Powder Technology 195 (2009) 15–24

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Evaluation of the physical and mechanical properties of high drug load formulations:Wet granulation vs. novel foam granulation

Stuart L. Cantor a,1, Sanjeev Kothari b,1, Otilia M.Y. Koo c,⁎a ICON Development Solutions, 6031 University Blvd., Ellicott City, MD 21043, USAb AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, DE 19850, USAc Bristol-Myers Squibb Company, 1 Squibb Drive, New Brunswick, NJ 08903, USA

⁎ Corresponding author. Biopharmaceutics Research aSquibb Company,1 Squibb Drive, New Brunswick, NJ 089fax: +1 732 227 3986.

E-mail address: otilia.koo@bms.com (O.M.Y. Koo).1 All of the work described here was conducted by

Squibb Company, New Brunswick, NJ, USA.

0032-5910/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.powtec.2009.05.003

a b s t r a c t

a r t i c l e i n f o

Article history:Received 9 July 2008Received in revised form 2 February 2009Accepted 6 May 2009Available online 12 May 2009

Keywords:Hiestand tableting indicesConventional wet granulationFoam granulationViscoelasticDuctileBrittle

The purpose of this study was to evaluate the influences of intrinsic drug mechanical properties and differentgranulation binder delivery processes on the physical and mechanical properties of high drug loadgranulations after wet granulation. Formulations (80% w/w) of acetaminophen (APAP), metformin andaspirin, which are brittle, viscoelastic, and ductile, respectively; were granulated by high-shear wetgranulation. Two modes of binder delivery for wet granulation, either conventional or binder foam, wereinvestigated. Particle size, surface area and pore size of the granulations were characterized. Compacts wereprepared at a solid fraction of 0.9 under tri-axial decompression and Hiestand indices (worst-case bondingindex (BIw) and brittle fracture index (BFI)) of the compacts were determined. APAP formulations exhibitedthe smallest geometric mean particle sizes (dg) and showed only slight differences in dg values between thetwo granulation processes. Binder delivery mode affected mechanical properties of the granulated modeldrugs differently. Foam granulation appeared to enhance the granule plasticity for APAP while aspirinshowed a mixed deformation mechanism based on both its high BIw and high BFI values. The higher BIwvalue for aspirin after foam granulation may be attributed to improved binder distribution among particlesduring granulation. On the other hand, conventional wet granulation improved the plasticity of metformin asmeasured by the higher BIw and lower BFI values. Therefore, conventional wet granulation process conferredadvantages in manufacturability and product quality for metformin; as compared to foam granulation whichdid not enhance plasticity for metformin. Based on this study, a wet granulation process can be selectedbased on knowledge of the intrinsic drug mechanical properties.

© 2009 Elsevier B.V. All rights reserved.

1. Introduction

The understanding of both physical and mechanical properties ofpharmaceutical granulations is critical for successful tablet formula-tion. Costly problems such as low tablet crushing strengths, poorfriability, poor coating uniformity, and capping/lamination canpotentially be avoided through an improved understanding of thephysico-mechanical properties of granulations. Such useful informa-tion to quantify a granulation's degree of brittleness or plasticity canbe gained by using dimensionless parameters known as the Hiestandtableting indices. In this study, the physical andmechanical propertiesof high drug load granulations prepared via both conventional wetand foam processes were evaluated. It was desired to determine boththe influences that the intrinsic drug mechanical properties and

nd Development, Bristol-Myers03, USA. Tel.: +1732 227 5341;

the authors at Bristol-Myers

ll rights reserved.

different binder delivery processes have on the properties of the finalgranules.

The two granulation processes compared in this study are theconventional wet granulation and a new foam granulation process.High drug loads, i.e. 80% w/w, were used in this study to minimizeformulation effects and enable an accurate comparison of thedifferences between the mechanical properties of the three modeldrugs in affecting granulation properties. The foam-mediated wetgranulation process where the binder is delivered as foam has beengaining increasing attention in the pharmaceutical industry due to itsadvantages over conventional wet granulation. Foam granulationyields a more homogeneous dispersion of binder throughout thepowder bed during granulation and can potentially reduce dryingtime due to the lower soak-to-spread ratio of binder foam comparedto a conventional spray of binder solution [1]. Moreover, delivery ofthe binder foam through rigid plastic tubing eliminates the need tooptimize nozzle placement and geometry. Excipients suitable for foamgeneration include commonly used binders such as hydroxypropylcellulose (HPC), hypromellose (HPMC) and other cellulose ethers [1].Surfactants (e.g., sodium laurel sulfate, Poloxamer® 188) may also beused as aids to generate foam. The typical binder solution viscosity

16 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

range for foam generation is between 5 and 100 cP [2]. HPC solutionhas the viscosity and surface tension properties to generate highquality foam of low density and was selected for this study.

Recently, scale-up trials of sodium naproxen immediate- andcontrolled-release formulations using foam granulation technologyshowed that this process prevented localized over wetting duringgranulation. Furthermore, drug dissolution rate profiles were similaracross the different batch sizes, from laboratory to pilot andmanufacturing scale [3].

In addition to the granulationmoisture level, physical properties ofgranulations such as surface area, particle size, particle size distribu-tion, and pore diameter can influence subsequent tablet strength oncompaction. It is known that porous particles are mechanicallyweaker and readily deform to create new bonding surfaces whichcan lead to increased inter-particulate bonding and thus, hardertablets [4,5]. Similarly, granulations with higher surface areas areexpected to result in harder tablets through increased inter-particlebonding provided that true contact distances are reached between thedeforming particles. Therefore, an adequate tensile strength, indica-tive of good bond formation, is one criterion to determine a successfultablet formulation. However, physical measurements of granulationsare typically studied because mechanical properties are not pre-dictable a priori [6].

Some processes such as conventional wet granulation can have asignificant effect on themechanical properties of certainmaterials; forexample, the compactability of microcrystalline cellulose (MCC) issignificantly reduced after granulation [7]. It was found that a loss ofcompactability following conventional wet granulation is associatedwith a decrease in the particle porosity of MCC [8]. This is due to thestrain hardening effect of the wetting and drying process that leads tostrong hydrogen bonds between the hydroxyl groups of the cellulosechains and results in an increased elastic modulus. Mechanicalproperties of pure excipients have been extensively studied sincethey can impact a successful tablet formulation. For instance,viscoelastic materials such as starch [9] or polyethylene oxides forcontrolled-release applications [10] are known to be strain-ratesensitive; thus, when scaling-up to faster tablet machines withdecreased dwell times, a reduction in tablet tensile strength can beobserved because the material did not receive sufficient time underload for good bond formation.

Hiestand tableting indices have traditionally been employed tostudy the mechanical properties of pure excipients or drugs. Thesetableting indices, developed over 30 years ago, have been found to besufficiently sensitive to detect lot-to-lot variations in raw materials[11]. Hiestand indices provide a fundamental understanding of thebehavior of materials under compression and decompression. Whiletypically used to characterize pure materials, this research is anattempt to study the mechanical properties of pharmaceuticalgranulations prepared using two different binder delivery processesfor wet granulation and three drugs of different intrinsic mechanicalproperties. The indices of relevance here include the worst-casebonding index (BIw) and the brittle fracture index (BFI).

BIw is a ratio of the compact's tensile strength to its dynamicindentation hardness and indicates the ability of intra-particulatebonds formed during the compression phase to survive during thedecompression process. Relatively speaking, a higher BIw valueindicates a more plastic material, and such materials will likely havelower dynamic hardness values. Plastic deformation occurs duringtablet compression and decompression. As compression takes place,particles initially rearrange and repack to assume a smaller bedvolume. When no further reduction in volume is possible throughrearrangement, particles begin to deform. When their elastic limit isexceeded, permanent deformation occurs through brittle fractureand/or plastic deformation, and the particle bed is sheared. When theshear strength is greater than the breaking strength, particle fractureoccurs. When the shear strength is less than the breaking strength,

plastic deformation occurs [4]. Plastic deformation is predominant inthe decompression stage for viscoelastic materials that exhibit flowafter release of the compression stress.

Brittle fracture index (BFI) is the ratio of the tensile strength of thetablets without a hole and with a hole at their center. This ratio mayindicate the ability or inability of compact to relieve stress at a cracktip within the compact by plastic deformation [12]. The BFI is based onthe Griffith crack propagation theory, which states that a crack will beinitiated and propagated when the incremental change of elasticenergy during crack growth provides the incremental gain of surfaceenergy for the new surfaces [13]. It is assumed that the origin of thecrack is from a defect site where the elastic stress is concentrated. It ishigher than the nominal stress, and hence the first region to reach thestress level needed for crack growth. Since the crack tip may continueto be a stress concentrator; the crack often continues to propagate.Therefore the material fails at much lower applied stress thanexpected from the theoretical bond strength and/or theoreticalshear strength. However, if a material relieves some of the stress inthe region of concentrated stress by plastic deformation, then thestresses may not build to the level required for crack propagation. TheGriffith theory is modified to include the absorption of energy byplastic deformation when calculating the BFI.

Three representative model drugs with different deformationmechanisms were chosen: 1) metformin was selected as the modelviscoelastic drug in this study. Viscoelastic materials are uniquelyaffected by their sensitivity to both moisture [9,12] and time underload [12,14]; 2) acetylsalicylic acid (aspirin), a drug known to deformplastically [15], and 3) acetaminophen (APAP), known to undergobrittle fracture. APAP exhibits poor tableting characteristics becausethe particles of this drug are very hard, and therefore, inter-particulatebonding is very weak [16]. Furthermore, APAP has been shown to besusceptible to capping following compression [16–19].

Interestingly, while the thermodynamically stable and commer-cially available monoclinic polymorph of APAP (form I) requiresbinders for tablet formation, the metastable, orthorhombic form doesnot. The reason for the significant difference in mechanical propertieslies in the fact that the crystal structure of form I consists of puckeredhydrogen-bonded sheets which are relatively stiff and do not easilyslip over each other during compression. However, the crystalstructure of form II has parallel hydrogen-bonded sheets which giverise to slip planes that allow for plastic deformation and improvedcompression properties [20].

Aspirin and APAP were chosen specifically because there isrepresentative data on the Hiestand indices already reported in theliterature for comparison purposes [11]. On the other hand, to ourknowledge, this is the first work that Hiestand tableting indices ofmetformin are discussed. This work is also important because muchprevious work has focused on the mechanical properties of pureexcipients [3,21–23] or pure drugs [11,23] as well as model formula-tions without drug [24,25] but not on drug-based granulations.

The objectives of this study are to 1) establish a fundamentalunderstanding of the physico-mechanical properties of high drug loadgranulations manufactured using conventional wet or foam granula-tion techniques and determine the influence of the binder deliverytechnique on the granulation mechanical properties; 2) provideguidance for selection of the most appropriate granulation processbased on the mechanical properties of drug; and 3) determine if anyrelationship exists between the physical properties (i.e., particle size,surface area) and mechanical properties of each granulation.

2. Experimental

Acetylsalicylic acid USP was purchased from Spectrum Chemicals(New Brunswick, NJ), metformin hydrochloride USP was obtainedfrom Bristol-Myers Squibb (Evansville, IN) and acetaminophen USPand magnesium stearate NF were purchased fromMallincrodt Inc. (St.

Table 1Formulations for conventional wet or foam granulations.

Material Wet process % Foam process %

Drug 80.0 80.0Microcrystalline cellulose 17.0 17.0Hydroxypropyl cellulose 3.0 Dry 2.0

As foam 1.0Water added during granulation 12–14 12–14

17S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

Louis, MO). Microcrystalline cellulose NF (Avicel® PH-102, FMC,Philadelphia, PA) and hydroxypropylcellulose (HPC) NF (Klucel®,Aqualon, Wilmington, DE) were also used in this study.

2.1. Granulation batches using a high-shear mixer

Table 1 lists the conventional wet and foam granulation formula-tions used in this study. The rationale for devising simple modelformulations consisting of only three ingredients is because acomparison of results using the Hiestand Indices can become difficultif a more complex system of materials is used [26]. The drug load waskept constant at 80.0% w/w. Since a high drug load was used, it isassumed that physical and mechanical properties of the drugsthemselves exert a significant impact on the properties of theresultant granulations. Granulations containing each of the threedrugs (metformin, aspirin, and APAP) were manufactured by eitherconventional wet or foam granulation processes. Mixing andgranulation was performed in a 6-L Diosna high-shear granulator(Osnabruck, Germany) at a batch size of 1 kg. All powders were pre-blended in the mixer for 2 min before granulation, with the mixerimpeller set at 200 rpm and the chopper set at 500 rpm.

During conventional wet granulation, mixer impeller and chopperwere set at 300 rpm and 1300 rpm, respectively. Water was added at arate between 55 and 65 g/min using a peristaltic pump and theimpeller power was recorded at several fixed time intervals duringgranulation. The total amounts of water added were adjusted for eachdrug, but kept constant for both conventional wet and foamgranulation processes for a drug.

The foam granulation process utilized the samemixer impeller andchopper settings as for the conventional wet granulation process. A10% w/w HPC stock solutionwas prepared by dissolving HPC in waterwith gentle stirring overnight. The concentration of the HPC solutionwas further adjusted before granulation so that 1% of HPC in theformulation was added as foam and 2% HPC as dry powder in the pre-blend. Therefore, final quantity of HPC (3%) was the same as informulations used in conventional wet granulation.

HPC foam was generated utilizing the same concepts previouslydescribed by Keary and Shesky [1]. The compressed air and liquid flowrates were adjusted to achieve a ≥90% foam quality, according to Eq.(1):

Foam quality =Rate of air flow − Rate of liquid flow

Rate of air flowT100 ð1Þ

Air flow rate and liquid flow rate were 2.0 L/min and 0.1 L/min,respectively. The rate of addition of the foamed binder was kept thesame as for water during the conventional wet granulation process,approximately 55–65 g/min. A high foam quality enables the foam tobehave more solid-like and retain its properties better as it flowsthrough a rigid plastic pipe from the foam generator into the high-shear mixer. The foamwas homogeneously dispersed into the powderduring granulation.

The wet granules were dried in a hot-air convection oven at 60 °Cfor 6 h to a loss on drying (LOD) value of less than 2.0%. Forcomparison purposes using aspirin, an additional conventional wetgranulation batch was also prepared and dried for a longer drying

time of 12 h. The LOD of the granulations was determined using aMettler DSC HFT-2000M Moisture balance (Columbus, OH). Samplesof approximately 2.0 g were dried to constant weight at 105 °C for10 min.

2.2. Physical characterization of granulations

Particle size of the dried granulations was determined in duplicateby sieve analysis using a sonic sifter (Allen Bradley ATM Model L3PSonic Sifter®, Milwaukee, WI). Sieving was run for 5 min at anamplitude setting of five and a pulse setting of 5. The percentage byweight retained on each sieve was determined and the geometricmean diameter, labeled as GMD or dg, and geometric standarddeviation, σg, of the particle size distributions were calculated usingEqs. (2) and (3), respectively [27]:

logdg =P

ni T logdið ÞPni

ð2Þ

where ni is the weight percent of particles in the ith interval, for all ni;and di is equal to the midpoint of the diameter of the size interval inthe ith interval, for all di.

logσg =

Pni logdg− logdi� �2

Pni

264

3751=2

ð3Þ

The spread of the data was calculated as D90−D10, where D90 and D10

are the diameters of the 90th and 10th percentiles of the cumulativeparticle size distribution, respectively. The particle size span, Sx, whichgives a description of the width of the distribution and is independentof the median size, was calculated according to Eq. (4) [28]:

Sx =D90 − D10

D50ð4Þ

According to Fan et al. [28] if the span of the distribution is b2, it isconsidered narrow;≥2 but b3, moderate; and≥3, considered a broaddistribution. All spans calculated from the granulation data were lessthan 2, indicating that the breadth of the distributions were relativelynarrow.

Optical microscopy was used to examine the particle morphologyof the pure materials as well as the conventional wet granulationand foam granulation samples (Nikon SMZ 1500 digital camera usingAct-1 v.1 2.63 software (Micron Optics, Cedar Knolls, NJ) at 50×magnification.

All granulations were hand sieved using a mesh cut of #30/#80(595–177 μm) to eliminate oversize and fines and only particlesretained on #80 were used for the following characterizations and toprepare compacts. Using a narrow particle size range minimizedparticle size effects and improved comparability among the differentdrug granulations.

The true densities of dried, sieved granulations were determinedby a helium pcynometer (AccuPyc 1330, Micromeritics, Norcross, GA).The true densities used in the solid fraction calculations were theaverage of five determinations.

Surface area and average pore diameter were determined bynitrogen adsorption (Gemini 2380, Micromeritics, Norcross, GA) forpowdered formulations before conventional wet granulation (i.e.before water addition) and all dried granulations, which includesconventional wet granulation and foam granulation batches (i.e. afterwet granulation). Accurately weighed samples (1.0–1.3 g) weredegassed by nitrogen flow and dried at 60 °C overnight (VacPrep061, Micromeritics). The amount of nitrogen adsorbed was deter-mined at partial nitrogen vapor pressures (P/Po) ranging between0.05 and 0.98. Surface area was determined by the Gemini software

18 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

using the Brunauer, Emmett, and Teller (BET) isotherm calculation forthe nitrogen adsorption data in the P/Po range from 0.05 to 0.30. Poresize diameter was also calculated by the Gemini software using theBETanalysis (4×pore volume/surface area) for the adsorption data inthe P/Po range from 0.05 to 0.30 [29].

2.3. Mechanical characterization of granulations

The relative degree of brittleness or plasticity of a high drug loadgranulation can be calculated following the well established methodsof Hiestand [6,11,30,31]. Flawless square compacts were created usingtri-axial decompression. This method is selected due to its ability torelease elastic stresses in three dimensions following decompression.Three discrete tests are then subsequently performed on the compact,(tensile strength, dynamic indentation hardness, and chordal radius)and this combined information was used to calculate the Hiestandtableting indices. Conventional wet granulation formulations, bothbefore and after water addition (e.g., dried), and foam granulationbatches were characterized for their mechanical properties.

2.3.1. Preparation of square compacts by tri-axial decompressionSquare compacts of approximately 3.0 g measuring 2.0 cm×

2.0 cm×0.6 cm were prepared using a custom-built tri-axial decom-pression press. A split-die block was used along with a computer-controlled hydraulic system (Loomis Engineering and ManufacturingCompany, Caldwell, NJ). Compression forces ranged from 6000 to30,000 lb and a 10 s dwell time at maximum compression force wasused. The compression forces employed for aspirin, metformin, andAPAP granulations were 6000, 20000, and 30000 lb, respectively. Theedges of the die surface were sparingly lubricated with magnesiumstearate suspended in acetonewhen needed. For evaluating the brittlefracture index, a stress concentrator was also introduced in the centerof the compacts using an upper punch equipped with a 1.1-mmdiameter, round, spring-loaded retractable pin.

This tri-axial press allows for release of elastic stresses in threedimensions during decompression by allowing the split die to expandand hence to produce flawless compacts suitable for tensile strengthtesting. While the compact dimensions were measured with a caliperimmediately after ejection, compacts were allowed to undergo elasticrecovery for a 24 h period prior to testing. The solid fraction is definedas the proportion of solid material contained in the compact and wascalculated according to Eqs. (5a) and (5b). The pressure of the tri-axialpress was adjusted for each granulation to achieve a constant solidfraction of 0.90±0.01 or 10% porosity.

Apparentdensity ρapp: =compactweightcompact volume

ð5aÞ

Solid fraction =ρapp:

ρTð5bÞ

where ρT represents the average true density of the granulationdetermined in Section 2.2.

2.3.2. Determination of tensile strengthAn Instron® Model 5567 stress–strain analyzer equipped with a

30 kN load cell and using a Bluehill® software (version M-K2-ENRevision B, Norwood, MA) was used for tensile strength (σT) testing ofcompacts according to Eq. (6):

Tensile Strength N=m2� �

=Peak Force

lenght Twidthð Þ ð6Þ

The ramp rate was set at 1.0 mm/min and the failure wasdetermined both by when the true strain was ≤10% and when thecompressive load threshold fell below 5 N. Testing was performedunder transverse compression between two platens eachwith awidth

of 0.4 times the compact width; and a vertical fracture through thecenter of the compacts indicated that the failure occurred in tension.The platens were padded with cardboard paper to decrease thestress concentration at their edges and this minimized the shearfailure of the compact [32]. The time constant between loading tofracture process was set at approximately 10 s, which is the amountof time between 1/e, or 0.368, of the fracture force and the timeof the fracture force (the mathematical constant, e, has a value of2.718).

The tensile strengths of compacts without holes (σT) and ofcompacts with holes (σTo) were measured. A total of at least 6compacts were tested for each granulation and the average was usedto calculate the Hiestand tableting indices.

2.3.3. Dynamic indentation hardnessThe dynamic indentation hardness (H) test employed a custom-

built pendulum impact device using a steel sphere with a weight of0.0618 g as the indenter, which was suspended from a one-meterlength of 15-pound fishing line. The face of the compact is coveredwith a small strip of carbon paper before being clamped onto thetesting platform. The sphere is held in place by an electromagnet andthen released, once the sphere impacts the compact, the carbon istransferred to the dent and enables easier viewing. The short dwelltime of the indenter acting on the compact minimized any strain-ratedependent effects. The inbound and rebound velocities in m/s of thesphere were measured using an optical ballistic sensor and areconverted into the initial height, hi, and rebound height, hr, by usingEq. (7):

h =velocityð Þ22 × g

=velocityð Þ219:62

: ð7Þ

The degree of rebound of the sphere occurs as a result of the elasticmodulus or hardness of the material [32]. The chordal radius of theindentation was determined using a Mahr Federal PerthometerConcept #3754341 (Gottingen, Germany) equipped with a dia-mond-tip stylus to trace through the surface roughness of the indenton the compact. Two measurements were taken per compact byrotating each sample by 90°. A total of 10 measurements weretaken for the chordal radius of each granulation and the averagescalculated. At least 5 compacts were tested for each granulation andthe dynamic indentation hardness (H) was calculated according toEq. (8):where:

H =4mgrhrπa4

hihr

− 38

� �ð8Þ

where:

m mass of the indenter,g gravitational constant,r radius of indenter,hi initial height of indenter,hr rebound height of indenter, anda chordal radius of the dent.

2.3.4. Hiestand tableting indicesThe worst-case bonding index (BIw) is calculated according to Eq.

(9):

BIw =σT

Hð9Þ

where σT is tensile strength and H is the dynamic indentationhardness.

Fig. 1. Granulation power plots for the different drugs (A) wet granulation and (B) foam granulation.

Fig. 2. Optical microscopy pictures of APAP particle morphology. Pure material (P), wetgranulation (W), and foam granulation (F).

19S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

The brittle fracture index (BFI) is the ratio of the tensile strength ofthe compacts without a hole, (σT), and with a hole, (σTo), at theircenter and is given by Eq. (10):

BFI =σT

2σTo− 1

2

� �ð10Þ

The BFI scale ranges from zero, which represents highly ductile/plastic materials, to one, which indicates highly brittle materials thatshow a greater propensity to cap or laminate during decompression/ejection [33].

3. Results and discussion

3.1. Granulation particle size

For a given drug, impeller power vs. time plots were higher forconventional wet granulation (Fig. 1A) than foam granulation(Fig. 1B). During conventional wet granulation, water droplet sizecan influence the extent of development of large granules or oversizeand binder distribution at short mixing times [34]. However, Ax et al.[34] also noted that the distinction between spraying binder liquidwith different droplet sizes becomes less pronounced on thegranulations as process time increases. This is likely due to the factthat competing breakage and re-agglomeration phenomena will beoccurring simultaneously during high-shear mixing. Furthermore,conventional wet granulation typically involves areas of localized overwetting of particles which then become agglomerated. Therefore, inorder to optimize particle size distribution and improve flow proper-ties, conventional wet granulations usually require a milling operationafter drying. Interestingly, the foam process showed a less steep slopefrom the power profile and lower power consumption compared toconventional wet granulation particularly for metformin and aspirin.This suggests less viscous granulation and more controlled initialgranule growth for these two drugs due to improved binderdistribution and less localized over wetting during foam granulationas compared to conventional wet granulation. Water added via theconventional drip method have larger droplet sizes compared to abinder solution added as aerated foam. On the other hand, APAPpower consumption profiles for both the conventional wet granula-tion and foam granulations were more similar; therefore, the effect oflocalized over wetting was not as pronounced for conventional wetgranulation of APAP.

Keary and Sheskey proposed the hypothesis of foam granulationand how the foamed binder circumvents localized overwetting duringconventional wet granulation [1]. A foam is by definition, air dispersedin a liquid continuous phase. In foams prepared using the same liquid,this phase inverted relationship of liquid-to-air is significant and

increases the surface area per gram of liquid several fold compared tothe sprayed system. Furthermore, foam has the capacity to spreadrather than to soak (i.e. a low soak-to-spread ratio), and particles thatare initially non-coated become surface-coated by the spreading foam.

20 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

This is in contrast to the conventional wet granulation process wherethe dry binder is dispersed in the powder bed and larger waterdroplets are dripped or sprayed on top of the particles. In this case, thespray droplets are typically of the same size range as the powders tobe granulated.

In general, there appeared to be some level of primary particleagglomeration in all three drug samples for both granulationprocesses. However, it is unclear whether there are differences inthe spatial distribution and thickness of the binder solution aroundthe granules in the conventional wet as compared to foam granulationprocesses. It appears from the optical microscopy pictures that thegranulation processes had the most effect on the APAP particlemorphology and physical properties (Fig. 2). While pure APAP (P) is acohesive, poorly flowable powder comprised of acicular needles, thisdrug became appreciably less cohesive following either conventionalwet (W) or foam granulation (F) processes. Furthermore, there alsoappeared to be some particle agglomeration occurring in addition tothe distribution of uneven binder for both APAP granulation samples.While there was some primary particle agglomeration occurring onlywith the smaller size fractions of aspirin in conventional wet (W) andfoam granulation (F) samples (Fig. 3), granules from the twogranulation processes appeared similar. Pure metformin (P) (Fig. 4)showed a heterogeneous mixture of particle size and shape. Both

Fig. 3. Optical microscopy pictures of aspirin particle morphology. Pure material (P),wet granulation (W), and foam granulation (F).

Fig. 4.Optical microscopy pictures of metformin particle morphology. Purematerial (P),wet granulation (W), and foam granulation (F).

metformin granulations showed similar particle agglomeration,however, there appeared to be an appreciable reduction in theamount of fines for metformin granulations relative to APAP andaspirin granulations.

Geometric mean diameter (dg) and geometric standard deviation(σg) were similar for both conventional wet and foam granulationprocesses for a given model drug (Table 2). Among the three drugs,APAP granulations processed by both conventional wet and foamgranulation exhibited the smallest granule size as compared tometformin and aspirin (Table 2). Granule particle size distributionsof the model drugs are illustrated in Fig. 5A–C. Generally, the higherpercentage of larger granules for aspirin and metformin compared toAPAP can be attributed to the relatively larger particle sizes of thesepurematerials (P) (Figs. 3 and 4). Comparedwith the other two drugs,the APAP granulations had the greatest percentage of fines, ca. 10%b74 µm (Fig. 5A) and a wider span (Table 2). It is interesting to notethat the foam granulation process yielded a higher proportion oflarger particles (≥500 µm), for the APAP and metformin samples.This, together with the generally lower impeller power current vs.time plots observed for the foam granulation process (Fig. 1), suggestthat other factors other than drug mechanical properties, such as drugsurface hydrophlicity/hydrophobicity and wettability can influence

Table 2Physical characterization of granulations for three model drugs.

Geometric meandiametera andgeometric standarddeviationb (μm)

Spreadof data(μm)c,d

Spanof datac,d

LOD%

Surfacearea(m2/g)

Averageporediameter(nm)

Dried granulationsConventional Wet

Metformin 421.0 (1.7) 505.6(2.5)

1.20(0.02)

0.9 0.17 6.7

Aspirin 541.6 (1.5) 483.9(0.5)

0.86(0.05)

1.7 0.19 4.5

APAP 147.7 (1.9) 215.4(0.7)

1.61(0.00)

0.8 0.29 7.8

FoamMetformin 507.9 (1.6) 503.9

(1.6)0.99(0.01)

1.3 0.13 7.4

Aspirin 452.1 (2.2) 539.4(4.1)

1.44(0.15)

2.0 0.16 4.1

APAP 157.8 (2.0) 232.3(0.8)

1.47(0.01)

1.1 0.28 10.1

Powder before wet granulationMetformin – – – – 0.213 10.20Aspirin – – – – 0.180d 8.7d

APAP – – – – 0.304 8.99

a Geometric mean diameter, (dg).b Values in parenthesis represent the geometric standard deviation, (σg).c Values in parenthesis represent the arithmetic standard deviation.d Values are the average of 2 measurements.

21S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

the granulation properties and granule growth during the 2 granula-tion processes. It will be worthy to probe these factors and determineif these are different during the 2 granulation process in future studies.

Fig. 5. Particle size distributions for (A) APAP, (B) aspirin, and (C) metformin,conventional wet granulation vs. foam granulation.

3.2. Surface area and pore diameter

The surface area of a granulation is an important physical propertythat can affect granule flowability as well as final tablet hardness. Thesurface area results for metformin and aspirin sieved granulationswere similar, while sieved APAP granulations had a smaller meanparticle size and a larger surface area than metformin and aspirin. Inorder to investigate the effects of wet granulation and the method ofgranulating liquid addition on the powder formulations, surface areaand pore diameters were also measured for the dry powderformulations before granulation (Table 2). Generally, there wereminimal changes in the surface area and pore diameter results for allsamples, and when comparing between the two granulationprocesses.

While all granulations were dried to b2.0% LOD for 6 h, to furtherinvestigate the effect of over-drying aspirin formulation prepared byconventional wet granulation, a batch was dried for an additional 6 hto study the effect of additional drying time on the mechanicalproperties of the granulation. The surface area and pore diametervalues for the aspirin granulation dried for 12 h (LOD 1.9%) were0.05 m2/g and 3.2 nm, respectively. However, for the aspiringranulation dried for 6 h (LOD 1.7%), the surface area and porediameter values were 0.19 m2/g and 4.5 nm, respectively. While thepore diameter remained essentially unchanged, this additional dryingtime for the aspirin conventional wet granulation sample caused asignificant reduction in the surface area. This can be attributed to thedrying process that removes the added water first from the surfaceand then from the pores within the particles. As the internal waterwas removed from the structure, the granules begin to densify due tothe collapsing of their pore structure. Even though there is a negligibleLOD difference between aspirin granulations dried for either 6 or 12 h,such granule densification will likely have a major impact on the

mechanical properties of these conventional wet granulations. This isdiscussed further in Section 3.3.

3.3. Mechanical properties of granulations

Mechanical properties of compacts from all granulations werecharacterized by their dynamic indentation hardness, tensilestrengths, BIw, and BFI values (Table 3). The dynamic indentationhardness (H) indicates the resistance of a material to permanentplastic deformation under a compressive load andwill vary dependingon the ductility or brittle nature of the material. The tensile strengthrepresents the strength of a compact after permanent plasticdeformation has occurred and gives an indication of the extent ofintra-particulate bonding due to true contact areas formed betweenthe surfaces. In evaluating the different processes for metformin, foamgranulation showed a higher H, while the tensile strength was the

Table 3Mechanical characterization of granulations for three model drugs.

Dynamic hardness(H) N/m2 109

Tensile strengthN/m2×106

BIw10−3

BFI

Dried granulationsConventional Wet

Metformin 0.4 (0.01)a 0.7 (0.0) 1.7 0.001Aspirin wet (6 h drying) 0.1 (0.0) 0.7 (0.0) 7.0 0.002Aspirin wet (12 h drying) 0.2 (0.0) 0.7 (0.0) 3.5 0.1APAP 0.5 (0.01) 0.7 (0.16) 1.6 0.02

FoamMetformin 0.7 (0.01) 0.7 (0.0) 1.0 0.1Aspirin 0.1 (0.0) 0.7 (0.0) 8.9 0.5APAP 0.3 (0.0) 1.0 (0.03) 3.8 0.005

Powder before wet granulationMetformin – 0.03 (0.31) – 0.81Aspirin 0.08 (0.00) 0.4 (0.15) 4.7 0.08APAP 1.2 (0.01) 0.7 (0.0) 0.55 0.06

a Values in parenthesis represent the arithmetic standard deviation.

22 S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

same for both processes. However, the higher H values resulted in alower bonding index, BIw for the foam granulation suggesting that thisprocess may not be beneficial for metformin. Lower BIw indicates lessplastic deformation behavior and lower ability of intra-particulatebonds formed during the compression phase to survive during thedecompression process.

Compacts were prepared from the metformin formulations beforeconventional wet granulation (dry powder) as well as after conven-tional wet granulation (dried) in order to compare their tensilestrength values (Table 3). The average peak strengths of the beforeand after conventional wet granulation samples were 10.5 N/m2 and272 N/m2, respectively; which corresponds to tensile strength valuesof approximately 0.026×106 N/m2 and 0.7×106 N/m2, respectively. Itis interesting that after conventional wet granulation, the metforminformulation displayed roughly a 27-fold increase in the tensilestrength of the compacts. This significant increase in tensile strengthwith the addition of water from the conventional wet granulationprocess indicates that metformin has viscoelastic properties. Based onthe data thus far, the conventional wet granulation process offers themost benefit for metformin in terms of improvement in mechanicalproperties.

A brittle material will resist permanent deformation and hence,show a smaller indentation from the sphere, with a resultant smallerchordal radius. Also, less of the impact energy will be absorbed by abrittlematerial and that will result in a higher rebound velocity. This isin contrast to a compact composed of a ductile material. Such a plasticcompact is relatively softer and will deform around the sphere,absorbing its impact energy and leaving a much larger dent, thereforedisplaying a larger chordal radius.

Different properties were observed for aspirin, a known ductilematerial. For the conventional wet granulation process three sampleswere evaluated; before granulation (without any added water), aftergranulation dried for 6 h, as well as the granules over-dried for 12 h.The conventional wet granulation sample that was over-dried for 12 hbehaved very differently. The extra drying time caused the granulesurface area to collapse. Therefore, as the water evaporated fromwithin the pores of the particles, the particles became denser, harderand more brittle. This is clearly seen in the doubling of the dynamichardness value (H).

Furthermore, interesting relationships were observed whenexamining the chordal radius and rebound velocity data for thedifferent aspirin granulations. While the chordal radii and reboundvelocities were similar in both the 6 and 12 h granulations, the chordalradius for the aspirin foam granulationwas approximately 30% higher

than for either conventionally wet granulated sample, indicatingenhanced plasticity. The chordal radius determined from the aspirinbefore granulation compact was slightly less than the value from thefoam granulated compact. Thus, while the foam granulation processappears to enhance the plasticity of aspirin, the conventional wetgranulation process decreases its plasticity. However, the reboundvelocity data offers some contrasts. The highest rebound velocitieswere obtained for the aspirin before wet granulation sample and thelowest values observed were for the aspirin granulations dried foreither 6 or 12 h. This data indicates that the conventionally wetgranulated samples are more ductile than either the aspirin beforewet granulation or the foam granulated sample. The contrastsbetween the chordal radius and rebound velocity results supportthe likelihood that aspirin undergoes a mixed deformationmechanism.

In their study comparing microcrystalline cellulose granulatedwith 3% HPC, Badawy et al. [8] found that there was a significantdecrease in the surface area when comparing under-granulated withover-granulated samples; 0.91 m2/g vs. 0.53 m2/g, respectively. Theauthors reported that the difference in surface area can impact andreduce the compactability of the microcrystalline cellulose to varyingdegrees.

Similarly, lactose, an excipient with some brittle character, showedlowered compactability after being over-granulated with excess waterand high-shear forces. The reason for this effect was found to be theinability of the larger, denser granules with reduced surface area tosignificantly fracture or deformwhen subjected to a compressive load[35,36]. It is noteworthy to also mention that the extent of brittlecharacteristics and thereby the mechanical properties can vary quitesignificantly depending on the preparation method of the grade oflactose selected [37,38]. In addition, such brittle excipients can cause adecrease in tablet crushing strength due to the fact that thesematerials are characteristically harder and tend to be poor at formingstrong inter-particulate bonds [39].

There were significant differences in dynamic hardness betweenthe two granulation processes for APAP, the model drug known toundergo brittle fracture. The results showed that the powder beforeconventional wet granulation had the highest H value of all thesamples tested, indicating the brittle character of APAP. However, thedynamic hardness was reduced by N50% after conventional wetgranulation and further still after foam granulation (Table 3).Furthermore, it was only for APAP that an improvement in tensilestrength was observed when comparing after granulation samplesfrom the conventional wet and foam granulation processes to beforegranulation samples. Tensile strength value of 1.0 N/m2 for APAP foamgranulation was the highest of all the granulations. These resultsindicate that for a brittle drug such as APAP, the foam process is moreappropriate to improve the mechanical properties of the drug. Thismay be attributed to the higher surface area of solution in the form oftiny bubbles of foam that enabled a more uniform distribution of theplastic binder to cover the drug granules, thus modifying theirmechanical properties more effectively.

3.4. Hiestand tableting indices

The BIw and BFI values can be used to further elucidate whichgranulation process is best suited to improve the intrinsic mechanicalproperties of the drug. These two indices have an inverse relationship;therefore, a higher BIw and/or a lower BFI are indicative of plasticdeformation behavior. BIw and BFI values of the formulations are listedin Table 3.

In comparing the conventional wet and foam granulations formetformin, the conventional wet granulation (after) sample yieldedthe highest BIw as well as the lowest overall BFI value of 0.001. On theother hand, the powder blend before conventional wet granulationshowed the highest overall BFI value of 0.81. The addition of water in

23S.L. Cantor et al. / Powder Technology 195 (2009) 15–24

the conventional wet granulation process dramatically improved theBFI value of metformin by 800-fold and showed markedly improvedplasticity as compared with the powder blend before granulation.These results were also an improvement over the foam granulationprocess. This supports the data discussed previously that conventionalwet granulation is the best process for this drug (Table 3). BIwmeasures the survival success of true contact areas formed atmaximum compressive stress; viscoelastic materials such as metfor-min will produce compacts with higher tensile strengths due toenhanced intra-particulate bonding in the presence of highermoisture levels. BFI indicates the ability of a material to relieve stressby plastic deformation in accordance with the Griffith crack propaga-tion theory. If the BFI is less than 0.2 there will typically be no cappingor lamination. However, if the BFI is N0.2 in conjunctionwith poor BIwvalues, there is a greater probability of capping or lamination [4,11].

Among the aspirin granulations, the lowest BIw value of 0.0035was observed for the over-dried, low surface area (0.05 m2/g)conventional wet granulation sample, indicating relative brittlebehavior. This effect has been previously reported for conventionallywet granulated microcrystalline cellulose where the authors foundthat dense, less porous granules would be less prone to fragmentationor plastic deformation during compression [8]. A comparison of BIwand BFI values before and after conventional wet granulation (6 hdrying) indicated that the aspirin formulation improved in plasticityafter conventional wet granulation. Foam granulated aspirin exhibitedthe highest BIw value of 0.0089 of all the granulations. However, theBFI value of 0.5 observed for foam granulated aspirin was high giventhat aspirin is known to be ductile. Therefore, the deformationbehavior of the aspirin foam granulation can be considered asanomalous or mixed, showing both plastic and brittle characteristics.Phenacetin, a drug known to exhibit a brittle deformation behavior,was reported to demonstrate very similar results to the aspirin foamgranulation with 0.0088 and 0.43 for BIw and BFI values, respectively[11]. High BIw and BFI values also suggest a mixed deformationmechanism for phenacetin. However, Hiestand classified phenacetinas a “normal” material that compresses in a viscoelastic manner [31]whereas APAP, a brittle drug, would be classified as a “special case”material. Special case materials exhibit extremely poor tabletingcharacteristics because their particles are very hard and bondingbetween them is very weak. Additionally, special case particles do notdeform plastically under compressive load to form bonding surfaces.Instead, particles easily rearrange by sliding past each other. Thisoccurrence leads to greatly diminished inter-particulate bonding andlow tensile strength of compacts [23,31].

In comparing BIw and BFI values of APAP before and afterconventional wet granulation a three-fold increase in the BIw and athree-fold decrease in the BFI value was observed after granulation.This suggested some beneficial effect of the conventional wetgranulation process in improving the plasticity of this brittle drug.However, the foam process further resulted a two-fold increase in theBIw coupled with a decrease in BFI of granulated APAP over theconventional wet granulation process, indicating that this is the bestprocess to improve the mechanical properties of this drug. Theseresults can be attributed to the fact that the foamed binder has anenhanced surface area compared with water alone. Therefore, HPC,being a surface-active binder with ductile characteristics, can morehomogeneously coat the APAP granules containing this brittle drug.Thus, by improving the intrinsic APAP granule plasticity the mechan-ical properties of the compacts were also improved.

4. Conclusions

The physico-mechanical properties of high drug load granulationsmanufactured using conventional wet granulation or foam granula-tion techniques were studied. Thus, influence of binder deliverytechniques on granulationmechanical properties of the 3model drugs

was determined. While there do not appear to be major differences insurface area and pore size for the different granulation batches, therewere discernible differences in their mechanical properties. The foamprocess appeared to significantly enhance the plasticity of a granula-tion containing a brittle drug such as APAP. However, foam granula-tion with a ductile drug like aspirin produced a material with mixeddeformation behavior based on the high BIw and BFI values. This is incontrast to the conventional wet granulated aspirin that showed aninverse relationship between high BIw and low BFI values.

Foam granulation did not enhance the plasticity for viscoelasticmaterials like metformin and the conventional wet granulationprocess was observed to confer the greatest advantage for metformin.The increase in plasticity for foam granulated formulations may bedue to the improved surface coverage of HPC on the drug particles ascompared to the conventional wet granulation process. In conclusion,the selection of the most appropriate granulation process (conven-tional wet or foam) to improve a drug product's manufacturability canbe guided by knowledge of the intrinsic mechanical properties of thedrug.

Acknowledgements

The authors would like to acknowledge BMS for providing theopportunity and summer internship funding to S. Cantor to conductthis work and also to the BMS foam granulation team membersespecially F. Nikfar; C. Keary and P.J. Sheskey (Dow Chemical) for theirtechnical input and assistance.

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