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Journal of Pharmaceutical Sciences 108 (2019) 3657-3666

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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

http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/https://doi.org/10.1016/j.xphs.2019.08.008mailto:[email protected]://crossmark.crossref.org/dialog/?doi=10.1016/j.xphs.2019.08.008&domain=pdfwww.sciencedirect.com/science/journal/00223549http://www.jpharmsci.orghttps://doi.org/10.1016/j.xphs.2019.08.008http://creativecommons.org/licenses/by-nc-nd/4.0/https://doi.org/10.1016/j.xphs.2019.08.008

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

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


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.


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.


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.


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.


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


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

effect of spray-dried particle morphology on mechanical and … · 2020. 6. 26. · pharmaceutics,...

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