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lable at ScienceDirect
Journal of Pharmaceutical Sciences 108 (2019) 3657-3666
Contents lists avai
Journal of Pharmaceutical Sciences
journal homepage: www.jpharmsci .org
Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Effect of Spray-Dried Particle Morphology on Mechanical and
FlowProperties of Felodipine in PVP VA Amorphous Solid
Dispersions
Alyssa Ekdahl 1, Deanna Mudie 1, *, David Malewski 2, 3, Greg
Amidon 2,Aaron Goodwin 1, 4
1 Dosage Forms and Delivery Systems, Lonza Pharma and Biotech,
Bend, Oregon 977032 Pharmaceutical Sciences, College of Pharmacy,
University of Michigan, Ann Arbor, Michigan 481093 Social,
Behavioral & Administrative Sciences, College of Pharmacy,
Touro University California, Vallejo, California 945924 Formulation
Development, Pfizer Inc., Boulder, Colorado 80301
a r t i c l e i n f o
Article history:Received 3 May 2019Revised 9 August 2019Accepted
13 August 2019Available online 22 August 2019
Keywords:amorphous solid dispersionsmechanical propertiesspray
dryingtabletingpoorly water-soluble drugsoral drug deliveryparticle
sizesolid dosage formbioavailability
Conflicts of interest: The authors declare no conflict ofreceive
any specific grant from funding agencies in thfor-profit
sectors.This article contains supplementary material availableor
via the Internet at https://doi.org/10.1016/j.xphs.20*
Correspondence to: Deanna Mudie (Telephone: þ1
E-mail address: [email protected] (D. Mu
https://doi.org/10.1016/j.xphs.2019.08.0080022-3549/© 2019 The
Authors. Published by
Elsevier(http://creativecommons.org/licenses/by-nc-nd/4.0/).
a b s t r a c t
Amorphous solid dispersions (ASDs) are commonly used to enhance
the oral absorption of drugs withsolubility or dissolution rate
limitations. Although the ASD formulation is typically constrained
byphysical stability and in vivo performance considerations, ASD
particles can be engineered using thespray-drying process to
influence mechanical and flow properties critical to tableting.
Using the ASDformulation of 20% w/w felodipine dispersed in
polyvinyl pyrrolidone vinyl acetate, spray-drying at-omization and
drying conditions were tuned to achieve 4 different powders with
varying particleproperties. The resulting particles ranged in
volume moment mean diameter from 4 to 115 mm, bulkdensity from 0.05
to 0.38 g cm�3, and morphologies of intact, collapsed, and
fractured hollow spheres.Powder flowability by shear cell ranged
from poor to easy flowing, whereas mechanical property
testssuggested all samples will produce strong tablets at
reasonable solid fractions and compression pres-sures. In addition,
Hiestand dynamic tableting indices showed excellent dynamic bonding
for 3 powders,and low viscoelasticity with high brittleness for all
powders. This work demonstrates the extent spray-dried ASD particle
morphologies can be engineered to achieve desired powder flow and
mechanicalproperties to mitigate downstream processing risks and
increase process throughput.© 2019 The Authors. Published by
Elsevier Inc. on behalf of the American Pharmacists Association®.
Thisis an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/
4.0/).
Introduction
Amorphous solid dispersions (ASDs) improve the oral
bioavail-ability of drugs whose absorption rate is limited by
solubility ordissolution ratewhen administered in their crystalline
form.1,2 Overthe past 2 decades, ASDs have become a preferred
formulationstrategy for poorly water-soluble drugs, as evidenced by
the largenumber of marketed drug products using ASDs.3,4 ASDs
typicallycontain a drug substance and a polymer, whose function is
to sta-bilize the drug in the amorphous state during storage and to
inhibitprecipitation in vivo.5-11 As a drug product intermediate,
ASDs arecommonly blendedwith additional excipients and compressed
intotablets or filled into capsules to create an oral drug
product.3,12,13
interest. This research did note public, commercial or not-
from the authors by request19.08.008.-541-706-8262).die).
Inc. on behalf of the American Pha
Multiple manufacturing techniques are used to produce
ASDformulations. The most commonly used mature technologies
arespray drying8 and hot melt extrusion (HME).14 Some
less-commontechniques include the KinetiSol®15 process and
coprecipitation.16
Spray drying and coprecipitation both require solubility of
thedrug and excipient(s) in a common solvent. Spray drying uses
heatto evaporate off the solvent, whereas coprecipitation uses
anantisolvent to precipitate the drug and polymer. By contrast,
HMEand KinetiSol aremechanical mixing techniques that use high
shearmixing and elevated temperatures to create a homogenous ASD
ofdrug and excipient(s). Selecting a technique largely depends on
thedrug and excipient physiochemical properties, such as
solubility,miscibility, melting point, and glass transition
temperature.1 Spraydrying offers compelling advantages over other
ASD technologies,including scalability and breadth of formulation
space.2,3,8,16
The spray-drying process begins with preparation of a
spraysolution, where the drug substance and excipient(s) are
dissolvedor suspended in a volatile solvent. The spray solution is
atomizedinto a stream of cocurrent or counter-current drying
gas.4,17 Droplet
rmacists Association®. This is an open access article under the
CC BY-NC-ND license
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-
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-36663658
size is governed by the type and size of atomizer, the
atomizationconditions, and such spray solution properties as
viscosity andsurface tension.18 As the solvent evaporates from the
droplet, thesolutes surpass their solubilities in the solvent and
rapidly precip-itate and solidify. Owing to the millisecond time
scale betweenatomization and particle solidification and the
increase in thedroplet viscosity as a function of solvent loss,
drug diffusion withinthe droplet becomes limited, with the aim to
trap the drug in anamorphous state mixed with the excipient(s).19
Given that ASDformulations typically contain a film-forming polymer
as thedispersant, the particle morphology and wall thickness can
bemodulated by changing the droplet drying kinetics.20-23
Theseparticle attributes determine the bulk powder properties, such
asflowability, tabletability, and surface area. Therefore, using
rationalselection of the spray-drying formulation and process
parameters,the ASDs can be engineered concurrently with the final
dosageform, ensuring optimum bioperformance, stability, and
manufac-turability. While the performance and stability of ASDs
generallytake precedence during development and, as a result, have
beenhighly studied in literature,24,25 the
downstreammanufacturabilityof ASDs into a final dosage form has
received far less attention.
A few studies have compared the mechanical properties of
ASDsmanufactured by spray drying, HME, and coprecipitation. Iyeret
al.26 compared the impact of spray drying and HME on themechanical
properties and tableting indices for ASDs made withthe L grade of
hydroxypropyl methylcellulose acetate succinate(HPMCAS) and
copovidone. The researchers found that spray dry-ing and HME
altered the mechanical properties of both HPMCASand copovidone,
including altering the compactibility, compress-ibility,
brittleness, and elasticity. It was speculated that the HMEprocess
densifies the material through high pressures and tem-peratures,
thus increasing the hardness and reducing the com-pactibility.
However, no mechanistic conclusions were made on thespray-drying
process. Davis et al.27 also compared the impact ofHME and spray
drying on powder flow and compression, but used aternary ASD
formulation of itraconazole, Soluplus®, and the HP-55grade of
hypromellose phthalate. The spray-dried powder exhibi-ted
diminished powder flow properties, a faster dissolution rate,and
improved tabletability compared to the milled HME powder.These
differences were hypothesized to be due to differences inparticle
size and morphology, where the spray-dried powders hadsmaller
particle size and more complex morphology than the mil-led HME
powder. As for manufacturing by coprecipitation, Houet al.28
compared the impact of spray drying and coprecipitation byeither
overhead or resonant acoustic mixing on the powder flowand
mechanical properties of an ASD containing 50% active and the
List of Abbreviations
ASD amorphous solid dispersionBFI brittle fracture indexBIw
dynamic bonding indexCTC compressibility, tabletability, and
compactibilityDCP-A dibasic calcium phosphate anhydrousd10, d50,
d90 maximum particle diameter below which 10%, 50%,
and 90% v/v of sample existsd[4,3] volume moment mean
diameterffc flow function coefficientHd dynamic indentation
hardnessHDTI Hiestand dimensionless tableting indicesHqs
quasi-static indentation hardnessHME hot melt extrusion
M grade of HPMCAS. The coprecipitated powders had better
tab-letability and powder flow properties than the spray-dried
powder,likely due to their larger particle size and higher surface
area forparticle contacts from their porous morphology.
Although these studies compared the effects of
differentmanufacturing processes on the mechanical properties of
theresulting powders, they did not explore the impact of the
pro-cessing conditions for each method used to manufacture the
ASDs.Specifically, each spray-dried ASD mentioned previously was
pro-duced using a single set of process conditions on
laboratory-scalespray dryers, which typically produce small and
low-density par-ticles withmechanical properties that do not scale
up to productionequipment. Therefore, the particle properties of
the spray-driedASDs in the studies described previously represent
only a smallsubset within the achievable range of particle
properties.
If the particle sizes and morphologies can be
dramaticallyaltered using the spray-drying process conditions, then
theresulting powder flow and mechanical properties can also
bedramatically altered to aid downstream processing. This study
in-vestigates the wide range of mechanical and flow
propertiesachievable for a single binary ASD formulation by
rationally varyingthe spray-drying process conditions at small
production scale. Thiswork demonstrates the potential to engineer
the particle propertiesof spray-dried ASDs to optimize tablet
design.
Materials and Methods
Materials
The ASD formulation consisted of 20% w/w felodipine
(BOCSciences, Shirley, NY) dispersed in the VA64 grade of
polyvinylpyrrolidone vinyl acetate (PVP VA) (Kollidon VA64; BASF
SE, Lud-wigshafen, Germany). The powder flow properties were
comparedto MCC PH102 (Avicel PH102; FMC Biopolymers, Philadelphia,
PA).The mechanical properties of the ASDs were compared to a
selec-tion of 4 as-received tableting excipients: PVP VA (Kollidon
VA64;BASF SE, Ludwigshafen, Germany); microcrystalline
cellulose(MCC) (Avicel PH101; FMC Biopolymers); lactosemonohydrate
(310NF; Foremost Farms, Baraboo, WI); dibasic calcium
phosphateanhydrous (JRS Pharma, Patterson, NY).
Manufacture of Spray-dried ASDs
Four solutions were prepared by dissolving felodipine and PVPVA
at a 1:4mass ratio in acetone at 2 different solids
concentrationsfor a total solids batch size of 350 g. Solutions
were spray-dried on a
HPMCAS hydroxypropyl methylcellulose acetate succinateMCC
microcrystalline cellulosemDSC modulated differential scanning
calorimetryPdryer Pressure in the dryerPparticle Pressure in the
particlePVP VA polyvinyl pyrrolidone vinyl acetateRH relative
humiditySEM scanning electron microscopySF85 solid fraction of
0.85SSA specific surface areaTS tensile strengthTSo compromised
tensile strengthUSP United States PharmacopeiaVE degree of
viscoelasticityXRPD X-ray powder diffraction
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A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-3666 3659
custom dryer similar in scale to a Niro pharmaceutical spray
dryer(PSD-1) but with an additional 6-foot cylindrical extension.
Twosizes of cyclones were used to separate powder from the outlet
gasstream: either 10.2 cm diameter (for samples A and B) or 15.2
cmdiameter (for samples C and D). A smaller cyclone, and thus
largerpressure differential, was used for the small particle size
samples, Aand B, to achieve a smaller cutoff diameter and thus
better yield.Two samples were spray-dried with a 2-fluid nozzle to
make rela-tively small droplets: size 1650 liquid orifice (Part No.
PF1650-316SS, Spraying Systems Co., Wheaton, IL) and size 120 gas
orificecap (Part No. PA120-316SS, Spraying Systems). Two samples
werespray-dried with a pressure swirl nozzle to make relatively
largedroplets: an SK series size 70 liquid orifice (Part No.
SIY-70, SprayingSystems) and a 16 swirl insert (Part No. SKY-16,
Spraying Systems).
Samples underwent secondary drying to remove residual sol-vent,
which was measured by gas chromatography. Solvent wasremoved to
less than 1% w/w by vacuum drying at 50�C at 20 MPaabsolute
pressure for 2.5 days for samples A, B, and C because ofthose
powders’ tendency to aerosolize. Sample D was dried by traydrying
at 40�C and 15% relative humidity (RH) for 3.5 days. Allsamples
were equilibrated together to room temperature (20�C-30�C) and
humidity (20%-35% RH) before testing unless otherwisenoted. The
samples were stored at ambient conditions in sealedjars, where
temperature and humidity were not explicitlycontrolled. Owing to
high water affinity of PVP VA, it is estimatedfrom in house data of
water uptake of PVP VA that all samplescontained equal amounts of
water between 2% and 5% w/w duringtesting. Owing to felodipine’s
hydrophobic nature, the ASD is notexpected to exceed the measured
PVP VA sorption values.
Characterization of Particle Properties
X-ray Powder DiffractionX-ray powder diffraction (XRPD)
diffractograms were obtained
to confirm samples were amorphous (n ¼ 1) using a Bruker AXS
D8Advance X-ray diffractometer (Bruker Corporation, Billerica,
MA)equipped with a Cu Ka source and set in modified parallel
beamgeometry between 4� and 40� 2Q. The scan rate was set to
2.4�
min�1 with a 0.04� step size.
Modulated Differential Scanning CalorimetryThermograms were
obtained to confirm the samples consisted
of a single amorphous phase (n ¼ 3) as evidenced by one
glasstransition event using a TA Instruments Q1000 differential
scan-ning calorimeter (TA Instruments-Waters LLC, Wakefield,
MA).Samples were prepared as loose powder, loaded into a Tzero
non-hermetically sealed pan, and equilibrated at
-
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-36663660
5 mm s�1 sawtooth strain-rate profile. Both the upper and
lowerpunch and die were lubricated with magnesium stearate
beforeeach compression. To obtain compressibility, tabletability,
andcompactibility (CTC) profiles, samples of 100 mg each (n ¼ 3)
wereprepared at 4 different peak compression pressures (50, 80,
160,and 220 MPa), yielding a total of 12 compacts per sample.34
Tensilestrength (TS) was measured using a Dr. Schleuniger
Pharmatron 6Dtablet hardness tester (Sotax Group, Aesch,
Switzerland). TS andcompression pressure associated with a solid
fraction of 0.85 (SF85)was interpolated for each sample using
semilogarithmic and log-arithmic regression analyses,
respectively.
Hiestand Dimensionless Tableting IndicesThe tableting behavior
of each ASD sample and tableting
excipient was orthogonally tested using a triaxial press.
Beforetesting, all powders were equilibrated to room temperature at
25%RH for at least 1 h, protected from light. For each
material,approximately 4.5 g was compressed into a square 0.75 inch
(1.9cm) flat-faced compact using a custom, single-station triaxial
tabletpress equipped with a split die.35 Compacts with solid
fractionsbetween 0.80 and 0.90 (n ¼ 3) were prepared by
varyingcompression pressure. Pressure was held for 1.5 min and then
thepressure was relieved to allow slow, triaxial decompression
over2 min, during which time punch and die wall pressures were
heldapproximately equal. For each material, the same procedure
wasused to manufacture square compacts containing a hole, or
well-defined defect, using a punch with a 1 mm diameter pin.
Com-pacts were stored at room temperature at 25% RH overnight
andprotected from light before mechanical properties were
tested.
The following mechanical properties were measured: TS (n¼
3),compromised tensile strength (TSo) (n ¼ 1), dynamic
indentationhardness (Hd) (n ¼ 3), and quasi-static indentation
hardness (Hqs)(n ¼ 1). Hiestand dimensionless tableting indices
(HDTI) calculatedfrom the aforementioned mechanical properties
interpolated bysemilogarithmic regression to SF85 included the
following: dy-namic bonding index (BIw), brittle fracture index
(BFI), and degreeof viscoelasticity (VE). Calculations and methods
for determinationof each mechanical property and HDTI were
performed usingmethods described in the literature, with HDTI
calculations andfurther description of methods provided in the
SupplementaryMaterial.35-38
Results and Discussion
Manufacture of Spray-dried ASDs
The goal of the study was to engineer 4 ASD samples with thesame
formulation but with different particle properties to illustratethe
range of particle properties achievable using the
spray-dryingprocess. The process parameter settings were
deliberatelyselected at the edges of success to obtain different
particle prop-erties within equipment constraints. They were
adjusted in amultivariate manner to produce fast and slow drying
kinetics forsmall and large droplets within the spray dryer.
Table 1Average Spray-drying Process Parameters
Sample Nozzle Solids Loading inSolution (% w/w)
Liquid FlowRate (g/min)
AtomizPres
A Two-fluid 2.0 112 30B Two-fluid 2.0 110 30C Pressure swirl
20.0 182 99D Pressure swirl 20.0 188 95
The average process parameter values are presented in Table
1.Because this was not a process optimization study, parameterswere
not changed systematically to investigate their effects.Instead,
for example, small and large particles were engineered tomeasure
the extent powder flow improves with size, whereasmorphology was
altered to measure the extent surface area im-proves the mechanical
properties such as TS and hardness.
The process yields were 66%, 73%, 82%, and 90%w/w for samplesA
through D, respectively. Given the primary focus of these
sprayswere to vary the ASD particle properties, yield was not
consideredwhen selecting process conditions. Furthermore, yield
generallyimproves with batch size and can be further optimized by
variablesnot investigated in the present study such as collection
cyclonedesign.
Particle Properties Resulting From the Spray-drying Process
Physical state characterization of the ASDs demonstrated
allsamples were amorphous and did not phase separate after
sec-ondary drying, regardless of the spray-drying conditions used
toprepare them. This was evidenced by the absence of
diffractionpeaks by XRPD, a single glass transition event between
89�C and92�C for all samples bymodulated differential scanning
calorimetry(mDSC), and absence of surface crystals by SEM. XRPD
diffracto-grams and mDSC thermograms are provided in the
SupplementaryMaterial. No crystals were detected on the particles’
surface, whichis often the first place crystals will appear.19 The
detection of sur-face crystals by SEM, although qualitative, is
often considered moresensitive than detection by XRPD and mDSC.
Surface compositionof the materials is assumed to be similar, but
measurement wasbeyond the scope of this study.39 As shown in Table
2, samples alsohad similar true densities and, while true density
is not a directmeasure of the amorphous structure, similar values
corroborate theclaim of like materials.
Although there were no measurable differences in the
materialproperties between samples, there were large differences in
par-ticle size distributions and particle morphologies due to
differencesin the spray-drying process parameters. SEM micrographs,
pro-vided in Figure 1, showed predominant morphologies were
smallhollow spheres for sample A, small collapsed hollow spheres
forsample B, large shards for sample C, and large collapsed
hollowspheres for sample D. In addition to SEM microscopy, particle
sizedistributions were measured by laser diffraction. The d[4,3]
andmaximum particle diameters belowwhich 10%, 50%, and 90% v/v
ofsample exists (d10, d50, and d90) are listed in Table 2. The
d[4,3] for asample is calculated assuming spherical particle
geometry and,while not all ASD particles are spherical, the results
of the laserdiffraction generally agreed with the SEM
micrographs.
The difference in particle size between samples was as
expectedbased on differences in the spray solution solids loading,
andtherefore viscosity, as well as atomizer size and type and
atomi-zation conditions.18 The small 2-fluid nozzle with low
solidsloading produced small particles, whereas the large pressure
swirlnozzle with high solids loading produced large particles.
Theresulting particle morphologies were also as expected, based on
the
ationsure (psi)
Drying Gas FlowRate (g/min)
Inlet Temperature(�C)
Outlet Temperature(�C)
1086 167 611847 72 321222 184 611835 81 33
-
Table 2Average Particle, Bulk Powder, and Flow Properties of
Spray-dried ASDs
Sample D10 (mm) d50 (mm) d90 (mm) d[4,3] (mm) Bulk Density(g
cm�3)
Tapped Density(g cm�3)
True Density(g cm�3)a
SSA (m2 g�1) Carr Index ffc
A 1 3 6 4 0.31 0.44 1.23 1.6 28 1.1B 1 3 7 4 0.20 0.32 1.24 3.0
37 1.3C 25 93 231 115 0.05 0.07 1.26 0.9 36 6.1D 30 69 129 75 0.38
0.51 1.23 0.2 26 7.5
a Performed in singlicate averaging 5 repeat measurements
(standard deviations below 0.01 g cm�3). All other tests performed
in duplicate.
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-3666 3661
droplet drying mechanism of film-forming polymers, which
isillustrated in Figure 2.21,22 The schematic assumes rapid drying,
or ahigh Peclet number, such that a solute concentration
gradientwithin the droplets develops during drying. Once the
polymer
Figure 1. SEM micrographs of ASD powders (left) and ASD compacts
after ejection from psamples A and B, and 300� for samples C and D.
Powders had solid fractions of 0.77 to 0morphologies are provided
for each sample on the far left.
solubility at the liquid-gas interface is exceeded, a viscous
skinforms, reducing the diffusion of the solvent to the particle
surfaceand thus the rate of evaporation. Depending on the rate of
dryingand excipient properties, the particle walls deflate or
inflate based
eak pressure of 80 MPa (middle) and 220 MPa (right).
Magnifications are 3000� for.82 (middle) and 0.91 to 0.93 (right).
Simplified cartoons of the predominant powder
-
Figure 2. Droplet drying kinetics for a film-forming polymer
solution assuming a high Peclet number. Pdryer and Pparticle
represent the pressure in the spray dryer and particle
duringparticle formation.
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-36663662
on the partial pressure of the solvent trapped in the
particle,creating either collapsed hollow spheres, hollow spheres
or, occa-sionally, fractured hollow spheres or shards.
The drying rate of the droplets is governed by the energy
inputinto the dryer, which is equal to the product of inlet
temperature,drying gas flow rate, and heat capacity. For sample A,
the smalldroplets exposed to higher energy input for drying
resulted in thesmall round spheres shown in Figure 1, indicative of
fast dryingand thus a high solvent partial pressure inside the
droplet. SampleB, prepared with equal atomization conditions and a
lower outlettemperature, had a collapsed hollow sphere morphology.
This ispresumably due to the lower internal solvent partial
pressure,causing the particle to collapse in on itself. It is
predicted thatsample A had a higher Peclet number than sample B, as
the ve-locity of the droplet interface during drying would also be
faster.The same can be said for the larger droplet samples, with
thenotable exception of sample C, inwhich the particles fractured
intoshards. PVP VA, a brittle polymer, is prone to fracturing. The
shardslikely result from thin hollow spheres fracturing when
colliding
Figure 3. CTC profiles of the ASDs. Lines betwe
with other particles in the cyclone or the walls of the dryer
andcyclone.
Influence of Particle Properties on Bulk Powder Properties
The bulk powder properties, including SSAs and bulk and tap-ped
densities are reported in Table 2. The SSAs are determined bythe
particle size distributions and morphologies of the
powders.Although samples B and D had similar morphologies as
expected,the SSA of sample B was more than an order of magnitude
largerthan that of sample D because it had amuch smaller particle
size, asevidenced by its lower d[4,3] value (Table 2). Although SSA
and d[4,3]displayed an inverse relationship for these 2 samples,
this inverserelationship did not hold true when comparing the
results of all 4samples. The reason for this difference was due to
the inadequateassumption of spherical morphologies. For instance,
sample C had alarger d[4,3] than sample D, but also had a larger
SSA. This is pre-sumably due to the increase in SSA from the
exposed inner wall ofthe fractured spheres compared with an intact
spherical geometry
en points are provided to aid visualization.
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A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-3666 3663
assuming a fixed diameter. In addition, sample B had almost
twicethe SSA of sample A despite having an equal d[4,3]. This may
bebecause the collapsed particle walls increased the SSA.
Notably,sample A had a lower SSA than predicted using the spherical
ge-ometry assumption and measured particle size distributions.
TheSSA of the ASDs impacts the mechanical properties by affecting
thecontact area available for particle-particle bond formation,
withmore SSA generally leading to higher TS.40
Like SSA, the powder bulk and tapped densities depend onparticle
properties, such as morphology and size. The 7-fold span ofbulk and
tapped densities measured across samples suggests var-iations in
wall thickness and consolidation propensity (Table 2).23
For example, samples A and B had similar particle size
distribu-tions, but the bulk and tapped densities for sample A were
greaterthan those for sample B. Differences in morphology can
impact thedegree of consolidation during bulk and tapped density
measure-ments, which is hypothesized to be the cause for this
difference.41 Itcould also be because sample A had thicker walls
than sample B,but this is unlikely because the faster drying
kinetics of sample Awould have resulted in a larger concentration
gradient of the sol-utes at the surface, leading to a larger
skinning droplet diameterand thus a thinner particle wall.21
Another possible factor notinvestigated in this study is static
charge on particles, which canlead to cohesion and affect powder
flow and densities.42 On theother hand, for the large particles,
sample C was fluffy with a lowbulk and tapped density due to the
thin walls and irregularmorphology that resisted consolidation,
whereas sample D, whichconsisted of large thick-walled particles
that were relatively round,promoted denser packing.
Influence of Particle Properties on Powder Flowability
Particle size and morphology not only determine bulk
powderproperties such as SSA, they can also greatly influence
powderhandling and flow, with poor powder flow increasing the risk
forpoor tablet content uniformity and limitations on
productionthroughput.43,44 Powder flow is a complex phenomenon and
re-quires extensive testing to quantify. For the purposes of this
study,shear cell and Carr index were used for preliminary
comparisons,but additional testing is recommended before
downstreamprocessing.
Generally, powder flow improves with increasing particle
sizebecause of increased body forces that overcome cohesion
andfriction forces.45 This was observed during the shear cell
mea-surements of the ASDs (Table 2). The ffc values, which indicate
howeasily a consolidated powder can transition from a static to a
dy-namic state under amoderate to high stress environment, were
lessthan 2 for samples A and B, suggesting these powders are
“verycohesive.” By contrast, the large particle samples, C and D,
had ffcvalues greater than 6 placing them in the “easy-flowing”
range
Table 3Material Properties and HDTI From Square Compacts of ASDs
at SF85a,b
Sample Material Property
Compaction Pressure (MPa) TS (MPa) TSo (MPa)
A 65.6 (5.6) 1.1 (47.2) 0.2
B 66.4 (8.1) 5.5 (12.9) 1.7
C 88.5 (20.5) 5.0 (11.5) 1.6
D 78.5 (4.4) 3.3 (4.8) 1.5
a Values interpolated by semilogarithmic regression to SF85.
Colors for the HDTI illustratgray) range.
b %RSD values presented in parentheses for values measured in
triplicate.
provided by the USP General Chapter 46 on shear cellmethodology.
For reference, MCC PH102 was measured alongsidethe ASDs and
resulted in an ffc value of 7.3, just slightly belowsample D.
The Carr index provides a measure of the compressibility of
apowder due to interparticle friction and is often correlated to
how apowder will flow. Carr index values, also listed in Table 2,
did notcorrelate with particle size, specifically d[4,3]. According
to USPChapter on powder flow, samples A and D fell in the
“poor”flow range (26-31), whereas samples B and C fell within the
“verypoor” flow range (32-37).31 In reference to MCC PH102, the
re-ported Carr index was 25.8, similar to sample D.47When
comparingthe effect of particle shape at a similar particle size,
sample B, whichconsisted of small collapsed hollow spheres, had
worse Carr indexvalues than sample A, which consisted of hollow
spheres. Thisdifference was likely due to the interlocking nature
of irregularlyshaped particles, resulting in a lower bulk
density.45 Similarly forthe large particle ASDs, sample C had a
poorer Carr index thansample D, likely due to the former’s more
irregular shardmorphology. As mentioned previously, varying static
charge on theparticles could also impact powder flow but was not
investigated inthis study.42
Influence of Particle Properties on the Mechanical Properties
forTableting
The ability of powders to be compressed and create strongtablets
is fundamental for reducing manufacturing risks such aslamination
and capping and for maintaining tablet integrity duringhandling and
storage. The mechanical properties related to tab-leting of the
ASDs were evaluated using 2 measures: (1) CTC pro-files of round
compacts and (2) HDTI of square compacts. The CTCprofile TS values
at SF85 (shown in Fig. 3) show the same trends asthe values
measured using square compacts for the HDTI (listed inTable 3),
even though the tests were performed at different speedsusing
different methods. Both tests showed all the ASDs are ex-pected to
produce strong tablets (>1.5 MPa TS) at reasonable
solidfractions (0.70 to 0.85) using reasonable compression
pressures (50to 200 MPa).
As mentioned previously, the SSA of a spray-dried ASD particleis
largely a function of particle size and morphology. Powders
withsmaller particle sizes tend to have higher TS values on
compactionthan larger particles of the same material with similar
bondingstrength and surface roughness.40 This is because the SSA
isinversely proportional to the number of particles for a given
mass,resulting in a greater number of potential particle-particle
bonds.However, the bonding area on compaction and resulting
strength ofa tablet is governed not only by the initial available
SSA, but alsodepends on the deformation behavior of the particles
as influencedby morphology, material hardness, and elasticity.40,48
When
HDTI
Hd (MPa) Hqs (MPa) BIw BFI VE
172 (47.8) 51 0.006 1.9 3.4
149 (26.4) 50 0.037 1.2 3.0
219 (0.2) 85 0.023 1.0 2.6
147 (3.7) 44 0.023 0.6 3.3
e whether the value is in the desirable (bold), marginal (light
gray), or deficient (dark
-
Figure 4. HDTI of the ASDs compared to common tableting
excipients as received atSF85 except DCP-A, which is reported at a
solid fraction of 0.65. Colored bars illustratethe desired range
(green), marginal (yellow), and deficient range (red) for each
index.DCP-A, dibasic calcium phosphate anhydrous.
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-36663664
particles are compacted, they can plastically deform and
createadditional contact area beyond the initial consolidation
contacts,increasing strength. Materials can also deform by brittle
fracture,which effectively decreases the particle size distribution
of a givenmaterial during compaction, thereby increasing the number
ofcontacts and thus total bonding area. On the other hand, once
thepressure is removed, the elastic relaxation of thematerial can
resultin these bonds being broken, diminishing the TS. Therefore,
theoverall measured TS is dependent on the deformation and
relaxa-tion mechanisms of the material in addition to the initial
SSA of thebulk powder.
SEM micrographs of cross sections of the round compacts alongthe
dimension of tensile fracture are depicted in the center andright
columns of Figure 1. These images qualitatively depict thedegrees
of particle deformation and areas of particle-particlebonding after
the compacts were ejected from the die after 80and 220 MPa peak
compression pressures. As the images show, thelarge particles
fractured under pressure, whereas the small parti-cles remained
intact. The small particles retained their shape,possibly because
they were below the critical diameter and wallthickness for
fracturing.49
TS at a given solid fraction for both round and square
compactspositively correlated with the SSAs listed in Table 2,
except forsample A. Despite having the second highest SSA, sample A
had thelowest TS at a given solid fraction. For hollow spheres such
as spray-dried ASDs, the wall thickness, radius, and material
properties suchas Poisson’s ratio and Young’s modulus can affect
the degree andtype of deformation and, therefore, the available
contact area at agiven solid fraction.50 It is hypothesized that
sample A has lower TSeither because the spherical particles have
thick walls relative totheir small radii that minimize plastic
deformation and preventbrittle fracture, or they experienced
extensive elastic relaxationafter compaction. This can be seen in
the SEM micrographs ofsample A in Figure 1, where the individual
particles remain intactand distinguishable from each other even
after 220 MPa ofcompression pressure. This results in lower contact
area andtherefore TS for a given compression pressure. Sample B, on
theother hand, showed signs of plastic deformation in the SEM
mi-crographs after a compression pressure of 220MPa, where
particlesbecame indiscernible from each other. The collapsed
spheremorphology, when compressed, enabled the creation of
morecontacts through deformation and interlocking even at similar
d[4,3]to sample A.
Table 3 reports TS and compression pressures at SF85 for
thesquare compacts. Relative standard deviations (%) are provided
inparentheses for values measured in triplicate. During
tensiletesting, all samples experienced shear rather than tensile
failure,characterized by arch-shaped cracks on each side of the
compactoriginating at the corner of each platen. It is speculated
that the TSof the square compacts was likely greater than
themeasured valuesbecause shear failure occurred before tensile
failure. Even so, the TSand TSo at SF85 were in the same ranked
order for the squarecompacts as for the round compacts (B > C
> D > A), varying 5-foldacross all samples. The mechanical
properties measured on thesquare compacts were used to calculate
the HDTI for each sample(Table 3). They have been categorized by
color as desirable (green),marginal (yellow), and deficient (red)
for tableting, based onextensive pharmaceutical material testing
experience and pub-lished measurements.38,51 Exact ranges are
listed in theSupplementary Material. The BIw was generally high for
all ASDsamples, with sample A being the only one in the marginal
range.As illustrated in Figure 4, the BIw values span the range of
commonexcipients. Sample A measured similarly to lactose
monohydrateand dibasic calcium phosphate anhydrous, whereas sample
Branked near PVP VA and MCC.
Owing to their polymeric nature, these ASDs may have strain-rate
dependence. This would mean that the material cannotrecover quickly
after pressure is removed, leading to laminationand capping risks
on scale-up.34,52 However, the VE values for allsamples were in the
desirable range, suggesting low strain-ratedependence. Samples B
and C had VE values similar to that oflactose monohydrate, whereas
the VE values for samples A and Dmeasured just below that of MCC.
However, high-speed compac-tion testing would be required to verify
this because the VE has notbeen validated in literature as
correlating to strain-rate dependenceat production scale.
The BFI values were in the deficient range for all samples,
likely aresult of PVP VA’s brittle nature (the BFI of the
as-received PVP VAwas 0.73). Brittle materials deform under
pressure predominantlyby fracturing instead of by plastic
deformation. This behavior wasevident in the micrographs of the
compacts, suggesting anisotropiceffects for large particles that
fractured and stacked.53 The litera-ture suggests that high
anisotropy correlates to higher BFI in tab-leting excipients.49,53
This, coupled with the shear failure observedduring TS measurements
of the square compacts, suggests thematerials are brittle, with
heightened friability and lamination riskduring tableting.
Implications for Downstream Processing
Overall, the particle sizes and morphologies of ASDs made
fromthe various spray-drying process conditions directly
affecteddownstream processing through powder flow and
mechanicalproperties related to tableting. Regarding powder flow,
samples A,B, and C had worse ffc and Carr index values than MCC
PH102,whereas sample D had comparable values. MCC PH102 has
been
-
A. Ekdahl et al. / Journal of Pharmaceutical Sciences 108 (2019)
3657-3666 3665
used as an indicator of successful flow behavior through a
KorschXL100 tablet press run at 70 rpm using a gravity feeder.47
Thepowder flowability results suggest the potential need for
drygranulation before tableting to improve flow and mitigate
contentuniformity risks for samples A, B, and C. The use of dry
granulationis standard for ASD containing tablets because most ASDs
requiredensification and flow improvement. Flow behavior of a
singlecomponent is not directly indicative of the tablet
formulation flowand can be improved through formulation selection.
However, asthe single component loading is increased in the tablet,
such as theASD to increase drug loading, there are less tableting
excipients bymass available to attenuate the poor flow behavior.
Therefore,granulation is a viable technique to improve flow when
rationalexcipient selection is not enough. Notably, the effect of
granulationon themeasuredmechanical properties was not investigated
in thisstudy, but granulation has been shown to reduce
compactibility ofmaterials and should be considered during tablet
formulation.54,55
Depending on the tablet formulation, sample Dmay be amenable
todirect compression under similar tableting conditions with
theaddition of flow aids, eliminating the need for dry
granulation.56
As for the mechanical properties, all samples demonstrated
theability to form strong tablets at reasonable solid fractions
andcompression pressures. They did have high BFI, suggesting the
needfor tablet fillers with higher plasticity, such asMCC, to
attenuate thebrittleness of PVP VA ASDs. However, owing to the
samples havingstrong bonding strength and potentially low
viscoelasticity, theseresults could be used to design a tablet
formulation that requiresminimal amounts of binders,
compressibility aids, and brittle ex-cipients such as lactose
monohydrate to boost drug loading andreduce pill burden, the
required number and size of dosage formunits to achieve target
dose.
Because the purpose of the study was to produce particles at
theedge of success to illustrate the range of particle
propertiesachievable, optimization of particle size and morphology
fordownstream processing was not performed. Overall, it wasobserved
that larger particle sizes likely will improve powder flowwhile
diminishing compaction properties. Second, the collapsedhollow
sphere morphology may be more desirable than the hollowsphere
morphology for mechanical properties, but the interlockingnature
could diminish powder flow. Owing to sample A and B’ssmall particle
size and sample C’s poor bulk density, sample D islikely the only
sample in this study recommended for large-scaleproduction and
downstream processing, assuming the ASD’s bio-performance has
little or no dependence on particle size. For for-mulations where
reduced particle size improves dissolution rateand bioperformance,
a moderate particle size with collapsed hol-low sphere morphology
may be better suited to achieve highersurface area for dissolution
and compactibility.
Conclusion
Particle engineering by tuning the spray-drying process of
asingle binary ASD formulation was shown to produce ASD
particleswith a wide range of particle sizes, densities, and
particle mor-phologies, demonstrating that this approach can be
directly used tooptimize downstream manufacturability of a finished
dosage form.
The results presented in this article suggest that particle
engi-neering may enable concurrent optimization of the
spray-driedASD and tablet formulation. Careful selection of process
variablesto produce ASDs with the desired mechanical and powder
flowproperties could reduce the number and amount of fillers
currentlyused to attenuate nonoptimal ASD properties. This could
reduce pillburden, especially for drugs with high therapeutic
doses, byincreasing the possible amount of active ingredient in the
tabletformulation. In addition, optimization of ASD properties
through
particle engineering could simplify the
tablet-manufacturingprocessdfor example, by reducing the need for
dry granulationand enabling direct compressiondand, thus,
manufacturing timeand cost. Future work should include determining
the achievablerange of powder flow and mechanical properties of
tablet formu-lations incorporating ASDs with various particle
morphologies,varying the type and quantity of excipients and
processingmethods, while maximizing drug loading and bioperformance
inthe final tablet.
Acknowledgments
The authors would like to thank the many scientists at Lonzaand
the University of Michigan for their valuable support for thiswork
and critical review of this article.
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Effect of Spray-Dried Particle Morphology on Mechanical and Flow
Properties of Felodipine in PVP VA Amorphous Solid
DispersionsIntroductionMaterials and MethodsMaterialsManufacture of
Spray-dried ASDsCharacterization of Particle PropertiesX-ray Powder
DiffractionModulated Differential Scanning CalorimetryScanning
Electron Microscopy (SEM) of PowderTrue DensityLaser Diffraction
Particle Size Analysis
Characterization of Bulk Powder Properties and FlowabilityBulk
and Tapped Density and Carr IndexBrunauer-Emmett-Teller Specific
Surface AreaFlow Function Coefficient (ffc)
Characterization of Mechanical PropertiesSEM of
CompactsCompressibility, Tabletability, and Compactibility
ProfilesHiestand Dimensionless Tableting Indices
Results and DiscussionManufacture of Spray-dried ASDsParticle
Properties Resulting From the Spray-drying ProcessInfluence of
Particle Properties on Bulk Powder PropertiesInfluence of Particle
Properties on Powder FlowabilityInfluence of Particle Properties on
the Mechanical Properties for TabletingImplications for Downstream
Processing
ConclusionAcknowledgmentsReferences