secondary rearrangement ofthe particles proceeded after the completion of primary rearrange-ments under advanced stage of tapping breaking down the unstablepacking arrangements, often termed as “arches” or “bridges” andleading to a closer packing. Due to particle friction, energy is dissi-pated. The physical properties of the original particles are retained.In all cases K2 increased from respective K1. The fraction of the theo-retical maximum densification achieved by filling voids by primaryrearrangement (a ) out of total rearrangements due to tapping

-2.6

IBSMM5 IBSM M10 IBSMP5

Fig. 2. Plots of Ln(1/R′o − 1/R)/(1/R

′o − 1) vs. 1/N for characterization of particle

rearrangements.

S. Mallick et al. / International Journal of Biological Macromolecules 60 (2013) 148– 155 151

Table 1Formulation of powder samples of microcrystalline cellulose (Avicel® PH 101) containing ibuprofen as model drug and colloidal silicon dioxide (Aerosil®).

Formulation code % Aerosil in Avicel (SMCC)a IBC: SMCC ratio Status % Aerosil in formulation Particle size (�m)

D90 D50

IBC – Ibuprofend Unmilled – ∼354 ∼251IBSMP5

b 5.0 1:1 Unmilled 2.5 ∼178 ∼152IBSMM1

c 1.0 1:1 Milled 0.5 ∼125 ∼104IBSMM2

c 2.0 1:1 Milled 1.0 ∼125 ∼104IBSMM5

c 5.0 1:1 Milled 2.5 ∼125 ∼104IBSMM10

c 10.0 1:1 Milled 5.0 ∼125 ∼104

a Blending was done by physical mixing in a mortar with spatula before use;b Physical mixture prepared by blending native crystalline ibuprofen and SMCC in a mortar with spatula;c Milling of physical mixtures was performed for 1 h at laboratory ambient temperature (∼27 ◦C);d Native crystalline.

Table 2Compression parameters of Cooper–Eaton profiles of the dense compacts.

Formulation code Compression pressure range (MPa) (−)Kb (MPa) (mean ± sd) (a + b) (mean ± sd) R2

IBC 24.5–294.2 4.927 ± 0.827 0.987 ± 0.111 0.955IBSMP5 24.5–294.2 18.525 ± 1.761 0.955 ± 0.078 0.986IBSMM1 24.5–294.2 7.467 ± 0.613 0.970 ± 0.081 0.989IBSMM2 24.5–294.2 6.218 ± 0.673 1.027 ± 0.091 0.988IBSMM5 24.5–294.2 6.358 ± 0.715 1.024 ± 0.103 0.984IBSMM10 24.5–294.2 10.001 ± 1.189 0.984 ± 0.091 0.931

Kb = pressure at which the theoretical maximal densification achieved in the second stage by filling of small voids by deformation or fragmentation at a higher pressure;(a + b) = total fraction of theoretical densification. (n = 4).

Table 3Characteristics of rearrangement of particles from the plots of Ln(1/R

′o − 1/R)/(1/R

′o − 1) versus 1/N, based upon tapping on the basis of equilibrium apparent density

(mean ± sd, n = 4).

Formulation code Primary rearrangement Secondary rearrangement (a1 + a2) Packinga (%) Npc

(−) K1 a1 R2 (−) K2 a2 R2

IBC 2.272 (0.33) 0.924 (0.130) 0.974 3.933 (0.498) 0.084 (0.004) 0.911 1.013 (0.12) 33.4 25IBSMP5 5.499 (0.82) 0.899 (0.134) 0.989 6.220 (0.980) 0.065 (0.002) 0.979 0.964 (0.13) 40.1 25–30IBSMM1 9.752 (1.24) 0.927 (0.119) 0.997 11.408 (1.36) 0.090 (0.010) 0.988 1.017 (0.11) 46.4 30–35IBSMM2 11.339 (0.92) 0.774 (0.063) 0.992 16.355 (1.22) 0.236 (0.017) 0.984 1.010 (0.07) 50.0 45–50IBSMM5 7.432 (0.55) 0.745 (0.055) 0.958 11.407 (0.97) 0.276 (0.021) 0.974 1.021 (0.09) 54.3 35–40IBSMM10 8.061 (0.82) 0.722 (0.071) 0.997 17.049 (1.38) 0.281 (0.016) 0.996 1.003 (0.09) 51.1 35

K1 represents the tapping required to induce densification by primary particle rearrangement, and K2 is representative of the tapping required to induce densification bysecondary particle rearrangement;a1, a2 = dimensionless constants that indicate the fraction of the theoretical maximum densification achieved by filling voids by primary rearrangement (a1) and by secondaryrearrangement (a2);N ent.

tapping process; Value in the parentheses indicates standard deviation with number ofr

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3a

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-2.5

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-1.5

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0 50 10 0 15 0 20 0 25 0

Ln(

d t –

d n )

N

pc is the transitional tapping of primary rearrangement and secondary rearrangema % packing calculated on the basis of particle density by total rearrangements via

eplicates of three or more;

BSMM2, IBSMM5 and IBSMM10. The sample IBSMM10 exhibitedinimum primary densification fraction (a1 = 0.722 ± 0.071) andaximum secondary densification fraction (a2) of 0.281 ± 0.016.alues of (a1 + a2) are closer to unity 0.964 (±0.13)–1.021 (±0.09).ensification by particle rearrangement proceeded mainly by pri-ary rearrangement process rather than the secondary one in all

he powder samples. Total packing fraction of comilled ibuprofenowder calculated on the basis of particle density by total rear-angements via tapping process varied 0.464–0.543. That means6.4%–54.3% packing could be possible by rearrangement of thearticles right from its cascaded state understood by tapping pro-ess based on Eq. (2) without applying pressure whereas, unmilledamples of IBC and IBSMP5 have shown reduced packing of 33.4nd 40.1% respectively.

.3. Properties of particle applying plots of Ln (dt − dn) versus Nnd Ln (dT − d) versus P

Plot of Ln (dt − dn) versus N of the physical mixture and milledixtures has been illustrated in Fig. 3 to describe the change

f density under tapping. Two distinct linear regions have been

-6

-5.5 IBC IBSMM1 IBSM M2

IBSMM5 IBSM M10 IBSMP5

Fig. 3. Plots of Ln (dt − dn) vs. N of powder samples.

152 S. Mallick et al. / International Journal of Biolog

-3.3

-3.1

-2.9

-2.7

-2.5

-2.3

-2.1

-1.9

-1.7

-1.5

15 55 95 13 5 17 5 21 5 25 5 29 5

IBSMM 1 IBSMM 2 IBS MM 5

Ln( d

T–

d )

P

i(

ooattdcaii

FI

IBSMM 10 IBC IBS MP 5

Fig. 4. Plots of Ln (dT − d) vs. P of the dense compact of powder samples.

dentified in each profile and found to fit the biexponential equationR2 values 0.923–0.998).

Rate of the packing process can be described by the processf particle rearrangement under tapping. The two major stepsf particle rearrangement namely, (i) primary rearrangementnd (ii) secondary rearrangement can be explained as thewo rearrangement parameters. The rearrangement parame-ers of all the samples are tabulated in the Table 4. Densityifference due to total rearrangement phenomena that is the

ompaction achieved after both the primary rearrangementnd secondary rearrangement altogether (dt − do) has beenmproved in all the milled powder samples than the purebuprofen. Improvement was noticed in (dt − do) in the order

ig. 5. Representative micrographs showing morphology of particles: (A) IBC (magnificatBSMM5 (magnification 100).

ical Macromolecules 60 (2013) 148– 155

IBC < IBSMP5 < IBSMM1 < IBSMM2 < IBSMM10 < IBSMM5. PackingRate during primary rearrangement (Kp) and packing rate dur-ing secondary rearrangement (Ka) of all the powder samplesvaried from 1.767 × 10−2 to 3.928 × 10−2 and 0.542 × 10−2 to1.104 × 10−2 (all mean values) respectively. Density difference dueto primary rearrangements of fine discrete particles (dp − do) andthat due to the secondary stage of packing after achieving primaryrearrangement (dt − dp) are also reported in the Table 4. Moreover,apparent density of the powder column that describes the extentof primary rearrangement (dp) of discrete particles has been cal-culated and exhibited in the same table which varied in a narrowrange from 0.423 to 0.506 g/ml. Milled powder has shown greatervalue of total density difference (dt − do) than physical mixture andibuprofen alone. That means particles arranged more compactedwhen they were milled as understood by tapping because ofoccupying smaller voids by the smaller particles and release ofvoids. Transitional tapping between primary rearrangement andthe secondary rearrangement (Npc and Npk applying Eqs. (2) and (3)respectively) [16,17] are almost matching each other and occurredat 25 taps with crystalline ibuprofen and increased up to 50 tapswith the formulated milled powders. The values are reported inTable 3 and Table 4 respectively. Compaction phenomenon of thedense compact of all ibuprofen powder samples has also beenexplained by plotting Ln (dT − d) versus P and is illustrated in theFig. 4. For all the powder samples the graphs maintained practicallylinear (R2 values are 0.961–0.982) to produce dense compact inthe pressure range 24.5–294.2 MPa. All the parameters of thedense compact prepared by pressure are listed in the Table 5. Thepacking rate process during plastic deformation (K2) or packing

rate for dense compaction did not change to a greater extent in allthe powder samples. Density difference achieved after combinedparticle rearrangement and plastic deformation (dT − di) of milledand physical mixtures has been increased significantly compared

ion 100); (B) IBSMP5 (magnification 100); (C) IBSMM1 (magnification 500) and (D)

S. Mallick et al. / International Journal of Biological Macromolecules 60 (2013) 148– 155 153

Table 4Characteristics of rearrangement of particles under tapping using plots of Ln (dt − dn) versus N.

Formulation code Primary rearrangement Secondary rearrangement (dp−do) (dt−do) (dt−dp) dp Npk

(−)Kp × 102 R2 (−)Ka × 102 R2

IBC 3.776 (0.224) 0.971 0.940 (0.081) 0.983 0.076 0.103 0.027 0.506 25IBSMP5 3.928 (0.290) 0.990 0.542 (0.038) 0.923 0.119 0.158 0.039 0.495 35–40IBSMM1 2.915 (0.238) 0.987 1.104 (0.102) 0.988 0.107 0.187 0.080 0.493 45–50IBSMM2 1.767 (0.122) 0.984 0.828 (0.052) 0.966 0.097 0.196 0.099 0.458 45–50IBSMM5 2.406 (0.223) 0.987 0.947 (0.070) 0.927 0.121 0.222 0.101 0.444 45IBSMM10 1.919 (0.121) 0.998 0.666 (0.032) 0.969 0.107 0.202 0.095 0.423 45–50

Where, (dp − do) indicates density difference due to primary rearrangement of fine discrete particles; (dt − dp) is the density difference due to secondary rearrangement onlyafter achieving primary rearrangement; (dt − do) describes the density difference for total rearrangement phenomena that is the maximal compaction achieved after primaryrearrangement and secondary rearrangement altogether; dp is the apparent density of powder column that describes the extent of primary rearrangement (all in g/ml);Kp and Ka are the constants measure the rate of packing during primary rearrangement and rate of packing during secondary rearrangement respectively.Npk is the transitional tapping of primary rearrangement and secondary rearrangement of this plot. Value in the parentheses indicates standard deviation of three or morereplicates.

Table 5Compression parameters using plots of Ln (dT − d) versus P of the dense compacts.

Formulation code Compression pressure range (MPa) (−)K2 × 103 R2 (dT − di) (dr − di) (dT − dr) dr(mean ± sd, n = 4)

IBC 24.5–294.2 0.222 (0.024) 0.982 0.687 0.045 0.642 0.475 ± 0.051IBSMP5 24.5–294.2 0.234 (0.025) 0.967 0.992 0.196 0.796 0.573 ± 0.048IBSMM1 24.5–294.2 0.351 (0.028) 0.966 0.976 0.181 0.796 0.561 ± 0.041IBSMM2 24.5–294.2 0.165 (0.018) 0.980 0.999 0.138 0.861 0.498 ± 0.035IBSMM5 24.5–294.2 0.088 (0.016) 0.973 1.046 0.082 0.963 0.405 ± 0.025IBSMM10 24.5–294.2 0.306 (0.034) 0.961 1.069 0.173 0.896 0.488 ± 0.021

K1 = rate of packing or consolidation during die filling and particle rearrangement;K2 = rate of packing or consolidation during plastic deformation;(dT − di) = density difference that indicates the theoretical maximal compaction which achieved by two combined steps: (i) die filling and particle rearrangement and, (ii)plastic deformation and bond formation of discrete particle;(dT − dr) = density difference due to die filling and particle rearrangement;(d le reard

wfiosrTimeat

3

pcofi(sisaimp

3

(

been decreased slightly in IBSMM5, and moderately in IBSMM10.Presence of 5% colloidal silicon dioxide in IBSMM10 has broughtabout the major transformation of crystalline to the amorphous

dr − di) = density difference due to plastic deformation and bond formation only;r = apparent density of powder column describes the extent of die filling and particetermined from three or more replicates.

ith that of the original crystals. Density difference due to dielling and particle rearrangement (dT − dr) actually dominatedver that of plastic deformation (dr − di). Values of apparent den-ity of the powder column achieving after die filling and particleearrangement (dr) are reported in the same Table 5 (0.405–0.573).hus, it may be understood from the plot Ln (dT − d) versus P thatncreased compaction can be achieved by silicification and even

ore can be achieved by milling after the silicification. The totalffect of die filling, particle rearrangement, particle deformationnd bonding of discrete particles improved to a greater extent inhe formulated milled mixtures containing silicon dioxide.

.4. Scanning electron microscopy studies

Fig. 5 illustrates the scanning electron micrographs for the mor-hology of particles of the crystalline ibuprofen and formulatedomilled powdered samples. IBC shows distinct crystalline shapef the pure drug. Ibuprofen crystal particles are clearly identi-ed in IBSMP5 which are not damaged. Shape of milled particlesIBSMM1 and IBSMM5) is markedly changed, and the size becomesmaller than the native crystals. The native crystalline shape ofbuprofen is slightly damaged in IBSMM1. Crystal geometry isignificantly damaged, and the rod shaped crystals are almost dis-ppeared in IBSMM5. In our previous publications, comilling ofbuprofen–aluminum hydroxide and ibuprofen–kaolin loss of geo-

etric shape of the ibuprofen crystal has been observed in thehotomicrographs [9,10].

.5. Infrared spectroscopy studies

The FT-IR spectra of crystalline ibuprofen (IBC), physical mixtureIBSMP5) and milled samples (IBSMM5 and IBSMM10) are shown in

rangement (density in g/ml); Value in the parentheses indicates standard deviation

Fig. 6. IBC shows characteristic peak of ibuprofen at 1719 cm−1 ofhigh intensity due to carbonyl stretching [19,20]. The weak bandsat about 1507 and 1461 cm−1 could be attributed to ring vibrationsof the organic molecules [21]. IBSMP5, IBSMM5 and IBSMM10 showthat the carbonyl peak still existing without major shifting and ofsome gradual decreased intensity. Typical (CH) stretching vibra-tions of ibuprofen are observed near 2962 cm−1 for pure ibuprofen(IBC) as well as other powder mixtures [21]. Minor changes in shif-ting and intensity of peak supposed to be related to the amorphoustransformation. The powder mixtures give peak near 3347 cm−1

indicating formation of H-bond between OH of COOH and Si ofSiO2 which leads to the formation of bridging bond of Si O C[22]. Formation of H-bond was previously reported on co-grindingof carboxylic acid containing drugs with silicon containing exci-pient [9,22,23]. That means crystalline intensity of ibuprofen has

Fig. 6. The FT-IR spectra of powder samples (IBC, IBSMP5, IBSMM5 and IBSMM10).

154 S. Mallick et al. / International Journal of Biological Macromolecules 60 (2013) 148– 155

Fig. 7. DSC thermograms of IBC, IBSMP5, IBSMM5 and IBSMM10.

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 10 0 12 0

IBC IBSMM1

IBSMM2 IBSM M5

IBSMM10 IBSMP5

% C

um

ula

tiv

e d

rug r

elea

se

Tim

SMM5

scericacm

3

Ta1satooaco[

Fig. 8. In vitro drug dissolution profiles of IBC, IBSMP5, IBSMM1, IBSMM2, IB

tate when the blends are milled. Attrition of ibuprofen crystalsoated with silicon dioxide by the balls of mill occurred and thenergy dissipated into the blends transformed the change. Theesults indicate no major interaction between ibuprofen and SMCCn the mixtures. Small changes in the FTIR spectra such as shift ofharacteristic bands, disappearance or reduction in intensity, andppearance of new bands mainly are related to the possible physi-al interaction and/or amorphization [16,17,19,22] of the comilledixtures.

.6. Differential scanning calorimetry studies

DSC thermograms of ibuprofen samples are depicted in Fig. 7.he DSC thermogram of crystalline ibuprofen (IBC) showed

melting endotherm at 76.6 ◦C with normalized energy of21.9 J/g. The thermogram of IBSMP5, IBSMM5 and IBSMM10howed gradual decrease of melting endotherm (at 75.5, 74.7nd 74.6 ◦C with energies 66.50 J/g, 55.25 J/g, and 51.88 J/g respec-ively) attributing to a gradual decrease in crystalline intensityf ibuprofen in the respective samples. The ibuprofen melting

nset temperature (74.4 ◦C) also gradually decreased (73.7, 72.8nd 71.9 ◦C respectively) may be due to the presence of sili-on dioxide in MCC (SMCC). DSC results might be an indicationf partial amorphization of ibuprofen in IBSMM5 and IBSMM1016,24].

e (min)

and IBSMM10. Each data point represents the mean ± sd of four repetitions.

3.7. Drug release

Fig. 8 shows dissolution patterns of ibuprofen from tablet ofcrystalline drug (IBC), physical mixture (IBSMP5) and other milledsamples (IBSMM1, IBSMM2, IBSMM5 and IBSMM10). The dissolu-tion rate of the pure ibuprofen was very low: in fact the percentageof drug dissolved in 120 min was 44.1 ± 2.3%. Several studies havealready proved the poor dissolution of ibuprofen in its crystallinestate [1,25]. The dissolution rate was greatly increased in IBSMM1,IBSMM2, IBSMM5 and IBSMM10 tablets in comparison to IBCtablet. These results suggest that milling of blends of ibuprofen andSMCC decreased particle size and improved wettability due to theincreased amorphization of the drug. The dissolution of ibuprofenhas been exceeded 75% in the physical mixture (IBSMP5) and two-fold or more in the milled samples. The improvement in dissolutionof ibuprofen has also been reported previously when ibuprofen wasco-milled with silicon containing clay (kaolin) because of amor-phization of drug [9].

4. Conclusions

The compressibility by primary particle rearrangement and sec-

ondary particle rearrangement of microcrystalline cellulose basedibuprofen powder was greatly improved in milled powders than thecrystalline ibuprofen and unmilled physical mixture. Total pack-ing fraction by particle rearrangement has been improved, and

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284–290.

S. Mallick et al. / International Journal of

hat was mainly by primary rearrangement process rather thanhe secondary one in all the formulations. Particles arranged moreompacted when they were milled. Pressure required to achievingompaction in the second stage by filling of small voids by deforma-ion at a higher pressure was more in the formulated mixture thanbuprofen alone. Increased compaction can be achieved in presencef Aerosil® and even more can be achieved by comilling for a periodf 1hr after the silicification. The dissolution of ibuprofen has beenmproved significantly in the milled samples than the crystallinerug and physical mixture.

cknowledgments

The authors are very much thankful to Prof. Manoj Ranjanayak, President, Siksha O Anusandhan University for facilities andncouragement.

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