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Granule deformation and densification during compression of binary mixtures of granules

International Journal of Pharmaceutics222(2001)65–76

Granule deformation and densi?cation during compression

of binary mixtures of granules

A sa Tuno′n,Go¨ran Alderborn*

Department of Pharmacy,Uppsala Uni6ersity,Box580,SE-75123Uppsala,Sweden

Received11December2000;received in revised form2April2001;accepted6April2001

Abstract

The purpose of this study was to investigate whether the deformation and densi?cation during compression of one type of granules are affected by adjacent granules of a different porosity,corresponding to different mechanical strength.Three mixtures were prepared,each consisting of two types of microcrystalline cellulose pellets(intermediate porosity study pellets plus low,intermediate or high porosity surrounding pellets)in the proportion1:7.The mixtures were compressed and the study pellets were retrieved and analysed in terms of porosity,thickness,surface area and shape.It was shown that the study pellets were compressed by deformation and densi?cation.The degree of densi?cation(decrease in porosity)of the study pellets was independent of the porosity of the surrounding pellets but the deformability(changes in the thickness,surface area and shape)of the study pellets was linked with the porosity of the surrounding pellets.It is concluded that the mode of deformation of the study pellets was regulated by the porosity of the surrounding granules;in a mixture containing granules with a low porosity,compression resulted in irregular study granules with regularly positioned indentations caused by the surrounding granules.The compression properties of the surrounding granules affected the?attening of the study granules to a lesser degree.?2001Elsevier Science B.V.All rights reserved.

Keywords:Microcrystalline cellulose;Extrusion/spheronisation;Intragranular porosity;Deformation;Densi?cation;Mode of deformation

https://www.sodocs.net/doc/0816218537.html,/locate/ijpharm

1.Introduction

The most common way to engineer particles used in pharmaceutical manufacturing, e.g.in terms of improving their tabletting properties and their ability to be uniformly coated with a drug release controlling membrane,is to form granules from?ne particle mixtures.Consequently,there has been some investigation of the compression behaviour of granules and the possibilities of modifying this behaviour to enable the engineer-ing of granules to be used in immediate and modi?ed release tablets.In this context,it has been shown that granules can be deformed(i.e. can change in shape)(Rubinstein,1976;Van der

*Corresponding author.Tel:+46-18-4714473;fax:+46-

18-4714223.

E-mail address:goran.alderborn@galenik.uu.se(G.Alder-

born).

0378-5173/01/$-see front matter?2001Elsevier Science B.V.All rights reserved. PII:S0378-5173(01)00686-X

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–76 66

Zwan and Siskens,1982;Johansson and Alder-born,1996)and become more dense(i.e.change in porosity)(Rubinstein,1976;Van der Zwan and Siskens,1982;Johansson and Alderborn,1996; Nicklasson and Alderborn,1999)during compres-sion.In addition,several reports conclude that granules can fracture or fragment during com-pression(Selkirk and Ganderton,1970;Wikberg and Alderborn,1990;Maganti and Celik,1993; Adams et al.,1994;Schwartz et al.,1994;Salako et al.,1998).However,experiments performed at our laboratory(e.g.Johansson et al.,1995;Nick-lasson et al.,1999)indicate that fragmentation of granules,i.e.the process of splitting them into smaller agglomerates,occurs only to a minor de-gree during compression and that deformation and densi?cation are the main mechanisms in-volved in the compression of granules consisting of microcrystalline cellulose.Since granule defor-mation and densi?cation are probably caused by a?ow of primary particles within the granules,i.e.

a shearing mechanism,granular factors interfering with the interaction between primary particles within the granule will also affect the compression behaviour of the granules.In this context,the granule porosity seems to be one such granule factor.

In the studies cited above,the investigated pow-ders contained only one type of granule.It is not uncommon,however,for tablets to be formed from a mixture of different types of granules.This is especially applicable to the formation of modi?ed release tablets from granulated drug par-ticles coated with a drug release controlling mem-brane(commonly referred to as reservoir units).It has,for example,been shown that the compres-sion induced change in drug release from reservoir granules depends on the type of excipient which is combined with the reservoir granules before tabletting(Torrado and Augsburger,1994;Beck-ert et al.,1996;Mount and Schwartz,1996;Pinto et al.,1997;Lundqvist et al.,1998).The charac-teristics of the excipient particles,often referred to as cushioning particles,thus represent an extra-granular material factor that has potential impor-tance for the compression behaviour of granules. For excipient particles which are granules,the compression mechanics can be controlled by vary-ing their porosity(Johansson et al.,1995;Nicklas-son and Alderborn,2000).The purpose of this study was thus to investigate whether the defor-mation and densi?cation during compression of one type of granules are affected by adjacent granules of a different porosity.

2.Materials and methods

2.1.Materials

Microcrystalline cellulose(Avicel PH101,FMC, Ireland,apparent particle density of1.58g/cm3), deionised water,ethanol(95%Finsprit,Kemetyl, Sweden),red dye(Saturnus AB,Sweden)and magnesium stearate(Ph.Eur.,Kebo,Sweden).

2.2.Preparation of pellets

Three batches of pellets of microcrystalline cel-lulose were prepared by wet granulation followed by extrusion–spheronisation.Different propor-tions of water and ethanol in the granulation liquid were used to prepare pellets of low,inter-mediate or high porosity(Table1).The powder (400g)was agitated in a planetary mixer(QMM-II,Donsmark Process Technology,Denmark)for 3min at500rpm and the granulation liquid(1.1 times the powder weight)was then sprayed into the mass at a rate of100ml/min through a spray nozzle(Schlick model940,Germany).Wet mixing was continued for5min at the same speed.The wet powder mass was then immediately extruded (model E140,NICA System,Sweden)through holes of1.0mm diameter and1.2mm length and spheronised(model S320-450,NICA System, Sweden)for3min on a32cm diameter friction plate with a radially designed grid.The pellets were?nally dried under ambient conditions for4 days.

After drying,four sets of pellets were prepared as follows.The size fraction1000–1250m m was separated from the batch of pellets with interme-diate porosity by dry sieving with a set of stan-dard sieves(Endecotts Ltd.,UK).These pellets were then coloured(for recognition during sort-ing)with red dye dissolved in a mixture of25%

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water and75%ethanol by dipping the pellets in the dye solution and drying them under ambient conditions.By this procedure,a small amount of dye was deposited mainly on the surface of the pellets.These pellets are hereafter referred to as the study pellets.From all three batches of pellets, the size fraction710–1000m m was separated by dry sieving.These pellets are hereafter referred to as the excipient or surrounding pellets.

All four sets of pellets were stored in a desicca-tor at40%relative humidity and room tempera-ture for at least7days before further investigation.Thus,the moisture content of all pellets used was similar(about5wt.%)before further handling.

2.3.Preparation of tablets

Binary granule mixtures were prepared by mix-ing the study and excipient pellets in a tumbling mixer(Turbula,W.A.Bachofen,Switzerland)at 120rpm for5min in the proportion1:7(v/v).The coordination number in a bed of spheres is the maximum number of spheres theoretically able to be in contact with any single sphere.It has been reported that a bed of randomly arranged and loosely packed(by pouring)spheres with a bed voidage of about45%has a coordination number of approximately seven(Cumberland and Craw-ford,1987).Since the bed voidage values obtained for the pellets used in this study(Table1)were in the same order of magnitude as this,the relative proportions of the two types of pellets was chosen as1:7,so as to create a packing status before compression in which each study pellet was theo-retically surrounded by and in contact with only excipient pellets.

The mixtures of pellets were mixed with0.5% w/w of magnesium stearate for100min in the tumbling mixer.This procedure was used to de-crease bonding between the pellets in the formed tablets so as to enable easy mechanical deaggrega-tion of the tablets.We have earlier shown(Jo-hansson and Alderborn,1996)that a lubricant admixed to microcrystalline cellulose pellets under the conditions chosen in this study will only mar-ginally affect the compression behaviour of the pellets,in terms of the degree of compression as a function of compression pressure,compared with unlubricated pellets.

The lubricated pellet mixtures were compacted in an instrumented single punch press(Korsch EK0,Germany)equipped with circular?at faced punches(diameter11.3mm).For each tablet,the die was manually?lled with500mg(95mg)of pellets and tablets were formed at three different upper punch pressures(40,80and160MPa). Before each compaction,the punches and die were lubricated with an ethanol suspension of magnesium stearate.

2.4.Deaggregation of tablets

The tablets were gently deaggregated by manu-ally shaking them in a petri dish.The study pellets were then separated from the surrounding pellets in two steps.Firstly,the mixture was sieved through a1000m m sieve and,secondly,the two types of pellets were sorted manually from both fractions by colour.The retrieved study pellets were stored in a desiccator at40%relative humid-ity and room temperature for at least7days before characterisation.

2.5.Characterisation of pellets

The appearance of the pellets was investigated using photomicrographs taken with the aid of a scanning electron microscope(Philips SEM525, Holland).

The intragranular porosity of the pellets was calculated(n=3for uncompacted pellets and n= 2for retrieved pellets)as one minus the ratio of the effective and apparent particle densities.The apparent particle density of the microcrystalline cellulose powder was measured using a helium pycnometer(Accupyc1330,Micromeritics,USA). The effective particle(pellet)density was deter-mined by mercury pycnometry at100kPa(ap-proximately corresponding to atmospheric pressure)using a porosimeter(Autopore III9420, Micromeritics,USA).

The bulk density of the uncompacted pellets was assessed(n=3)using a tap volumeter(J. Engelsmann A.G.,Ludwigshafen,Germany,com-plying with DIN standard53194).The pellets

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–7669

were poured into a50ml cylinder which was tapped200times.The poured and tapped densi-ties were determined from the weight and volume of the pellet bed and the ratio of tapped to poured bulk density was calculated.

The bulk density of the retrieved study pellets was determined(n=3)from the weight and height of beds of pellets held within the container used for permeametry measurements(see below). The external surface area of the pellets was assessed(n=3)using steady-state air permeame-try.The pellets were poured manually into a glass cylinder of11.5mm diameter to an approximate bed height of4cm and subjected for10min to mild vibration.The weight and height of the pellet bed were then measured.The container was con-nected to a digital differential manometer(P200S, Digitron Instrumentation Ltd,UK)to detect the pressure drop over the bed of pellets.Air was pumped through the bed at a series of controlled ?ow rates(Brook?ow meter,Brook Instruments B.V.,The Netherlands)and the corresponding pressure drop recorded.The permeametry surface area was then calculated according to Eriksson et al.(1993).

The pellet thickness was determined(n=2)by ring gap sizing(F.O.A.,Sweden)as described earlier(Nystro¨m and Stanley-Wood,1976).Suit-able vibrating conditions for the sizing table were determined using pretrials.About1g of pellets was used for each experiment and the results were analysed in terms of the median of the number distribution.

The shape of the pellets was characterised using image analysis.The pellets were manually dis-persed on microscope slides and then pho-tographed in a light microscope(Olympus Vanox, Japan)at two times magni?cation.The photos were digitalised and the projected area(A),the projected area circle diameter(d)and the perimeter(P)of the pellets were determined (n=66)by image analysis(NIH Image,version 1.61,USA,available on the Internet at http:// https://www.sodocs.net/doc/0816218537.html,/nih-image/)with a pixel resolu-tion of5.1–5.3m m/pixel.The circularity(C)of the pellets(a measure of the closeness of the projected area of the pellet to the area of a circle of the same perimeter)(Cox,1927)was calculated as:C=

4y A

P2

and the Heywood shape coef?cient,h,(Heywood, 1954)was calculated as:

h=S v d

where S v is the volume speci?c external surface area of the pellets as determined by permeametry.

3.Results

The preparation procedure used gave pellets with a wide range of intragranular porosity(Table 1),as expected from earlier experience(Johansson et al.,1995).The intragranular porosity was the same for the excipient pellets of intermediate porosity and the study pellets.According to ear-lier experiences(Johansson et al.,1995;Nicklas-son and Alderborn,2000),the variation obtained in intragranular porosity for the surrounding pel-lets corresponds to marked differences in their mechanical strength in terms of both the single fracture strength and the compression shear strength of the pellets.

Visual examination of the pellets indicated that they were generally nearly spherical in shape with a smooth surface(Fig.1a).The values of inter-granular voidage and the ratios of tapped to poured bulk density were similar for all four sets of pellets.In addition,these ratios were close to unity,indicating pellets of a high?owability. Thus,the pellets could generally be described as smooth and nearly spherical.The shape measures (circularity and Heywood shape coef?cient,Table 2)for the study pellets con?rmed that these pellets were nearly spherical in shape before compaction. After deaggregation of the tablets,the retrieved pellets were similar in size to the original pellets (Fig.1).Only a few pellet fragments were ob-tained during deaggregation.Cracks were,how-ever,noticed in some pellets(Fig.1).The low incidence of fragmentation in these types of pel-lets during compression is consistent with earlier observations(Johansson et al.,1995)and sup-ports the premise that these types of pellets can-not be described as prone to fragmentation during compression.

A .Tuno ′n ,G .Alderborn /International Journal of Pharmaceutics 222(2001)65–7671

The surface area of the retrieved study pellets

increased and their thickness decreased as a result of compaction (Table 2,Figs.2and 3).Increased compaction pressure increased the pellet surface area and decreased the pellet thickness.The origi-nal porosity of the excipient pellets affected the changes in thickness and surface area of the study pellets in that excipient pellets with the lowest original porosity resulted in less ?at study pellets with a higher surface https://www.sodocs.net/doc/0816218537.html,paction also af-fected the shape of the individual study pellets (Table 2),resulting in generally more irregular pellets.There was a tendency for the circularity of the study pellets to decrease and the shape coef ?-cient to increase as the porosity of the excipient pellets decreased (Fig.4).

The photomicrographs (Fig.1)support the changes in shape of the study pellets with com-paction and the in ?uence of the porosity of the surrounding pellets on these changes.Including high porosity excipient pellets in the mixture re-sulted in elongated but relatively regularly shaped retrieved study pellets.Excipient pellets with lower porosity resulted in study pellets with a more irregular shape:the study pellets had regu-larly positioned cavities or indentations caused by the surrounding excipient pellets rather than in-creased ?attening (compare Fig.3).This type of irregularity was most pronounced for study pellets that had been compacted with excipient pellets of the lowest porosity (highest mechanical strength).

Fig.1.Scanning electron micrographs of uncompacted study pellets (a)and study pellets compacted at 160MPa with excipient pellets of (b)low porosity,(c)intermediate porosity and (d)high porosity.The white bar denotes 1mm.

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–76

72

Fig.2.Volume speci?c surface area of study pellets as a function of compaction pressure.Study pellets compacted with excipient pellets of low("),intermediate( )or high( )porosity.The error bars represent the standard deviation(S.D.).

Compaction also decreased the porosity of the pellets(Table2).The porosity of the retrieved study pellets was,however,independent of the porosity of the surrounding pellets,i.e.the poros-ity of the retrieved pellets was dependent only on the compaction pressure.

Changes in the thickness and porosity of micro-crystalline cellulose pellets(original porosity44%) during compaction were determined in an earlier study(Johansson and Alderborn,1996).Changes in the same characteristics of the pellets used in our study(original porosity27%)were slightly lower in magnitude,which seems reasonable con-sidering the difference in original porosity.

4.Discussion

Earlier studies(Johansson et al.,1995;Jo-hansson and Alderborn,1996)have demonstrated that granules formed from microcrystalline cellu-lose,like those used in this study,will deform and become denser during compaction under pres-sures of about5–200MPa.Those studies also showed that deformation and densi?cation are the dominating mechanisms involved in the compres-sion event,i.e.that,although cracking may occur, actual fragmentation occurs to only a minor de-gree.The results obtained in this study support those?ndings.Earlier studies also indicated that the degree of both deformation and densi?cation is affected by the original porosity of the granules, i.e.the original porosity is a granular physical factor which regulates the compression behaviour of those granules that only fragment to a minor degree.The effect of an extragranular material factor(the porosity or mechanical strength of the surrounding granules)on the deformation and densi?cation behaviour of granules has been in-vestigated in this study in order to broaden our understanding of the physical factors regulating the compression behaviour of granules.

The results show that the interaction between the study granules and the surrounding granules was dependent on the compression mechanism studied.The porosity of the surrounding pellets clearly affected the deformation of the study pel-lets.Although the degree of deformation(the amount of?attening)of the study pellets was affected by the porosity of the surrounding pellets to only a limited degree(Table2,Fig.3),changes in the shape of the study pellets(irregularity)with changes in the porosity of the surrounding pellets were more signi?cant(Table2,Figs.1and4).In contrast,the original porosity of the surrounding pellets had no effect on the densi?cation(decrease

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–7673

in porosity)of the study pellets during compres-sion(Table2),despite the differences in deformation.

In earlier discussions of the deformation be-haviour of granules,the term mode of deforma-tion(Nicklasson and Alderborn,1999)has been used to describe the types of changes in shape that granules undergo during compression.Two differ-ent modes of deformation(here referred to as mode I and mode II,respectively,)can in a generalised way explain the deformation be-haviour of granules.Mode I deformation de-scribes a local change in the geometry of the external surface of a granule in order to conform to the external surfaces of adjacent granules(i.e. no change in bulk dimensions).Mode II deforma-tion describes a change in the main dimensions of the granules,primarily expressed as a?attening of their bulk.

The compression process for microcrystalline cellulose granules has been described from a mechanistic view as occurring in four stages(Jo-hansson and Alderborn,1996),i.e.granule reposi-tioning(stage1),granule surface deformation (stage2),granule bulk deformation and densi?ca-tion(stage3)and?nally,ceased granule deforma-tion(stage4).It was thus suggested that granules deform at low pressures by a mode I deformation followed at higher pressures by bulk deformation (mode II deformation)parallel with a signi?cant granule densi?cation.Thus,the individual gran-ules will undergo one or both modes of deforma-tion depending on the compaction pressure(the degree of compression).This premise was further developed(Nicklasson and Alderborn,1999)to suggest that the relative incidence of mode I and mode II was also dependent on the composition of the granules,e.g.the presence of a soft compo-nent within the granules.In the discussion below, a possible variation in the deformation and den-si?cation behaviour of the pellets dependent on the localisation of the pellets within the powder column held within the die is not considered.Such a variation may occur dependent on a variation in transmitted compression force within the bed of pellets and it is of interest to investigate this problem.It seems though reasonable to assume that the general effects of the importance of the porosity of surrounding pellets for the deforma-tion and densi?cation of the study pellets is inde-pendent of the localisation of the pellets within the bed of pellets with the exception for pellets in contact with die wall and punch faces.For these relatively few pellets,their deformation will be controlled by the interaction with the die wall and punch faces rather than by the interaction with surrounding pellets.

Fig.3.Median thickness of study pellets as a function of compaction pressure.Study pellets compacted with excipient pellets of low ("),intermediate( )or high( )porosity.

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–76

74

Fig.4.Values for circularity(---)and Heywood shape coef?cient(---)of study pellets before and after compaction at160MPa (circularity ,Heywood shape coef?cient )as a function of original porosity of the excipient pellets.Con?dence limits for P=0.05are shown for circularity values(---).

The type of shape change reported in our study can be described as extended mode I deformation, i.e.local deformation leading to conformation with adjacent granule surfaces in such a way that indentations into the study granules were formed (Figs.1and5).Thus,the incidence and character of mode I deformation occurring in a given gran-ule will be dependent on the physical properties of the adjacent granules.The results generated in this study indicate that it is the relative mechani-cal strength of the adjacent granules that will primarily affect the character of the mode I defor-mation,i.e.whether indentations will be formed in the study granules or whether the granule surfaces will only be?attened.When the sur-rounding granules have a higher mechanical strength than the study granules,indentation will occur;however,if the mechanical strength of the surrounding granules is similar or lower than that of the study granules,indentation will not occur but mode I deformation expressed as?attening of the granule surfaces may take place. Concerning the densi?cation(i.e.the porosity reduction)of the pellets,the results(Table2) indicate a low porosity reduction at the lowest compaction pressure,followed by a higher densi?-cation rate at intermediate pressure which?nally will level off.Johansson and Alderborn(1996) suggested that surface deformation was associated only with a limited densi?cation,which became signi?cant during the bulk deformation phase. For the pellets used in our study,one can propose that in the early compression phase,mode I defor-mation expressed as a local?attening of the pellet surfaces occurs.This type of mode I deformation is associated with limited densi?cation.However, with increased compaction pressure,indentation by the surrounding granules occurs and this type Fig.5.Schematic representation of the mode of deformation of study pellets compacted with surrounding pellets of(a) lower porosity and(b)higher porosity.

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of extended mode I deformation occurs parallel to a signi?cant densi?cation of the pellets.

There was also a tendency for the surrounding granules to affect the thickness of the study gran-ules,i.e.a change towards more irregular study granules was associated with less?attening of these granules(Fig.3).Thus,the surrounding granules can also affect the mode II deformation of the study granules,but to a less signi?cant degree compared to the effects on mode I deformation.

5.Conclusions

The degree of densi?cation on compression of the study pellets was independent of the porosity of the surrounding pellets.Conversely,the defor-mation behaviour did depend on the porosity of the surrounding pellets.Less porous surrounding pellets caused indentations into the surface of the study pellets,resulting in irregular pellets with regularly positioned cavities,while more porous surrounding pellets did not indent the study pel-lets but did?atten their surfaces.Changes in study pellet dimensions were less dependent on the porosity of the surrounding pellets. Acknowledgements

Financial support for this study was obtained from Pharmacia AB,AstraZeneca AB,NUTEK (Swedish National Board for Industrial and Tech-nical Development)and the Wallenberg founda-tion in Sweden.Lisbeth Heiskanen is gratefully thanked for skilful experimental assistance. References

Adams,M.J.,Mullier,M.A.,Seville,J.P.K.,1994.Agglom-erate strength measurement using a uniaxial con?ned compression test.Powder Technol.78,5–13.

Beckert,T.E.,Lehmann,K.,Schmidt,P.C.,https://www.sodocs.net/doc/0816218537.html,pres-sion of enteric-coated pellets to disintegrating tablets.Int.

J.Pharm.143,13–23.

Cox,E.P.,1927.A method of assessing numerical and per-centage values to the degree of roundness of sand grains.

J.Paleontol.1,179–183.Cumberland,D.J.,Crawford,R.J.,1987.Handbook of Pow-der Technology:The packing of particles,vol. 6.El-sevier,Amsterdam,p.33.

Eriksson,M.,Nystro¨m,C.,Alderborn,G.,1993.The use of air permeametry for the assessment of external surface area and sphericity of pelletized granules.Int.J.Pharm.

99,197–207.

Heywood,H.,1954.Particle shape coef?cients.J.Imp.Coll.

Chem.Eng.Soc.8,25–33.

Johansson,B.,Alderborn,G.,1996.Degree of pellet defor-mation during compaction and its relationship to the tensile strength of tablets formed of microcrystalline cel-lulose pellets.Int.J.Pharm.132,207–220. Johansson, B.,Wikberg,M.,Ek,R.,Alderborn,G.,1995.

Compression behaviour and compactability of microcrys-talline cellulose pellets in relationship to their pore struc-ture and mechanical properties.Int.J.Pharm.117, 57–73.

Lundqvist,A.E.K.,Podczeck,F.,Newton,J.M.,https://www.sodocs.net/doc/0816218537.html,-paction of,and drug release from,coated drug pellets mixed with other pellets.Eur.J.Pharm.Biopharm.46, 369–379.

Maganti,L.,Celik,M.,https://www.sodocs.net/doc/0816218537.html,paction studies on pellets

I.Uncoated pellets.Int.J.Pharm.95,29–42.

Mount, D.L.,Schwartz,J.B.,1996.Formulation and com-paction of nonfracturing deformable coated beads.Drug Dev.Ind.Pharm.22,609–621.

Nicklasson, F.,Alderborn,G.,1999.Modulation of the tabletting behaviour of microcrystalline cellulose pellets by the incorporation of polyethylene glycol.Eur.J.

Pharm.Sci.9,57–65.

Nicklasson, F.,Alderborn,G.,2000.Analysis of the me-chanics of pharmaceutical agglomerates of different porosity and composition using the Adams and Kawak-ita equations.Pharm.Res.17,947–952.

Nicklasson,F.,Johansson,B.,Alderborn,G.,1999.Occur-rence of fragmentation during compression of pellets pre-pared from a4to1mixture of dicalcium phosphate dihydrate and microcrystalline cellulose.Eur.J.Pharm.

Sci.7,221–229.

Nystro¨m,C.,Stanley-Wood,N.,1976.Measurement of par-ticle size of free-?owing material with a ring gap sizer.

Acta Pharm.Suec.13,277–284.

Pinto,J.F.,Podczeck,F.,Newton,J.M.,1997.Investigations of tablets prepared from pellets produced by extrusion and spheronisation.Part I:the application of canonical analysis to correlate the properties of the tablets to the factors studied in combination with principal component analysis to select the most relevant factors.Int.J.

Pharm.147,79–93.

Rubinstein,M.H.,1976.Granule consolidation during com-paction.J.Pharm.Sci.65,376–379.

Salako,M.,Podczeck, F.,Newton,J.M.,1998.Investiga-tions into the deformability and tensile strength of pel-lets.Int.J.Pharm.168,49–57.

A.Tuno′n,G.Alderborn/International Journal of Pharmaceutics222(2001)65–76 76

Schwartz,J.B.,Nguyen,N.H.,Schnaare,R.L.,https://www.sodocs.net/doc/0816218537.html,-paction studies on beads:compression and consolidation parameters.Drug Dev.Ind.Pharm.20,3105–3129. Selkirk,A.B.,Ganderton,D.,1970.An investigation of the pore structure of tablets of sucrose and lactose by mercury porosimetry.J.Pharm.Pharmacol.Suppl.22,79S–85S. Torrado,J.J.,Augsburger,L.L.,1994.Effect of different excipients on the tableting of coated particles.Int.J.

Pharm.106,149–155.

Van der Zwan,J.,Siskens,C.A.M.,1982.The compaction and mechanical properties of agglomerated materials.Powder Technol.33,43–54.

Wikberg,M.,Alderborn,G.,https://www.sodocs.net/doc/0816218537.html,pression characteris-tics of granulated materials:II.Evaluation of granule fragmentation during compression by tablet permeability and porosity measurements.Int.J.Pharm.62,229–241.

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