Transcript
Page 1: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Pharmaceutical Development and Technology, 12:371–380, 2007 Copyright © Informa Healthcare USA, Inc.ISSN: 1083-7450 print / 1097-9867 onlineDOI: 10.1080/10837450701369311

371

LPDT

Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Non-meltable Additive Effects in Melt AgglomerationWai See Cheong and Paul Wan Sia HengDepartment of Pharmacy, Faculty of Science, National University of Singapore, Singapore

Tin Wui WongParticle Design Research Group, Faculty of Pharmacy, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia

The present study aims to investigate the behavior of meltagglomeration with a low-viscosity hydrophobic meltable binderby using a non-meltable additive. The size, crushing strength,and pore size distribution of resultant agglomerates, the rheologi-cal, surface tension, and wetting properties of the molten binder,as well as, the flow characteristics of preagglomeration powderblend were determined. The use of additive showed contradic-tory agglomerate growth-promoting and -retarding effects on themolten binder surface tension and the interparticulate frictionalforces. Critical concentration effects of additive corresponded tothreshold transition of agglomeration-promoting to -retardingbehavior were discussed.

Keywords frictional forces, melt agglomeration, non-meltableadditive, surface tension

INTRODUCTION

Melt agglomeration in a high-shear mixer is a viableprocess to produce granules or pellets that can be directlyfilled into capsules or compressed into tablets. The corefeature of melt agglomeration is that the process uses amolten liquid as the binder for solid particles. The moltenliquid is obtained through heating of a solid substance,which melts between 50 and 90°C. The molten liquid binds

the non-meltable solid particles by liquid bridges and sub-sequently solid bridges on its resolidification on cooling.

Examples of meltable binders include polyethyleneglycols, fatty acids, fatty alcohols, triglycerides, andwaxes.[1–12] The polyethylene glycols are relatively morewidely studied because of their good particle-bindingcapability as well as their low adhesiveness onto the pro-cessing chamber that produced melt agglomerates withrelatively narrow size distributions.[2] The hydrophobicmeltable binders have been explored particularly for thedevelopment of sustained-release formulations.[7–12] Themelt agglomerates prepared with hydrophobic meltablebinders have a high tendency to break and shatter underthe impact of the impeller because these meltable bindershad generally low-viscosity values of less than 50 mPa·s inthe temperature range between 60 and 90°C.[8,13] Never-theless, it was indicated that the agglomerative capabilityof hydrophobic meltable binders could not be entirelyascribed to their viscosity profiles.[8]

Practically, the sciences of melt agglomeration usinglow-viscosity hydrophobic meltable binders are lessunderstood than those of polyethylene glycols. In accor-dance to Ennis et al.[14] and Rumpf,[15] the viscosity, liquidsaturation, surface tension, and spreading property of thebinding liquid are important parameters controlling thestrength and growth profiles of agglomerates. In meltagglomeration using a low-viscosity hydrophobic meltablebinder, it was previously found by our laboratory that thegrowth of melt agglomerates was promoted by increasedinterparticulate binding strength, agglomerate surface wet-ness, and agglomerate density through modification in thebinding liquid’s viscosity, surface tension, as well as spe-cific molten volume with the use of meltable or partiallymeltable additive, sucrose stearate.[16] In conjunction withthe need to understand further the processes of melt

Received 3 October 2006, Accepted 12 February 2007.Address correspondence to Paul Wan Sia Heng, Department

of Pharmacy, Faculty of Science, National University ofSingapore, 18 Science Drive 4, Singapore 117543; E-mail:[email protected]

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 2: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

372 W.S. Cheong et al.

agglomeration, the present investigation aims to reinforcethe findings on the behavior of melt agglomeration with alow-viscosity hydrophobic meltable binder via the use of anon-meltable additive.

EXPERIMENTAL

Materials

Crystalline α-lactose monohydrate (Pharmatose450M, DMV, The Netherlands) was used as the solid fillerwith hydrogenated cottonseed oil (HCO; Sterotex NF,Abitec, USA) as the hydrophobic meltable binder similarto previously described.[16] Magnesium stearate (Produc-tos Metalest, Spain) was used as a non-meltable additivewithout further processing. The magnesium stearate had amelting range between 101 and 119°C (DSC-50;Shimadzu, Japan). The median volume particle diameterand span of magnesium stearate were 20 μm and 3.17,respectively. The span was calculated as the differencebetween the 90th and 10th percentiles of the cumulativesize distribution relative to the median diameter. Chlor-pheniramine maleate (Merck, Singapore) was selected as amodel drug of high water solubility. The median volumeparticle diameter of chlorpheniramine maleate wasreduced to 30 μm with a corresponding span of 2.47 byusing a pin mill (ZM 1000; Retsch, Germany) prior to use.

Agglomeration Procedure

Melt agglomerates were prepared by using a 10-Lvertical high-shear mixer (PMA-1 Processor, Aeromatic-Fielder, UK) equipped with online product temperature,impeller current consumption, and impeller speed record-ing as previously described.[16]

The total amount of processing material for each meltagglomeration run was kept at 1.2 kg, with a fixed amountof 3.33% w/w chlorpheniramine maleate, HCO variedbetween 18 and 20% w/w and magnesium stearate,between 0 and 0.5% w/w, expressed as the total weightpercentage of processing material. The melt agglomera-tion process was preceded with a premixing of the pow-ders at 500 rpm for 5 min, following by a mixing at 1200rpm to produce shear friction to melt the HCO withinabout 4 to 5 min. At 5 min after the onset of melting,which was detected as an inflection point on the impellercurrent consumption against processing time, the impellerspeed was adjusted to 400 rpm, and the mixing was con-tinued for another 10 min. On completion of each run, themelt agglomerates were collected, spread in thin layers ontrays, and allowed to cool to ambient temperature.

The weight of melt agglomerates harvested was deter-mined at the end of each run, and the amount of wet massadhesion was calculated as the weight percentage of unre-coverable material from the initial load. Duplicates werecarried out for each formulation, and the results were aver-aged. Throughout all experiments, the jacket temperaturewas set at 60°C. The average median and maximum prod-uct temperatures were 74.4 ± 1.6 and 87.8 ± 0.7°C,respectively. There was no marked difference in the pro-files of product temperatures among all batches of meltagglomeration runs (ANOVA: p > 0.05).

Characterization of Melt Agglomerates

Size and Size Distribution

The melt agglomerates from each run were randomlysubdivided by using a spinning riffler (PT; Retsch,Germany) into eight samples of 120–140 g each. A samplewas sized by using a series of 12 sieves (Endecott, UK) ona square root progression from 90 to 4000 μm on a sieveshaker (VS1000; Retsch, Germany) within a predeter-mined time interval. The weight percentage of meltagglomerates retained on each sieve was calculated. Theagglomerate size was represented by the mass mediandiameter defined as the diameter at 50th weight percentileof the cumulative agglomerate size distribution. The sizedistribution of melt agglomerates was represented by thespan and was calculated as the difference between 90thand 10th percentiles of the cumulative agglomerate sizedistribution relative to the mass median diameter. Theamounts of fines and lumps were expressed as the weightpercentage of sieve fraction smaller than 250 μm andlarger than 2800 μm, respectively.

Crushing Strength

The crushing strength measurement of melt agglom-erates was carried out by using a tensile tester (EZ test-500N; Shimadzu, Japan) mounted with a 500 N capacityload cell. An agglomerate, randomly sampled from meltagglomerates in the size range of 1000–1400 μm, wascrushed diametrically between two platens driven at a rateof 3 mm/min, and the maximum load (N) required to crusheach agglomerate was recorded from the force-time pro-file. A total of 50 measurements were carried out for eachbatch of melt agglomerates, and the results were averaged.

Intra-Agglomerate Pore Size and Size Distribution

The pore size and size distribution of melt agglomerateswithin the size fraction of 250– 2800 μm were determined

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 3: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Non-meltable Additive Effects in Melt Agglomeration 373

by using a mercury intrusion porosimeter (Poresizer 9320;Micromeritics, USA), similar to that described by Wonget al.[17] Intrusion pressures between 5 and 5000 psia wereused. The experiments were carried out in duplicates, andthe results were averaged. The plot of cumulative differen-tial specific intrusion volume against pore diameter wasused to characterize the pore size and size distribution ofmelt agglomerates.

Drug Release Study

Drug release study was performed on melt agglomer-ates of size fraction between 1000 and 1400 μm by usingthe USP Apparatus 2 with the paddle rotating at 50 rpm(Optimal DT-1, Optimal Control Inc., USA). The dissolu-tion medium was 900 mL of USP simulated gastric fluidwith 0.05% w/v polysorbate 20 added and was maintainedat 37.0 ± 0.5°C. At predetermined intervals, 5-mL aliquotswere withdrawn from each dissolution vessel, filtered, andanalyzed for chlorpheniramine maleate spectrophotometri-cally at 264.8 nm (UV-1201; Shimadzu, Japan). The per-centage of drug released was calculated with respect to thedrug content of the melt agglomerates. The drug contentwas expressed as the amount of drug in a unit weight ofmelt agglomerates. It was determined by subjecting thesame sample of melt agglomerates from the drug releasestudy to heating at 80°C to destroy the matrices by melt-ing, then, on cooling, 5-mL aliquots were withdrawn, fil-tered, and assayed as mentioned.

Characterization of Molten HCO

The surface tension, viscosity, and contact angle ofthe molten HCO, with and without the addition of magne-sium stearate, were characterized at 80°C, which repre-sented the intermediate temperature for median andmaximum product temperatures encountered during meltagglomeration. The molten HCO was a clear yellow liq-uid. The addition of magnesium stearate, in the range of0–3% w/w, with respect to the weight of HCO, broughtabout a turbid suspension due to insolubility of magne-sium salt in the molten HCO. The formed suspension wascontinuously stirred by using a magnetic stirrer and wasused for characterization without prior filtration. Therange of 0–3% w/w magnesium stearate in HCO was cho-sen because of the concentration ranges of magnesiumstearate, with respect to the total weight of processingmaterial, were equivalent to 0–2.78, 0–2.63, and 0–2.50%w/w magnesium stearate, with respect to 18, 19, and 20%w/w HCO used in the melt agglomeration runs. The meth-ods for surface tension and viscosity were the same as pre-viously described.[16] For contact angle, a lactose powder

bed containing 4.3% w/w chlorpheniramine maleate wasdetermined at 80 ± 2°C by the Washburn liquid penetra-tion method.[16,18] The contact angle of molten HCO, θ,was calculated by using Equation (1)[19]:

where l is the length of liquid penetration in time t, γ Land η are the surface tension and viscosity of the penetrat-ing liquid, respectively, and r is the effective pore size. θwas obtained from the gradient of the linear plot of l2 ver-sus t by least-square approximation method with r esti-mated by using Equation (2)[20]:

where φ is the particle shape factor, which was assumed tobe unity in the present study, and d32 is the surface meanparticle diameter of a sphere. The surface mean particlediameters of lactose and chlorpheniramine maleate were7.89 and 10.91 μm, respectively, determined by a laserdiffraction particle sizer. The surface mean particle diame-ter of the powder mixture was calculated by the propor-tional method based on the fractional weight of lactose andchlorpheniramine maleate. ε is the porosity of the powderbed and was calculated from the apparent porosity (εapp)and tapped porosity (εtap) of the powder mixture usingEquation (3)[20]:

where εapp and εtap were determined from the apparent andtapped densities of the powder mixture and pycnometricdensity values of lactose and chlorpherinaramine maleate.The apparent and tapped densities were determined on thebasis of the weight and volume of the powder mixture fill-ing the tube prior to and after tapping to a constant vol-ume. Pycnometric density values of lactose andchlorpheniramine maleate were 1.5394 and 1.2848 g/cm3,respectively, determined by using a gas displacement pyc-nometer (PYY-14; Quantachrome Instrument, USA) withhelium purge. Duplicates of contact angle measurementwere carried out for each batch of sample, and the resultswere averaged.

Characterization of Tensile Strength of Re-Solidified Molten HCO

Samples of resolidifed molten HCO containing 0–3%w/w magnesium stearate were prepared by melting theHCO or mixture of HCO and magnesium stearate and then

lr tL2

2=

γ θη

⋅ ⋅ ⋅cos (1)

r = ⋅−( )

φ εε

d32

3 1(2)

ε ε ε ε= − +( )tap app tap1 (3)

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 4: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

374 W.S. Cheong et al.

pouring into a cylindrical mould (9.5 mm in internal diam-eter and 6 mm in depth) and cooled to ambient tempera-ture. The cooled samples had an average weight of 406 ±3.6 mg. Samples were conditioned at 22 ± 2°C and 55%relative humidity for at least 24 hr prior to tensile strengthmeasurement. The tensile strength of each sample wasdetermined by using the cone penetration breakingstrength method as described by Chee et al.[21] A uniaxialpenetration load was applied from a conical tip onto theaxial surface of the sample. The maximum load (N)required to break each sample was recorded from theforce-time profiles. A total of 10 measurements were car-ried out for each batch of samples, and the results wereaveraged.

Characterization of Solid Powder

The flow properties of the preagglomeration powdermixtures of lactose and drug, with and without the addi-tion of magnesium stearate, were assessed by using tap-ping analysis and Hausner ratio (ratio of tapped densityto poured density of powder mixture) and Carr’s index(difference between tapped and poured densities relativeto tapped density in percentage) were calculated thereaf-ter. Representative samples of the powder mixture wasprepared by using a load of 400 g of powder mixture oflactose and chlorpheniramine maleate, with or withoutmagnesium stearate, by mixing at an impeller speed of500 rpm for 5 min followed by 1200 rpm for another 5min in the high-shear mixer. The powder mixture wasthen collected and conditioned at 50% relative humidityand 25°C for at least 24 hr prior to use. Magnesium stear-ate in concentrations of 0–0.64% w/w expressed as theweight percentage of powder mixture of lactose andchlorpheniramine maleate were used as required. Theconcentration range of magnesium stearate in the tappinganalysis was based on the concentration of magnesiumstearate between 0 and 0.5% w/w with respect to the totalweight-processing materials (i.e., equivalent to 0–0.63,0–0.62, and 0–0.61% w/w magnesium stearate),expressed with respect to the weight of powder mixtureof lactose and chlorpheniramine maleate for meltagglomeration runs using 18, 19, and 20% w/w HCO,respectively. The poured and tapped densities of a knownweight of powder sample were determined by using a10-mL graduated cylinder. The initial volume and finalvolume of powder sample, after 1000 taps (STAV 2003;Jel, Germany) were recorded. The poured and tappeddensities were defined as the quotient of weight to initialand final powder volume after 1000 taps, respectively.For each powder batch, five replicates were carried out,and the results were averaged.

RESULTS AND DISCUSSION

Effects of Magnesium Stearate on Melt Agglomeration

Figure 1 shows that an increase in HCO concentra-tion from 18 to 19% w/w promoted the growth of meltagglomerates from mass median diameter of 1027 to1419 μm with a concurrent decrease in the percentageof fines and an increase in the amount of lumps (Figure 2).This was attributed to the availability of a larger moltenliquid volume for wetting the surfaces of solid particlesand increasing surface deformability, thus promotinggrowth by coalescence and/or layering processes.Nonetheless, increasing the HCO concentration from 1920% w/w resulted in the formation of substantialamounts of fines and lumps, leading to a wide size dis-tribution of melt agglomerates with span valuesincreased from 0.94 to 4.13 (Figures 1 and 2). Clearly,20% w/w HCO increased the risk of localized wetting,producing HCO-rich domains, forming large lumps.These lumps were susceptible to breakage by theimpact forces, resulting in excessive amount of fines inthe process.

It was apparent that a homogeneous growth of meltagglomerates was not easily attained by solely usingincreasing amounts of HCO. It is of interest that the het-erogeneity in melt agglomeration can be counteracted bythe introduction of magnesium stearate as a non-meltableadditive. An appropriate amount of magnesium stearatewas able to promote a similar increase in melt agglomer-ate size without markedly altering the span of the prod-ucts obtained with 18 and 19% w/w HCO. The span ofmelt agglomerates varied between a narrow range of0.78–0.90 when the maximum levels of 0.4 and 0.2% w/w magnesium stearate were used for melt agglomerationusing 18 and 19% w/w HCO, respectively (Figure 1).With 20% w/w HCO, the span of melt agglomerates wasnarrowed. With the use of 0.1% w/w magnesium stear-ate but beyond that magnesium stearate concentration, asharp rise in the span of melt agglomerates was obtained(Figure 1). Magnesium stearate appeared to negate thesize enlargement process and homogeneity of meltagglomerates when its concentration became exces-sively high and produced smaller melt agglomerates ofbroader spans. It must be highlighted that the varyingmelt agglomerate growth profiles associated with differ-ent HCO and magnesium stearate concentrations werenot complicated by wet mass adhesion of each agglom-eration run as the adhesion was found to be low, typi-cally 3.2 ± 0.6, 2.5 ± 0.7, and 2.8 ± 1.1% in runs using18, 19, and 20% w/w HCO, respectively, and indepen-dent of magnesium stearate concentration (ANOVA: p >0.05).

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 5: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Non-meltable Additive Effects in Melt Agglomeration 375

Mechanism of Melt Agglomeration

During the process of melt agglomeration, the solidparticles principally undergo nucleation on wetting bymolten liquid, consolidation under impact forces, coales-cence and layering with other particle assemblies whensufficient degree of surface deformability through liquidsaturation is attained, which can be achieved by the addi-tion of binding liquid and/or liquid migration from

agglomerate core to the exterior on consolidation ofagglomerates under impact forces.

The balance between frictional, viscous, and capillaryforces acting on the particulate system has great influenceon the latter’s consolidation. In addition to the trend inmelt agglomerate size resulted by magnesium stearateaddition as mentioned, the crushing strength of meltagglomerates was similarly affected by magnesium stear-ate (Figure 3) whereby the crushing strength of melt

Figure 1. Effects of magnesium stearate on size and size distribution of melt agglomerates produced by using (a) 18, (b) 19, and (c)20% w/w HCO. Magnesium stearate concentration: (1) 0, (2) 0.1, (3) 0.2, (4) 0.3, (5) 0.4, and (6) 0.5% w/w. (mmd = mass mediandiameter).

% W

eigh

t ret

aine

d

a1mmd = 1027span = 0.80

b1mmd = 1419span = 0.94

c1mmd = 1650span = 4.13

a2mmd = 1095span = 0.79

b2mmd = 1331span = 0.85

c2mmd = 1930span = 0.81

a3mmd = 1320span = 0.86

b3mmd = 1809span = 0.86

c3mmd = 2112span = 2.14

a4mmd = 1657span = 0.90

b4mmd = 2516span = 3.40

a5mmd = 1890span = 0.88

b5mmd = 1905span = 5.07

a6mmd = 1148span = 7.54

0

20

40

60

0

20

40

60

0

20

40

60

0

20

40

60

0

20

40

60

0

20

40

60

0–90

90–1

2512

5–18

018

0–25

025

0–35

535

5–50

050

0–71

071

0–10

0010

00–1

400

1400

–200

020

00–2

800

2800

–400

0

0–90

90–1

2512

5–18

018

0–25

025

0–35

535

5–50

050

0–71

071

0–10

0010

00–1

400

1400

–200

020

00–2

800

2800

–400

0

0–90

90–1

2512

5–18

018

0–25

025

0–35

535

5–50

050

0–71

071

0–10

0010

00–1

400

1400

–200

020

00–2

800

2800

–400

0

b6mmd = 1299span = 7.59

c4mmd = 1370span = 9.58

c5mmd = 1100span = 8.50

c6mmd = 1229span = 9.04

Agglomerate size (µm)

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 6: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

376 W.S. Cheong et al.

agglomerates increased with magnesium stearate additionup to a critical concentration, beyond which, the crushingstrength decreased considerably. The crushing strength ofmelt agglomerates as a function of magnesium stearateconcentration appeared not to be governed by the intrinsictensile strength of the solid bridges binding the particlesbecause the tensile strength of resolidified molten HCOwas not significantly affected by the incorporation of mag-nesium stearate (ANOVA: p > 0.05), except at 3% w/wmagnesium stearate relative to the weight of HCO.

Nonetheless, the latter was not accompanied by the forma-tion of melt agglomerates with high crushing strength val-ues. Figure 4 shows that the pore size and size distributionof melt agglomerates varied with the concentrations ofHCO and magnesium stearate. In melt agglomerates con-taining 20% w/w HCO without magnesium stearate, therewas a markedly large pore population between 0.01 and10 μm compared to the pore distributions for melt agglom-erates containing 18 or 19% w/w HCO. The addition ofmagnesium stearate at low concentrations could reduce thevolume fraction of these pores showing the melt agglom-erate consolidation taking place. However, the introduc-tion of magnesium stearate beyond the criticalconcentrations at all levels of HCO tend to promote theformation of pores in the melt agglomerates. To elucidatethe action of magnesium stearate in melt agglomerate con-solidation and growth processes, the profiles of interpar-ticulate frictional, viscous, and capillary forces subsequentto the addition of magnesium stearate were examined.

Figure 2. Effects of magnesium stearate on (a) fines and (b)lumps formation in melt agglomeration processes using 18 (❍),19 (�), and 20 (Δ)% w/w HCO.

a

0

10

20

30

Fine

s (%

)

b

0

10

20

30

40

50

Concentration of magnesium stearate (% w/w)

Lum

ps (

%)

0 0.50.40.30.20.1

Figure 3. Effects of magnesium stearate on crushing strengthof melt agglomerates prepared by using 18 (❍), 19 (�), and 20(Δ) % w/w HCO.

3

4

5

Concentration of magnesium stearate (% w/w)

Cru

shin

g st

reng

th (

N)

0 0.50.40.30.20.1

Figure 4. Effects of magnesium stearate on pore size and porecumulative distribution of melt agglomerates prepared using (a)18, (b) 19, and (c) 20% w/w HCO. Magnesium stearateconcentration: 0 (❍), 0.1 (�), 0.3 (Δ), and 0.5 (×) % w/w.

a

0

0.04

0.08

0.12

b

0

0.04

0.08

0.12

c

0

0.04

0.08

0.12

Cum

ulat

ive

spec

ific

incr

emen

tal v

olum

e (m

l/g)

Pore diameter (µm)

0.001 1001010.10.01

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 7: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Non-meltable Additive Effects in Melt Agglomeration 377

Interparticulate Frictional Forces

As a non-meltable additive, magnesium stearate couldinteract with the solid particles of lactose and/or chlorphe-niramine maleate and affect the frictional forces betweenthe solid particles of the powder mixture. As shown by thevalue reduction in Hausner ratio and Carr’s index (Figure 5,ANOVA; p < 0.05), the incorporation of magnesium stear-ate at low concentrations could reduce the interparticulatefrictional forces (ANOVA: p < 0.05) through adhesion ofthe smaller magnesium stearate particles onto the lactoseand chlorpheniramine maleate particles. These valueswere less affected when higher concentrations of magne-sium stearate were used. This was most probably due tothe active sites of lactose, and chlorpheniramine maleatewere fully or almost completely occupied by the addedmagnesium stearate, and a further improvement in powderflow was not the result with successive addition of magne-sium stearate.

With the reduced interparticulate frictional forces atlow-magnesium stearate concentrations, the rearrange-ment of solid particles in the melt agglomerates during

agglomeration was induced and contributed consolidationand migration of molten HCO from core to surfaces ofmelt agglomerates, as well as transfer of molten HCOfrom the surfaces of an agglomerate to another. The sum-mative effects were an increase in size and crushingstrength of melt agglomerates, with a concomitant reduc-tion or no alteration in size distribution of the formedproducts. Nonetheless, the limited changes in interparticu-late frictional forces at high concentration of magnesiumstearate could not fully explain the formation of smallerand weaker melt agglomerates with wide size distribution.Other changes in the physicochemical properties of moltenHCO by magnesium stearate could also affect the meltagglomeration process.

Interparticulate Viscous Forces

Figure 6a shows that the viscosity of molten HCOwas minimally affected by the presence of magnesiumstearate. Magnesium stearate is a non-meltable salt andwas not appreciably soluble in molten HCO. The level ofphysicochemical interaction between the magnesiumstearate and molten HCO in the bulk liquid was not trans-lated to a noticeable increase in viscosity, except whenonly a high concentration of 3% w/w magnesium stearatewas present in HCO (ANOVA: p < 0.05).

Theoretically, an increase in viscous forces of moltenHCO with higher concentrations of magnesium stearatewas expected to promote the melt agglomerate growththrough stronger viscous binding. This in turn should leadto an increase in size and crushing strength of meltagglomerates. On the contrary, smaller and weaker meltagglomerates of wider size distribution were producedwhen a high concentration of magnesium stearate wasused. In addition, the increase in size and crushing strengthof melt agglomerates prepared by using magnesium stear-ate concentrations not exceeding 0.4, 0.2, or 0.1% w/w inmelt agglomeration with 18, 19, or 20% w/w HCO,respectively, was not accompanied by an apparent rise inviscous forces of the molten liquid. It can be inferred thatthe viscous forces of molten HCO did not contributeappreciably to the changes in melt agglomeration behaviorin the current investigation and were dominated by otherforces.

Interparticulate Capillary Forces

Unlike the viscosity, the surface tension of the mol-ten HCO was considerably reduced by magnesium stear-ate present at low concentrations (Figure 6b, ANOVA:p < 0.05). Magnesium stearate is a weak anionic surfactant

Figure 5. Effects of magnesium stearate on (a) Hausner ratioand (b) Carr’s index of powder mixtures of lactose andchlorpheniramine maleate.

a

1.8

2.0

2.2

2.4

2.6

2.8

Hau

sner

rat

io

b

40

50

60

70

Concentration of magnesium stearate in powdermixture (% w/w)

Car

r’s

inde

x

0 0.70.60.50.40.30.20.1Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 8: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

378 W.S. Cheong et al.

consisting of a hydrophobic fatty acid tail and a polarionic head. Its readiness to align at the molten HCO-airinterface aided in reducing the capillary and bindingforces acting on the intra-agglomerate solid particlesthrough lowering the surface tension of the molten HCO.Coupling with reduced frictional forces owing to thelubricant action of magnesium stearate, the reduced sur-face tension of molten HCO rendered the melt agglomer-ates to be more amendable to particulate rearrangement,consolidation, and growth. Further reduction in the sur-face tension of molten HCO at high concentrations ofmagnesium stearate eased molten HCO migration fromagglomerate core to exterior extensively, increasing therisk of overwetting and leading to increased lumps for-mation (Figure 2b). Nonetheless, a further reduction inthe surface tension of molten liquid, under the influenceof low interparticulate frictional forces, would

undermine the mechanical integrity of these meltagglomerates by lowering interparticulate tension andencouraging slippage. This reduced the agglomeratestrength, and they became prone to breakage, and gaverise to increased fines (Figure 2a). Thus, smaller meltagglomerates of wide size distribution, showing morelumps and fines in resultant products, were obtained.

Generally, the size enlargement and reduction pro-cesses of melt agglomeration prepared by using a largerpercentage of HCO were more sensitive to the changes inconcentration of magnesium stearate (Figure 1). For for-mulations using 19 and 20% w/w HCO, a larger volume ofmolten liquid was available than those of 18% w/w HCO.This could lead to agglomerate breakage through exces-sive lubrication and reduced interparticulate tension cou-pled with the reduced capillary and frictional forcesbetween solid particles by magnesium stearate. The sensi-tivity of melt agglomeration process using higher concen-trations of HCO to the influences of magnesium stearatewas unlikely to be related to the wetting properties of themolten HCO on the powder bed. The magnesium stearatedid not contribute to any significant changes on the contactangle of molten HCO over the powder bed (Figure 6c,ANOVA: p > 0.05).

Drug Release Characteristics

The chlorpheniramine maleate was released frommelt agglomerates containing HCO at a relatively fast rate,with more than 70–80% of drug being released within 2 hr(Figure 7a). The time for 50% drug release (t50) was lessthan 40 min (Figure 7b). It was observed that the incorpo-ration of 0.1, 0.2, and 0.4% w/w magnesium stearate withrespect to melt agglomeration runs using 20, 19, and 18%w/w HCO gave rise to higher t50 values (ANOVA: p <0.05) beyond which a higher concentration of added mag-nesium stearate brought about a reduction in t50 values ofthe melt agglomerates, similar to the trends observed formelt agglomerate size and crushing strength. The drugrelease kinetics of these melt agglomerates were bestdescribed by the square root of time equation (r2 = 0.930to 0.999) compared to zero order, first order, and Hixson-Crowell dissolution models of which the maximum r2

value attained was 0.830. This indicated that the drug dis-solution process followed an inert matrix release mecha-nism. The drug molecules were diffused through the poresand crevices of matrix prior to their release from the exte-rior of melt agglomerates into the dissolution medium.Below the critical concentration of magnesium stearate,the consolidation of melt agglomerates, brought about bymagnesium stearate as previously mentioned, would resultin a denser matrix system and increased the level of

Figure 6. Effects of magnesium stearate on (a) viscosity and(b) surface tension of molten HCO, and (c) contact angle ofmolten HCO on the powder mixture of lactose andchlorpheniramine maleate.

a

10

15

20

Vis

cosi

ty (

mPa

.s)

b

28.5

29.0

29.5

30.0

Surf

ace

tens

ion

(mN

/m)

c

600 0.5 1

Concentration of magnesium stearatein HCO (%w/w)

1.5 2 2.5 3

70

80

90

Con

tact

ang

le (

°)

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 9: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

Non-meltable Additive Effects in Melt Agglomeration 379

difficulty for drug to leach out from the inert matrix, asindicated by the increased t50 values.

CONCLUSIONS

A critical concentration of magnesium stearate as thenon-meltable additive was found at each level of HCOwith respect to the additive’s effects on size, crushingstrength, pore size distribution, and drug release retarda-tion of melt agglomerates. Below the critical concentra-tions of magnesium stearate, its use brought about anincrease in size and crushing strength of melt agglomer-ates. Beyond these critical concentrations of magnesiumstearate, a heterogeneous breakdown of melt agglomeratesresulted, giving rise to smaller melt agglomerates withreduced crushing strength and wider size distribution.

At low concentrations of magnesium stearate, the pro-motion of melt agglomerate consolidation and growth was

attributed to reduced interparticulate frictional forces andsurface tension, which allowed greater particle rearrange-ment and molten HCO migration to surface. At high con-centrations of magnesium stearate, excessive migration ofmolten HCO from core to surface of melt agglomeratesincreased the risk of overwetting and lumps formation.The lumps were prone to breakdown on impact becausethe melt agglomerate integrity was undermined by thelower interparticulate tension, which encouraged particleslippage.

With increased HCO concentration, the critical con-centration values of magnesium stearate representing thetransition from agglomerative growth-promoting toagglomerative growth-degrading decreased. High percent-ages of HCO eased solid particle slippage via excessivelubrication, and this could augment the effects of magne-sium stearate on melt agglomerate breakage. Practically,the incorporation of magnesium stearate could aid inretarding the drug release through promoting better meltagglomerate consolidation.

REFERENCES

1. Schæfer, T.; Mathiesen, C. Melt pelletization in a high shearmixer. VIII. Effects of binder viscosity. Int. J. Pharm. 1996,139, 125–138.

2. Schæfer, T.; Holm, P.; Kristensen, H.G. Melt granulation ina laboratory scale high shear mixer. Drug Dev. Ind. Pharm.1990, 16, 1249–1277.

3. Eliasen, H.; Schæfer, T.; Kristensen, H.G. Effects of binderrheology on melt agglomeration in a high shear mixer. Int. J.Pharm. 1998, 176, 73–83.

4. Wong, T.W.; Wan, L.S.C.; Heng, P.W.S. Effects of physicalproperties of PEG 6000 on pellets produced by melt pelleti-zation. Pharm. Dev. Technol. 1999, 4 (3), 449–456.

5. Seo, A.; Schæfer, T. Melt agglomeration with polyethyleneglycol beads at a low impeller speed in a high shear mixer.Eur. J. Pharm. Biopharm. 2001, 52, 315–325.

6. Thies, R.; Kleinebudde, P. Melt pelletization of a hygro-scopic drug in a high shear mixer. Part 3. Effects of bindervariation. Chem. Pharm. Bull. 2001, 49 (2), 140–146.

7. Thomsen, L.J. Prolonged release matrix pellets prepared bymelt pelletization. Part IV. Drug content, drug particle size,and binder composition. Pharm. Technol. Eur. 1994, 6 (9),19–24.

8. Thomsen, L.J.; Schæfer, T.; Kristensen, H.G. Prolongedrelease matrix pellets prepared by melt pelletization. Part II.Hydrophobic substances as meltable binders. Drug Dev. Ind.Pharm. 1994, 20 (7), 1179–1197.

9. Zhou, F.; Vervaet, C.; Remon, J.P. Matrix pellets basedon the combination of waxes, starches and maltodextrins.Int. J. Pharm. 1996, 133, 155–160.

10. Voinovich, D.; Moneghini, M.; Perissutti, B.; Filipovic-Grcic, J.; Grabnar, I. Preparation in high-shear mixer of

Figure 7. (a) Drug release profiles of melt agglomeratesprepared by using 18–20% w/w HCO without and with 0.1% w/wmagnesium stearate. (b) Effects of magnesium stearate on t50values of melt agglomerates prepared by using 18 (❍), 19 (�),and 20 (Δ) % w/w HCO.

b

0

10

20

30

40

50

Concentration of magnesium stearate (%w/w)

t 50

(min

)a

0

20

40

60

80

100

Time (hour)

% D

rug

rele

asee

d

18% HCO

19% HCO

20% HCO

18% HCO, 0.1%Magnesium stearate

19% HCO, 0.1%Magnesium stearate

20% HCO, 0.1%Magnesium stearate

0 2 4 6

0 0.50.40.30.20.1

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.

Page 10: Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

380 W.S. Cheong et al.

sustained-release pellets by melt pelletisation. Int. J. Pharm.2000, 203, 235–244.

11. Hamdani, J.; Moës, A.J.; Amighi, K. Development andevaluation of prolonged release pellets obtained bythe melt pelletization process. Int. J. Pharm. 2002, 245,167–177.

12. Grassi, M.; Voinovich, D; Moheghini, M.; Franceschinis,E.; Perissutti, B.; Filipovic-Grcic, J. Preparation and evalu-ation of a melt pelletised paracetamol / stearic acid sus-tained release delivery system. J. Control. Release 2003,88, 381–391.

13. Eliasen, H.; Kristensen, H.G.; Schæfer, T. Growth mecha-nisms in melt agglomeration with a low viscosity binder. Int.J. Pharm. 1999, 186, 149–159.

14. Ennis, B.J.; Tardos, G.I.; Pfeffer, R. A microlevel-basedcharacterization of granulation phenomena. Powder Technol.1991, 65, 257–272.

15. Rumpf, H. The strength of granules and agglomerates. InAgglomeration; Knepper, W.A., Ed.; Wiley-Interscience:New York, 1962, 379–414.

16. Heng, P.W.S.; Wong, T.W.; Cheong, W.S. Investigation ofmelt agglomeration process with a hydrophobic binder incombination with sucrose stearate. Eur. J. Pharm. Sci. 2003,19, 381–393.

17. Wong, T.W.; Chan, L.W.; Heng, P.W.S. Study of the meltpelletization process focusing on the micromeritic propertyof pellets. Chem. Pharm. Bull. 2000, 48 (11), 1639–1643.

18. Kiesvaara, J.; Yliruusi, J. The use of Washburn method indetermining the contact angles of lactose powder. Int. J.Pharm. 1993, 92, 81–88.

19. Washburn, E.W. The dynamics of capillary flow. Phys. Rev.1921, 8, 273–283.

20. Hapgood, K.P.; Litster, J.D.; Biggs, S.R.; Howes, T. Droppenetration into porous powder beds. J. Colloid InterfaceSci. 2002, 253, 353–366.

21. Chee, S.N.; Chan, L.W.; Heng, P.W.S. Study of cone pene-tration breaking strength test for assessing the mechanicalstrength of tablets and roller-compacted flakes. AAPSAnnual Meting and Exposition, Baltimore, Maryland,November 7–11, 2004.

Phar

mac

eutic

al D

evel

opm

ent a

nd T

echn

olog

y D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Uls

ter

at J

orda

nsto

wn

on 1

1/13

/14

For

pers

onal

use

onl

y.


Top Related