influence of particle size and shape on flowability and compactibility of

European Journal of Pharmaceutical Sciences 22 (2004) 173179

Influence of particle size and shape on flowability and compactibility ofbinary mixtures of paracetamol and microcrystalline cellulose

J. Sebastian Kaerger, Stephen Edge, Robert Price

Pharmaceutical Technology Research Group, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UKReceived 24 September 2003; received in revised form 2 March 2004; accepted 9 March 2004

Abstract

The influence of the size and shape of paracetamol particles on the flow and compression behavior of blends (1:1) of microcrystalline cellulose(MCC) was investigated. The effect of paracetamol particle shape was investigated by using two differently prepared samples, micronizedand novel engineered Solution Atomization and Xstallization by Sonication (SAXS) particles, which exhibited similar particle size ranges(26m). The results were compared to data obtained for an untreated paracetamol sample. The blends containing SAXS particles exhibitedincreased bulk and tapped density and improved flow, compared to the blend containing micronized particles. This may reflect differencesin shape since the SAXS particles exhibited spherical morphology. The compressibility of the blend containing untreated paracetamol wasgreater than blends containing the SAXS and micronized materials, which may reflect the different drug particle sizes and shapes. However,blends containing the needle-shaped particles of pure untreated sample, exhibited poor compactibility after storage at 10% RH. It was foundthat increasing the moisture content in the blends by storage at 44% RH resulted in an increase in the compactibility of the samples containinguntreated and SAXS paracetamol with the blends containing micronized paracetamol being relatively unaffected. In general, tablets preparedfrom blends containing smaller particles of paracetamol exhibited significantly greater compactibility compared to tablets prepared containingthe larger particle sized untreated paracetamol. The use of small, spherical drug particles may result in improvements in the bulk density,densification and compactibility of blends of paracetamol and microcrystalline cellulose. 2004 Elsevier B.V. All rights reserved.

Keywords: Paracetamol; Binary mixture; Particle shape; Compactibility; SAXS

1. Introduction

Even though paracetamol is a poorly compactable drug itis still widely used in a solid dosage forms for its analgesicand antipyretic properties. In terms of tablet formation, thespecifications of a finished tablet will be a consequenceof the compressibility, adhesive/cohesive interactions andmechanical properties of the component particles. Con-sequently, a poorly compactable drug may result in for-mulation difficulties. The poor compaction behavior ofparacetamol has been explained in terms of the crystalstructure of the material, which is based on a monocliniccrystal system, and its poor plastic deformation (Nicholsand Frampton, 1998; Beyer et al., 2001). In order to address

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E-mail address: [email protected] (R. Price).

this problem the crystal structure has been modified by rapidcooling of a paracetamol melt, resulting in an orthorhombicsystem. This material has also been prepared by crystal-lization from organic solvents such as benzyl alcohol andmethylated spirits (Nichols and Frampton, 1998). This ma-terial exhibited improved compactibility. However, its crys-tal structure is thermodynamically unstable and so far onlyrelatively small amounts have been produced (DiMartinoet al., 1996; Sacchetti, 2000). More recently, higher yieldsof orthorhombic paracetamol have been prepared by crystal-lization from ethanolic solution (Al-Zoubi and Malamatris,2003). Garekani et al. attempted to improve the poorcompaction properties of paracetamol by modifying thecrystal shape by employing polyvinylpyrrolidone (PVP)as a crystal growth inhibitor (Garekani et al., 2000a,b).The resulting particles exhibited improved compressionproperties. However, the degree to which PVP influencesthe compression behavior was not determined even though

0928-0987/$ see front matter 2004 Elsevier B.V. All rights reserved.doi:10.1016/j.ejps.2004.03.005

174 J.S. Kaerger et al. / European Journal of Pharmaceutical Sciences 22 (2004) 173179

the amount of PVP in the collected material was 44.5%(w/w).

In view of the poor flow properties of paracetamol, theactive can be granulated before compression (Rasenackand Mller, 2002). Nevertheless, in order to avoid thetime-consuming and expensive granulation process it maybe possible to produce an optimal blend of excipients anddrug which could afford formulations with improved com-pressibility and compactibility in direct compression. Manystudies of powder mixtures have described the relationshipsbetween particle size and ratio of excipients and drug andtablet strength (Fell, 1996; Kuentz and Leuenberger, 2000;Alderborn, 1996). However, the relationship between tabletstrength and the particle sizes in a binary mixture has beenrarely studied (Malamataris et al., 1984). In view of this,the effect of particle shape on the compactibility of puredrug has been reported (Alderborn and Nystrom, 1982;Karehill et al., 1990; Wong and Pilpel, 1990). Adolfssonet al. (1998) studied pure material and blends of drug andbinder, microcrystalline cellulose (MCC), to explore the in-fluence of surface roughness and molecular disorder on thecompactibility and the contribution of weak distance forcesand solid bridges to the tensile strength of resulting tablets.The drug particles used were much larger (250355m)than the MCC particles (20m).

The influence of moisture on the compaction behavior ofMCC, blends of MCC with different drugs and paraceta-mol has been extensively studied (Khan et al., 1981; Garrand Rubinstein, 1992; Amidon and Houghton, 1995;Bolhuis and Chowhan, 1996). These studies concluded thatincreasing the water content of MCC results in an increasein the compactibility. This was explained in terms of lubri-cation effects of moisture and its ability to facilitate slippageof the MCC fibrils. It would be expected that there wouldbe an optimum amount of water which will limit elasticrecovery after compression by the formation of hydrogenbond bridges (Khan et al., 1981; Bolhuis and Chowhan,1996). However, the wide range of studies of the effect ofmoisture on the compaction of MCC and blends of MCChas resulted in a variety of relationships which are difficultto fully interpret (compression pressure, compression speed,direction of compression, dwell time, decompression rate,storage, RH, excipient manufacturer, etc.). Nevertheless,these studies generally agree that the compressibility ofMCC is closely related to the amount of water in MCC or inthe blend at water contents above 5% (w/w). However, dataobtained for MCC with water contents below 5% (w/w)have been difficult to fully explain. For example, Khanet al. reported no significant dependence on water contentfor pure MCC at low compaction pressure (Khan et al.,1981). Conversely, in blends of MCC and paracetamol, itwas suggested that there was an influence of water contentat low compaction pressure (Amidon and Houghton, 1995;Akande et al., 1997; Malamataris et al., 1984, 1996).

The object of this work was to investigate the relation-ship between flowability, compressiblity and compactibility

in blends of paracetamol particles of different sizes andshapes with MCC at different water contents. Paracetamolwas employed as three different sizes and shapes: as sup-plied (particle size ca. 40m, needle shaped), micronized(particle size between ca. 2 and 6m, unevenly shaped)and produced by a novel particle engineering method (Solu-tion Atomization and Xstallization by SonicationSAXS;particle size between ca. 2 and 6m, spherically shaped).

2. Materials and methods

2.1. Materials

Paracetamol (Sigma-Aldrich, Steinheim, Germany),ethanol, cyclohexane (HPLC grade), magnesium stearate(all supplied by Fisher Chemicals, Loughborough, UK), mi-crocrystalline cellulose (Emcocel 90M, Lot-Nr. E9B8A01XPenwest, Patterson, USA) and talc (BDH, Poole, UK) wereused as supplied.

2.2. Production of paracetamol samples

Paracetamol samples were prepared using two techni-ques.

2.2.1. Novel particle engineering methodThe SAXS process has been previously described

(Kaerger and Price, 2004) and the system is diagramaticallyrepresented in Fig. 1. Simply, a solution of paracetamolin ethanol (10%, w/w) was sprayed (16 ml/h) using an airpressure atomizer (orifice 0.7 mm, air flow 600 l/h). Afterevaporation of the solvent the supersaturated droplets werecollected in a non-solvent, cyclohexane. Crystallization ofthe drug within the droplets was achieved using an ultra-sonic source (FS200b, Decon Laboratories, Hove, UK). Theresulting suspension was filtered through a membrane filter

Fig. 1. Schematic diagram of the apparatus employed to obtain sphericalparticles by Solution Atomization and Xstallization by Sonication (SAXS).

J.S. Kaerger et al. / European Journal of Pharmaceutical Sciences 22 (2004) 173179 175

(Isopore membrane filter 0.2 (m GTBP, Millipore, UK) andthe particles dried for 100 min at 50 C.

2.2.2. MicronizationParacetamol was micronized using a centrifuge mill

(ZM100, Rentsch, Haan, Germany). The centrifugal speedwas set at 18,000 rpm with a 80m sieve.

2.3. Preparation of powder blends

All blends were prepared using paracetamol (49.25%,untreated, micronized and SAXS-produced paracetamol),MCC (49.25%), talc (1%) and magnesium stearate (0.5%).Required mass of drug, MCC and talc (total, 5 g) weremixed for 5 min in a Turbula mixer in a 50 ml glass cylinder(46 rpm, Willy A. Bachofen AG, Basel, Switzerland). Mag-nesium stearate was then added and the blends were mixedfor a further 5 min. The resulting formulations were storedfor 5 h at 65 C to ensure crystallization. The blends werethen either stored over silica gel in a desiccator (10% RH)or at 44% RH (saturated solution of K2CO3 in water, in ahermetically sealed enclosure) at 21 C for at least 7 daysprior to use.

2.4. Physical characterization

2.4.1. Scanning electron microscopy (SEM)The morphology of the paracetamol particles was investi-

gated using scanning electron microscopy (SEM) (Jeol 6310,Jeol, Japan) at 10 keV. Samples were mounted on carbonsticky tabs and gold-coated prior to analysis (Edwards Sput-ter Coater, UK).

2.4.2. Particle size analysisParticle size distributions were determined by laser

diffraction (Mastersizer X, Malvern, UK), using a 100 mmlens in a small stirring cell (volume 10 ml) with an obscu-rity between 0.12 and 0.18. A small amount of drug wasdispersed in cyclohexane with 0.1% lecithin as surfactant.The suspension was sonicated for 5 min (FS200b, DeconLaboratories, Hove, UK) prior to analysis.

2.4.3. Differential scanning calorimetry (DSC)Thermal analysis (35 mg) was performed using a dif-

ferential scanning calorimeter (DSC2910, TA Instruments,USA) using hermetically sealed aluminium pans. The sam-ples were cooled to 70 C and heated to 300 C at a rateof 10 C/min.

2.4.4. Surface area measurementSurface areas were determined using helium/nitrogen gas

sorption (Gemini 2360 Surface Area Analyzer, Micromet-rics, Norcross, USA). Prior to measurements, samples (0.8 g)were degassed for 15 h to remove moisture and contami-nation (FlowPrep 060, Micrometrics, Norcross, USA). Thesurface area was calculated by employing the adsorption

theories of Brunauer, Emmett and Teller (BET) (Brunaueret al., 1938), and Langmuir (Langmuir, 1918).

2.4.5. Water contentThe water content of samples was determined by heat-

ing the powders (2 g) at 105 C (Mettler IR-heater LP16with balance PM2500) until the sample achieved constantmass. The mass difference was considered as the watercontent.

2.4.6. Bulk and tapped densityThe bulk density of blends was determined by pouring

a sample of the powder (2 g) into a 10 ml measuring glasscylinder and measuring the powder volume. The tap densitywas determined after tapping the cylinder using a joltingvolumeter (J. Engelsmann, Ludwigshafen, Germany). Thepowder volume was measured after successive 500 tap cy-cles until the volume was constant and the tapped density de-termined. Carrs compressibility index was calculated fromthe bulk and tapped densities (Carr, 1965).

2.4.7. FlowabilityThe flowability was determined by measuring the angle

of repose. The end of a funnel was placed 2 cm above aflat base. Powder (the mass depended on the bulk density ofthe material, around 2.5 g) was filled into the funnel, so thatafter releasing the powder out of the funnel the top of theresulting cone reached the end of the funnel. The powderwas released from the funnel. From the height of the cone(h) and the diameter at the base (d) the angle at the base,the angle of repose, () was determined.tan = 2h

d(1)

2.5. Powder compression and compaction

Tablets of the blends (250 mg, 10 mm diameter, silver steeldies) were prepared using a computer controlled texture an-alyzer (TA-XT2i, Stable Micro Systems, Godalming, UK).Before each compression the die and the punch faces werelubricated with a magnesium stearate suspension (acetone).The powder was added into the die and the die gently tappedfive times. Tablets were prepared at compression and decom-pression speeds of 5 mm/s at 62.4 MPa (4905 N, dwell time1 s). The compressibility, in millimeters, was in this case, de-fined as the die travel distance from 0.13 MPa (10 N) to themaximum load. In this case, the greater the compressibility,the greater the resistance to the applied stress. The tabletswere stored at 44% RH for 24 h before mechanical testing.The density was calculated after measurement of the mass,thickness and diameter of the tablets (Mitutoyo Micrometer,Tokyo, Japan). The compactibility was determined by dia-metric compression testing (0.17 mm/s, silver steel platens,Texture Analyzer, Stable Micro Systems, Godalming, UK).The failure load was converted to tensile strength (Fell andNewton, 1970).


3. Results and discussion

3.1. Production and characterization of paracetamolparticles

In order to investigate the influence of paracetamol par-ticle shape and size on the properties of paracetamol/MCCblends, two relatively small particle sized paracetamol sam-ples were prepared by two different methods, micronizationand a novel particle engineering technique technique. Theproperties of these materials were compared with unmodi-fied paracetamol.

Fig. 2. Scanning electron micrographs of (a) untreated, (b) micronized,(c) SAXS paracetamol.

Fig. 3. Size distribution of untreated, micronized and SAXS-processedparacetamol particles.

3.2. Characterization of paracetamol particles

3.2.1. SEMRepresentative SEM micrographs of the unmodified,

milled and SAXS paracetamol particles are shown in Fig. 2.The SEM micrographs suggest that milling and SAXS pro-cessing produce relatively small sized paracetamol particles.However, the samples produced by the SAXS process are,as expected, more spherical in appearance compared to themilled samples.

3.2.2. Particle size analysisThe particle size distributions of the three paraceta-

mol samples are represented in Fig. 3. As expected, theSAXS-processed and the micronized samples exhibit sim-ilar but smaller particle sizes compared to the unmodified,as supplied, sample.

3.2.3. DSCThe DSC thermograms of the untreated, micronized and

SAXS-processed paracetamol samples are shown in Fig. 4.The DSC melting point (Tm) was used to identify the crys-talline form of paracetamol present, monoclinic (form I, Tm

Fig. 4. DSC thermograph of paracetamol particles, untreated, micronizedand obtained by SAXS.


Table 1Experimental values of the surface area of single drug and binary mixtures

Drug Surface area (m2/g) Surface area ofthe blend (m2/g)

MCC 1.24 Untreated paracetamol 0.18 0.62Micronized paracetamol 2.13 1.42SAXS paracetamol 1.70 1.23

= 169 C) and the orthorombic form (form II, Tm = 156 C)(Nichols and Frampton, 1998). Untreated paracetamol wassupplied in form I. The data in Fig. 4 show endothermic tran-sitions at ca. 169 C for all samples. These correspond to themelting point of form I. No thermal transition was observedat 156 C, the melting point of form II. Furthermore, the ab-sence of an exothermic recrystallization event, at 76 C, in-dicates the absence of amorphous material (DiMartino et al.,1996). The heat of fusion at Tm was determined as 1985 J/gfor all three particle samples, which suggests that no degra-dation has taken place.

3.3. Preparation and characterization of the blend

Samples of untreated, micronized and SAXS producedparacetamol were blended with MCC, talc and Mg stearate.The resulting formulations were uniform in appearance.

The surface areas of the resulting blends were determined.The results are presented in Table 1 and suggest that, as ex-pected, a reduction in particle size of paracetamol results inan increase in surface area. Consequently, blends containingprocessed paracetamol samples exhibit higher surface areasthan the blend prepared containing unmodified paracetamol.

The flowability data for the blends are shown in Table 2.The data suggest that blends containing untreated and SAXSproduced paracetamol exhibit similar bulk and tapped den-sity, whereas the blend containing micronized drug exhibitslower bulk and tapped density. The Carrs compressibility in-dex of the blends containing micronized paracetamol (storedat both 10 and 44% RH) is also significantly higher than forthe blends containing SAXS-processed and untreated parac-etamol (ANOVA, P < 0.05). However, these values togetherwith the relatively high angles of repose, suggest that theseblends exhibit relatively poor flow. The effect when usingmicronized paracetamol may be explained in terms of the

Table 2Experimental values of flowability, density and water content of each blend

Paracetamol type Storage (% RH) Angle of repose () Bulk density (g/cm3) Tapped density (g/cm3) Carrs index Water content (%, w/w)Untreated 10 50 1 0.34 0.01 0.54 0.01 38 2 0.9Micronized 10 52 1 0.21 0.01 0.40 0.01 47 1 0.9SAXS 10 49 1 0.33 0.01 0.53 0.01 37 2 1.1Untreated 44 48 1 0.34 0.01 0.56 0.01 39 1 2.2Micronized 44 51 1 0.20 0.01 0.36 0.02 45 3 2.3SAXS 44 48 1 0.31 0.01 0.50 0.01 38 1 2.3Results are the mean and standard deviations of three determinations.

materials uneven morphology and consequent higher sur-face/volume ratio. This would be expected to inhibit flowdue to the increased number of inter-particulate interactionsat both macroscopic (mechanical) and microscopic (van derWaals) levels. This may also reflect surface properties of themicronized material, since micronized materials are knownto show higher electrostatic forces due to triboelectrifica-tion during the milling process. This effect is reduced whenblends are prepared using the spherically shaped SAXS par-ticles which would be expected to impart improved flow dueto their shape and lower surface free energy, as exemplifiedby the previously mentioned tapped and bulk density data.

The water content of each blend is shown in Table 2. Typ-ically, the amount of water in the blends was ca. 1% (w/w)and 2.3% (w/w) after storage at 10 and 44% RH, respec-tively. This is in agreement with a previous study (Amidonand Houghton, 1995). The majority of the moisture uptakeduring storage is due to MCC since paracetamol adsorbsonly up to 0.1% water between 0 and 90% RH as deter-mined by dynamic vapor sorption (results not shown). Theinfluence of the moisture on bulk properties of the blendsis shown in Table 2. No statistically significant differencewas found (ANOVA, P < 0.05) between the tapped andbulk densities of the blends after storage at 10 and 44% RHsuggesting that the density and flow characteristics of theseblends is not significantly affected at these water contents.

3.4. Mechanical behavior of blends3.4.1. Compressibility

Typical compression data of the blends, after storage at10% RH, are shown in Table 3. The data suggest that whenblended with paracetamol, the order of blend compressibil-ity is, as expected, untreated > milled > SAXS-processedafter storage at 10 and 44% RH. The greater compressibilityof the blend containing the untreated paracetamol proba-bly reflects the larger particle size of these drug particleswhich, because of their shape and relative brittleness offermore resistance to compression. In the case of the blendscontaining the smaller particle sized paracetamol samples,the presence of the SAXS-processed paracetamol facilitatesrearrangement of the powder column at low stress resultingin a blend which is apparently less compressible than theblend containing the micronized drug. This is also reflectedin the bulk density data where blends containing SAXS and


Table 3Compression values of 250 mg blend and characterization of resulting tablets, compressed at 62.4 0.4 MPa (flat punch face, diameter 10 mm, silversteel dies)Paracetamol type Storage (% RH) C (mm) Ec (J) Dt=0 (g/cm3) Dt=24 (g/cm3)a Tensile strength (MPa) NEf (J/m2)Untreated 10 4.21 0.05 4.85 0.07 1.07 0.01 1.05 0.01 0.35 0.05 21.4 1.4Micronized 10 4.04 0.12 4.32 0.08 1.04 0.01 1.03 0.01 0.65 0.09 36.0 7.9SAXS 10 3.77 0.06 4.48 0.07 1.07 0.01 1.06 0.01 0.59 0.12 33.7 4.2Untreated 44 4.23 0.07 4.81 0.07 1.12 0.01 1.10 0.01 0.56 0.05 29.5 3.0Micronized 44 4.05 0.04 4.53 0.13 1.07 0.01 1.05 0.01 0.65 0.07 40.9 7.7SAXS 44 3.79 0.11 4.64 0.15 1.10 0.01 1.08 0.01 0.70 0.06 35.9 8.1

a C: compressibility; Ec: energy of compression; Dt=0: density after ejection; Dt=24: density after storage at 44% RH, 24 h; NEf : normalized energyof failure during diametric compression test. Results are the mean and standard deviations of six determinations.

untreated paracetamol exhibit similar bulk densities, butdifferent compressibilities, and the energy of compressiondata in Table 3 where it can be seen that even though thereis no effect on the compressibility of the blends after stor-age at 10 and 44% RH, there is an increase in the energyof compression for the blends containing the micronizedand SAXS-processed paracetamol samples. The increase inthe energy of compression reflects water induced increasedelastic/plastic behavior. It has been reported that the com-pression of MCC required less pressure with increasingmoisture content to produce tablets of identical solid frac-tion (Amidon and Houghton, 1995). The fact that blendscontaining untreated paracetamol require comparable com-pression energies at 10 and 44% RH suggest that it is theshape and size of the paracetamol particles which deter-mines the energy of compression. This observation is alsomirrored in the tablet density data in Table 3 which sug-gests that blends containing untreated and SAXS-processedparacetamol exhibit comparable ejected tablet densitieswhich are greater than the tablets prepared from the blendcontaining micronized drug (ANOVA, P < 0.05).

Overall, the compressibility data in Table 3 suggest that,in the case of small particles of paracetamol, the energy ofcompression of the blends is dependant on moisture con-tent rather than apparent compressibility. However, the blendcontaining micronized sample is more compressible than theblend containing SAXS-processed paracetamol and affordstablets with lower density suggesting that particle process-ing and shape determine the apparent mechanical propertiessuch as compressibility and compactibility. This differencein behavior of the blend containing the micronized sample isalso reflected in the Carrs compressibility data in Table 2,where the blend containing the micronized drug exhibitslowest bulk and tapped density.

3.4.2. CompactibilityThe tensile strengths of tablets are reported in Table 3.

After storage at 10% RH, the blends containing untreatedparacetamol produced tablets which exhibited lower tensilestrength than those containing the smaller particle sizeddrugs (ANOVA, P < 0.05). There was no significant dif-ference in the tensile strengths of the tablets containingSAXS-processed and micronized drug (P > 0.05). The

compactibility increased after storage at 44% RH for blendscontaining untreated and SAXS-processed paracetamol(ANOVA, P < 0.05). However, the results seem to suggestthat the influence of humidity on the compactibility of theblends is untreated > SAXS-processed > micronized. Apossible explanation is that the hydration of the surfaceof the paracetamol crystals is now sufficient to offer somebonding capacity which is reflected in the increased tabletdensities. This is not the case for the blend containingthe micronized drug where there is no apparent change inthe compactibility suggesting that the inherent propertiesof the micronized drug have a strong influence on com-paction. Tablets containing small particles of drug exhibitedgreater tensile strength at low moisture content (ANOVA,P < 0.05) compared to untreated particles, whereas at 44%RH the probability of similarity was greater than 5%.

3.5. Conclusions

Three types of paracetamol powder were blended withMCC, untreated paracetamol and two small particle sizedsamples, one micronized and one SAXS-processed. Theblends containing the SAXS particles exhibited bulk andtapped densities and Carrs indices which were similar tothe blend containing untreated larger particle sized paraceta-mol, but greater density and smaller Carrs index than thosecontaining micronized paracetamol, after storage at 10 and44% RH. The Carrs index of all the blends suggested theformulations would exhibit relatively poor flow.

The tensile strengths of tablets of blends of MCC andboth the small paracetamol particles were greater thanfor a blend containing untreated paracetamol after storageat 10% RH. An increase in moisture content resulted ingreater compactibility of the blends containing untreatedand SAXS-processed paracetamol suggesting that the pro-cessing history of paracetamol may affect its tableting func-tionality. For blends containing untreated paracetamol, therewas no increase in the energy of compression after storageat 44% RH suggesting that it is the shape, and consequentbrittleness of the drug crystals which affects compressionenergy rather than a moisture induced increase in the com-pressibility of MCC. However, the effect of humidity whenincreased from 10 to 44% RH on compactibility appeared


to be greater for blends with pure untreated paracetamolcompared with blends containing processed material.

Overall, blends of MCC and SAXS-processed parac-etamol exhibited comparable flow and improved tabletingfunctionality to blends containing large sized untreatedparacetamol. The use of a miconized paracetamol inthe production of blends with MCC produced powderswhich exhibited poorer flow than blends prepared with acomparably sized SAXS-processed material. The use ofSAXS-processed drugs may afford formulations with im-proved flow and tableting functionality. Investigations areunderway further investigating the effect of these smallerparticle sized drugs powder and tableting functionality andon dissolution of poorly soluble drugs.

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Influence of particle size and shape on flowability and compactibility of binary mixtures of paracetamol and microcrystalline celluloseIntroductionMaterials and methodsMaterialsProduction of paracetamol samplesNovel particle engineering methodMicronization

Preparation of powder blendsPhysical characterizationScanning electron microscopy (SEM)Particle size analysisDifferential scanning calorimetry (DSC)Surface area measurementWater contentBulk and tapped densityFlowability

Powder compression and compaction

Results and discussionProduction and characterization of paracetamol particlesCharacterization of paracetamol particlesSEMParticle size analysisDSC

Preparation and characterization of the blendMechanical behavior of blendsCompressibilityCompactibility

Conclusions

References

influence of particle size and shape on flowability and compactibility of

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