Handbook of pharmaceutical wet granulation

395 Pages·2016·29.86 MB·English

by  AJIT S. NARANG

CHAPTER 13
Use of Mannitol as a Filler in Wet
Granulation
Sherif I.F. Badawy, Keyur R. Shah, Madhu S. Surapaneni, Marta M. Szemraj,
Munir Hussain
DrugProductScience&Technology,Bristol-MyersSquibbCo.,NewBrunswick,NJ,UnitedStates
1 INTRODUCTION
Wetgranulatedtabletformulationsbasedonmicrocrystallinecellulose(MCC)andlactose
as the fillers are commonly used in the pharmaceutical industry. It is well known,
however, that lactose could react chemically with drugs containing an amine moiety
(particularlyprimaryamine),andthereforetheuseoflactoseasafillerintheformulation
ofthosedrugsshould beavoided.In suchcases,MCC couldbeusedalone or couldbe
usedalongwithotherfillerssuchasdicalciumphosphatedihydrateandmannitol.Certain
problemsareassociatedwithusingMCCasthesolefiller.Theexcellentcompactibilityof
MCC could be reduced significantly upon wet granulation (Badawy, Gray, & Hussain,
2006; Gustafsson, Lennholm, Iversen, & Nystro€m, 2003). Reier and Shangraw (1966)
reported that exposure of tablets of MCC-based formulation to increased humidity
(75% RH, 1week) resulted in a softening and swelling of the tablets. Compactibility
ofMCCalsoisknowntobesensitivetotheeffectofcompressionspeedorpunchveloc-
ity.DavidandAugsburger(1977)studiedtheeffectofdurationoftheoverallcompres-
sioncycleontabletstrengthofsomecommondirectcompressionfillersincludingMCC.
They observed that an increase in the duration of the overall compression cycle from
0.09–10s resulted in significant increases in the tensile strength of the tablets prepared
from MCC. When MCC is used alone as a filler in a wet granulated formulation, all
thethreeincidences―lossofcompactibilityonwetgranulation,decreasedcompactibil-
ity at higher compression speeds (speed sensitivity), and loss of tablet hardness under
humid conditions (hardness decay)―could occur simultaneously, reducing the overall
compactibility of the formulations.
Dicalciumphosphateislesspreferredinaformulationbecauseoflowcompactibility
(Zhang,Law,&Chakrabarti,2003),andalsobecausethewaterofcrystallizationcouldbe
releasedduringprocessingorstorageandthereforechemicallyinteractwithdrugsprone
to hydrolysis (Schlack, Bauer-Brandl, Schubert, & Becker, 2001). Mannitol is an alter-
native excipient that is water soluble, nonhygroscopic, and produces a semisweet,
smooth cool taste. Therefore, it is a widely used filler in the formulation of chewable
HandbookofPharmaceuticalWetGranulation ©2019ElsevierInc.
https://doi.org/10.1016/B978-0-12-810460-6.00006-3 Allrightsreserved. 455
456 HandbookofPharmaceuticalWetGranulation
orrapidlydisintegratingtabletformulations.Mannitolalsocouldbeusedinconventional
tablets, where nonhygroscopicity and chemical inertness are desired. There have been
numerous reports about the various polymorphs of D-mannitol. According to Burger
et al. (2000), mannitol exists in three different polymorphic forms in the pure state:
the α form,theβ form, andthe δform. The βform is the main commercially available
polymorph.Severalcommercialgradesofmannitol,whichdiffermainlyintheirparticle
sizeandmanufacturingmethod,areavailable.Thedifferentgradesgenerallyarereferred
toaspowder,granulated,orspray-driedandshowsignificantdifferencesintheirbehavior
in the tablet compression process. Powder grades of mannitol generally have high
lubricantrequirementandexhibithighfrictionalforceduringtheejectionofthetablet.
Granulated grades have lower compactibility than the powder or spray-dried grades.
Spray-dried mannitol typically exhibits superior characteristics compared to the other
grades.
A study was conducted to evaluate the inclusion of a commercially available spray-
dried grade of mannitol along with MCC in the formulation instead of MCC alone,
inwhichlactosecouldnotbeaddedbecauseofchemicalincompactibilitywiththeactive
ingredient(Badawy,Shah,Surapaneni,Szemraj,&Hussain,2010).Anotherpurposeof
this study was to evaluate the processing advantage of incorporating this grade of man-
nitol in MCC-based wet granulated formulation compared to MCC alone, particularly
with respect to compactibility loss, speed sensitivity, and hardness loss in humid condi-
tions occurring in MCC based formulations. The granulating water-to-solids ratio and
the magnesium stearate required for optimum granulation properties depends on the
ratioofmannitoltoMCCusedintheformulation.Therefore,thewater-to-solidsratio
and lubricant level required for the optimum granulation performance also were
evaluated.
2 STUDY DESIGN
A two-level full factorial design with two center points (Table 1) was used to study the
effect of three variables of the mannitol to MCC ratio (mannitol weight fraction of the
filler:low0(nomannitol)andhigh0.5),watertointragranularsolidsratio(low0.25and
high 0.4), and magnesium stearate concentration, w/w (0.6% low and 1.2% high). In
additiontomicrocrystallinecellulose,mannitol,andmagnesiumstearate,allformulations
contained3%hydroxypropylcelluloseand4%croscarmellosesodium(2%intragranular
and 2% extragranular). Response variables evaluated were: granulation compactibility,
ejection force, normalized granule parameter, percentage of fines, flowability index
and percentage of hardness decay. Statistical analysis of the data was carried out in
SAS JMP 4.0 (SAS Institute Inc., Cary, NC, USA). Preliminary data analysis using a
regression model with main effects, and the two-way interactions indicated that the
UseofMannitolasaFillerinWetGranulation 457
Table1 Fullfactorialdesignwithtwocenterpoints
Run# Mannitolratio Waterratio Magnesiumstearateconcentration
1 1 (cid:1)1 1
2 (cid:1)1 (cid:1)1 1
3 1 1 (cid:1)1
4 0 0 0
5 1 1 1
6 (cid:1)1 1 1
7 1 (cid:1)1 –1
8 0 0 0
9 –1 1 –1
10 –1 –1 –1
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.
magnitudes of some of interaction terms were insignificant. As a result, data were ana-
lyzed subsequently with a regression model that excluded those interaction terms.
Granulation of the different experimental design batches was carried out in a 10-L
Fujihigh-sheargranulatoratabatchsizeof1.75kgusingwaterasthegranulatingliquid.
Microcrystalline cellulose, hydroxypropyl cellulose, intragranular croscarmellose
sodium,andmannitol(whenapplicable,asperthestudydesigninTable1)wereadded
tothebowlofthegranulatorandblendedfor2minatanimpellerspeedof300rpmanda
chopperspeedof1500rpm.Thespecifiedamountofwaterforthebatchthenwasadded
to the blend in the granulator using a peristaltic pump over a period of 2min, with the
impellerspeedmaintainedat300rpmandthechopperspeedat1500rpm.Aftercomplete
addition of water, the granulation was wet massed for 30s while maintaining
the same impeller and chopper speeds. The wet granulation was screened through a
12-mesh screen and dried in a hot air oven at 50°C to a moisture content of 1%–3%
w/w(determinedbyLossonDryingat105°C).Thedriedgranulationwasmilledusing
aconicalmill(Comil197S,QuadroInc.,Millburn,NJ,USA)througha20-meshscreen.
Subsequently,extragranularcroscarmellosesodiumwasaddedtothemilledgranulation
inan8.0quartV-blender(Patterson-Kelly,EastStroudsburg,PA,USA),andblendedfor
15min. The blend then was lubricated with magnesium stearate by additional mixing
for 5min.
Granulation was compressed into 90mg tablets on a Korsch 6-station press
(equipped with only two tooling sets) using 1/4-in. shallow concave tooling with
scored lower punch and upper punch embossed with “468.” The Korch press was
instrumented by Metropolitan Computing Corporation (East Hanover, NJ, USA).
At the beginning of the compression run, the compaction profile was obtained for
each granulation by determining mean tablet hardness of 10 tablets at different
458 HandbookofPharmaceuticalWetGranulation
compaction forces. Hardness was determined in Strong Cobb Units (SCU) using a
hardness tester (Key International, Englishtown, NJ, USA). The maximum hardness
obtained at the highest compression force for each granulation was used to compare
compactibility of the different batches. For the batches with high level of mannitol,
thecompressionrunwascontinuedatatargethardnessof6SCUforatleast5000hits
perpunch.Attheendoftherun,thetoolingwasinspectedforanyfilming,sticking,
or filling of the embossing.
3 CHARACTERIZATION OF GRANULATION AND TABLETS
CompactionprofilesofthelubricatedgranulationswereobtainedusingESHtabletcom-
paction simulator. A weight of 260mg of each batch was compressed on the simulator
using3/8-in.flatfacetoolingtoapredeterminedin-diethickness.Eachbatchwascom-
pressed to four different thickness targets with three tablets obtained at each thickness.
The actual thickness achieved for each compressed tablet was determined by the linear
variabledisplacementtransducer(LVDT)ofthecompactionsimulator.Compressionand
ejection forces were determined for each tablet. The hardness of each tablet was
determined by a diametrical compression test on a hardness tester (Key International,
Englishtown, NJ) and converted to a tensile strength. Compaction profiles then were
constructedusingthecompressionpressure(obtainedbydividingthecompressionforce
bypuncharea)andcorrespondingcompacttensilestrength.Thecompactibilityparam-
eterwascalculatedastheslopeofthelineobtainedbylinearregressionofthedatapoints
in the compaction profile. Two additional compaction parameters also were calculated
from thecompaction simulator data.The yield pressurewasobtainedfrom theslopeof
the linear portion of the natural logarithm of the reciprocal tablet porosity versus com-
pression pressure. A bonding parameter was calculated as the Y-intercept of the plot of
tensile strength versus tablet porosity and representstheoretical tablet tensile strength at
zero porosity. The effect of compression speed on granulation compactibility also was
evaluatedforfourbatchesusingthePresstercompactionsimulator(MetropolitanCom-
puting Corporation,East Hanover,NJ).Granulation frombatches5,6,7, and10 were
compressedinto260mgtabletsusing3/8-in.flatfacetooling.Compactionprofileswere
determinedatthreecompressiondwelltimes(7.4,14.8,and29.5ms)foreachgranulation
withthreetabletreplicatesateachcompressionforce.Compactibilityparameterwascal-
culated for each granulation at the different compression speeds from the slope of the
compactionprofileasdescribedabove.Acompressionspeedsensitivityindex(SSI)then
wascalculatedforeachgranulationastheratioofthecompactibilityatthe29.5msdwell
time to that at the 7.4ms dwell time. The effect of mannitol on compression speed
sensitivity was assessed by comparing the SSI values for batches 5 and 7 (high level of
mannitol) to batches 6 and 10 (no mannitol), respectively.
UseofMannitolasaFillerinWetGranulation 459
Particle size distribution of the dried granulation material was determined by mesh
analysis using an Allen Bradley sonic sifter (Allen Bradley, Milwaukee, WI, USA)
equipped with a series of six screens and a pan. Normalized granule growth parameter
wascalculatedastheratioofgeometricmeandiameterofthegranulestogeometricmean
diameterofthepre-blendpriortogranulation.Thepercentageoffineswascalculatedby
thesummationofthepercentagematerialretainedoverthemesh#325anddustcollected
in the pan of the sonic sifter (particle size <75μm).
TheflowabilityindexofthedifferentgranulationswasmeasuredusingFlodexpow-
derflowabilitytester(HansonResearch,Chatsworth,CA,USA).Theflowabilityindex
isthediameter(mm)ofthesmallestholethroughwhichthepowderfallsfreelyinthree
successivetrials.A(cid:3)30gofthetestsamplewaspouredthroughafunnelintoacylinder
andallowedtosettlefor30s.Thecylinderwasequippedwithseriesofreplaceableindex
flowdiscsofdifferentdiametersinthebottom,andtheholeisclosedwithamobileshut-
ter.Theleverdeviceattachedtothecylinderwasusedtoopentheholeandevaluatethe
flow of the powder through the index flow disc. The lower the flowability index, the
better the flow of the granules.
Tablet hardness decay was evaluated using 10 tablets from each of the experimental
runsontheKorsch6-stationpresscompressedtothetargethardnessof6SCU.Thetab-
letswerestoredinanopendishat25°C/65%RHfor6h.Thehardnessofeachtabletwas
determined by the diametrical compression test. The percentage of hardness decay
was calculated from the mean of the tablet hardness after storage and the initial tablet
hardness as follows:
%Hardnessdecay¼ðInitialhardness(cid:1)FinalhardnessÞ=Initialhardness:
4 COMPACTION STUDIES
4.1 Compactibility
The presence of mannitol in the formulation increased the maximum tablet hardness
achieved in the Korsch experiment (P¼0.0005) and the compactibility parameter in
the compaction simulator study (P¼0.0087) (Table 2). A higher level of magnesium
stearate,however,decreasedmaximumtablethardness(P¼0.0187)andthecompactibil-
ityparameter(P¼0.0302).Thenegativesignoftheparameterestimatefortheeffectof
wateronthevariouscompactionparameterssuggestsatrendofreducingcompactibility
asthe waterratio isincreased. Theeffect of water, however, wasnot statistically signif-
icant on any of the compaction parameters.
Thecompactionprofilealsowasdifferentbetweenformulationswithhighermanni-
tol ratio and those without mannitol (Fig. 1). Formulations without mannitol demon-
strate a biphasic profile with high initial slope followed by a region with minimal
increaseinthetablethardnessasthecompressionforcewasincreased.Compactionpro-
files, however, were more linear for formulations with high mannitol ratio, and tablet
460 HandbookofPharmaceuticalWetGranulation
Table2 Regressionanalysisofcompactiondata
Parameterestimate(Pvalue)
Maximum
Parameter hardnessa Compactibilityb Bondingb Yieldpressureb
Mannitol:MCC 1.91 (0.0005) 1.22 (0.0087) 0.91 (0.0041) 49.1 (<0.0001)
ratio
Waterratio (cid:1)0.463 (0.1087) (cid:1)0.095(0.7756) (cid:1)0.015(0.9431) 1.48 (0.7318)
Magnesium stearate (cid:1)0.0813(0.0187) (cid:1)0.90 (0.0302) (cid:1)0.29 (0.2005) 8.93 (0.0741)
concentration
Mannitol 0.8375 (0.0167) NSc NSc NSc
ratio(cid:4)water ratio
aKorsch6-stationexperiments.
bCompactionsimulatorstudy.
cInteractionnotstatisticallysignificant(P<0.05).
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.
16
14
12
)U
C 10
S
(
ss 8
e
n
d 6
ra
H High mannitol, low water
4 Low mannitol, low water
High mannitol, high water
2 Low mannitol, high water
0
0 1 2 3 4 5 6 7 8 9
Compression force (kN)
Data shown are for batches 1, 2, 5, and 6 with high level of magnesium stearate.
Fig. 1 Compaction profile of the granulations on the Korsch PH106 tablet press. (Reproduced with
permission from Badawy, S. I. F., Shah, K. R., Surapaneni, M. S., Szemraj, M. M., & Hussain, M. (2010).
Effect of spray-dried mannitol on the performance of microcrystalline cellulose-based wet granulated
tablet formulation. Pharmaceutical Development and Technology, 15(4), 339–345. https://doi.org/10.
3109/10837450903229065.)
UseofMannitolasaFillerinWetGranulation 461
hardness continued to increase as the compression force was increased up to the maxi-
mum compression force examined.
The interaction term between mannitol ratio and water ratio was significant for the
maximum tablet hardness in the Korsch study (P¼0.0167). The positive sign of the
parameter estimate for this interaction term reflects the enhanced maximum hardness
for the formulations with high mannitol ratio at the higher water ratio in contrast to
the formulations without mannitol that showed decreased tablet hardness as the water
ratiowasincreased.Thisinteractiontermwasnotstatisticallysignificantforthecompac-
tion simulator compactibility parameter. Because the compression cycle time is much
shorter in the Korsch, it can be inferred that this interaction becomes less important at
the slow compression speed of the compaction simulator.
Fig.2showsthesimulatorcompactionprofileoftwogranulatedbatches,onewitha
highmannitolratio,andtheotherwithoutmannitol.Bothbatchesweregranulatedwith
low water ratio and have low level of magnesium stearate. Compaction profiles of the
corresponding blends prior to granulation also are shown in Fig. 2 (lubricated with
the same concentration of magnesium stearate as the granulation). Compactibility of
pregranulated blend without mannitol was higher than the one with the high mannitol
ratio, reflecting the higher compactibility of MCC starting material compared to man-
nitol. Both formulations showed decreased compactibility upon wet granulation,
resultingin comparablecompactibilityforthetwogranulatedbatches.Becausethefor-
mulation without mannitol showed higher compactibility for the pregranulated blend,
8
7
)a 6
P
M
( 5
h
tg
ne 4
rts
e 3
lis
n Granulated blend — high mannitol
e 2
T Granulated blend — low mannitol
1 Pregranulated blend — high mannitol
Pregranulated blend — low mannitol
0
0 50 100 150 200 250 300 350 400 450
Compression pressure (MPa)
Fig. 2 Compaction profiles of the granulations and preblends obtained using the compaction
simulator. (Reproduced with permission from Badawy, S. I. F., Shah, K. R., Surapaneni, M. S.,
Szemraj, M. M., & Hussain, M. (2010). Effect of spray-dried mannitol on the performance of
microcrystalline cellulose-based wet granulated tablet formulation. Pharmaceutical Development and
Technology,15(4),339–345.https://doi.org/10.3109/10837450903229065.)
462 HandbookofPharmaceuticalWetGranulation
however,itcanbeconcludedthatformulationcontainingmannitolislesspronetocom-
pactibility loss than the one without mannitol. Wet granulation is known to decrease
compactibility of MCC. Compactibility of mannitol as an excipient, however, is not
reduced and might even be enhanced by wet granulation (Debord et al., 1987; Juppo,
Kervinen, Yliruusi, & Kristoffersson, 1995). As a result, addition of mannitol to the
MCCformulationdemonstrateddecreasedsusceptibilityoftheformulationtocompac-
tion loss upon wet granulation.
4.2 Compression Speed Sensitivity
Thespeedsensitivityindex(SSI)forbatches5,6,7,and10isshowninTable3.Incor-
poration of the high level of mannitol decreased compression speed sensitivity of the
granulation when other parameters are kept constant. Thus, the SSI decreased from
1.92 for batch 6 without mannitol to 1.11 for batch 5 with high level of mannitol
(bothbatchesprocessedusinghighlevelofwaterandhighlevelofmagnesiumstearate).
Similarly,theSSIdecreasedfrom1.86forbatch10withoutmannitolto1.20forbatch7
withhighlevelofmannitol,wherethetwobatchesweremanufacturedatalowlevelof
waterandlowlevelofmagnesiumstearate.Minimizingtheeffectofcompressionspeed
on compactibility is desirable because it facilitates process scaleup and allows for high
throughput tablet manufacture at the production scale.
4.3 Granule Lubrication
Nosticking,filming,orpickingwasobservedforthemannitolgranulationsafter>5000
hitsperpunchontheKorsch6-stationevenusingthe468embossedtooling,suggesting
that the formulations have sufficient anti-adherent characteristics even for those with
high mannitol ratio and low magnesium stearate concentration. Mean ejection forces
Table3 Effectofcompressionspeedoncompactibilityofdifferentgranulations
Batch Dwelltime(ms) Compactibility(SCU/kN) Speedsensitivityindex
5 29.5 1.22
5 7.4 1.1 1.11
6 29.5 0.566
6 7.4 0.295 1.92
7 29.5 0.838
7 7.4 0.7 1.20
10 29.5 1.06
10 7.4 0.57 1.86
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.
UseofMannitolasaFillerinWetGranulation 463
Table4 Ejectionforce,flowabilityindex,andtablethardnessdecaydata
Run Meanejection Flodexflowability %Decayhardnessafter6h
number force(kN) index(mm) at25/60
1 0.22 4 4
2 0.198 5 57
3 0.21 4 7
4 0.186 6 30
5 0.219 5 15
6 0.195 7 60
7 0.214 4 35
8 0.168 5 40
9 0.179 5 65
10 0.209 5 60
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.
Table5 Regressionanalysisofejectionforceandtablethardnessdecay
Parameterestimate(Pvalue)
Parameter Ejectionforce Tablethardnessdecay
Mannitol:MCCratio 0.010 (0.14) (cid:1)22.6 (0.0005)
Water ratio (cid:1)0.0048 (0.462) (cid:1)1.125 (0.751)
Mannitol ratio(cid:4)water ratio 0.0025 (0.694) (cid:1)3.875 (0.296)
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.
inthecompactionsimulatorstudiesrangedbetween168and220N(Table4),suggesting
adequatelubricationforallbatches.Neithermannitolrationormagnesiumstearatecon-
centrationshowedstatisticallysignificanteffectonejectionforce(P¼0.14,0.69,respec-
tively) (Table 5).
4.4 Tablet Hardness Decay
Tablets without mannitol showed substantial decrease in hardness upon storage at
25°C/60% RH for 6h. Percentage decrease in hardness for those tablets ranged from
57%–65% relative to initial tablet hardness. Tablets with high mannitol ratio, however,
werelesssusceptibletolossofhardnessuponstorageatthiscondition.Percenthardness
loss ranged between 4% and 35%. The effect of mannitol on tablet hardness decay was
statisticallysignificant(P¼0.0005).Neithermagnesiumstearate,waterratio,noranyof
the two-way interactions showed an effect on tablet hardness decay (Table 5).
464 HandbookofPharmaceuticalWetGranulation
5 PARTICLE SIZE DISTRIBUTION
Statisticalanalysisofparticlesizedistributiondidnotincludemagnesiumstearateconcen-
trationbecausegranulegrowthduringgranulationandsizereductionduringdrymilling
are not affected by the magnesium stearate added in the last processing steps. Granule
geometric mean diameter, percentage of fines (<75μm) and granule growth parameter
data(Table6)wereanalyzedforthedriedunmilledgranulationandthefinalgranulation.
Increasingmannitolratioresultedinastatisticallysignificantincreaseingeometricmean
diameterandgranulegrowthratioandadecreaseinthepercentageoffinesforboththe
unmilled and final granulation (Table 7). Because mannitol is less hydroscopic than
MCC,replacingpartoftheMCCwithmannitolmakesmorewateravailableforgranule
growthatagivenwaterratio.Theeffectofmannitolonparticleagglomerationandgran-
ule growth was maintained largely in the final granulation despite the subsequent
milling step.
Asexpected,increasingthewaterratioalsoresultedinstatisticallysignificantincrease
inthegeometricmeandiameterandgranulegrowthratioanddecreasedthepercentage
offinesfortheunmilledgranulation.Theeffectofwater,however,wasreducedsubstan-
tiallyinthefinalgranulationasshownbytheconsiderablereductioninthevalueofthe
parameterestimatesforthefinalgranulation.Unlikemannitol,theeffectofwateronpar-
ticle agglomeration appears to be lost during milling, which might be attributed to the
pronounced attrition of the large granules formed as the result of increased water ratio.
Theinteractiontermsbetweenmannitolratioandwaterratioweresignificantforthe
geometric mean diameter, granule growth ratio and percentage of fines for both the
unmilled granulation and milled granulations. The parameter estimates for those
Table6 Granulationparticlesizedata
Geometricmean Granule %Fines
Geometricmeandiameter diameter growth (unmilled
Run (μm,unmilledgranulation) (μm,preblend) ratio granulation)
1 135.8 85.1 1.6 15.38
2 133.85 76.2 1.76 17.595
3 231.8 85.1 2.72 4.665
4 151.15 80.6 1.88 14.02
5 224.25 85.1 2.64 3.635
6 135.75 76.2 1.78 17.815
7 153.7 85.1 1.81 10.805
8 148.3 80.6 1.84 13.82
9 127.1 76.2 1.67 21.29
10 119.55 76.2 1.57 21.735
ReproducedwithpermissionfromBadawy,S.I.F.,Shah,K.R.,Surapaneni,M.S.,Szemraj,M.M.,&Hussain,M.
(2010).Effectofspray-driedmannitolontheperformanceofmicrocrystallinecellulose-basedwetgranulatedtablet
formulation.PharmaceuticalDevelopmentandTechnology,15(4),339–345.https://doi.org/10.3109/10837450903229065.