A review of the terms agglomerate and aggregate with a recommendation for nomenclature used in...

COMMENTARY

A Review of the Terms Agglomerate and Aggregate witha Recommendation for Nomenclature Used in Powderand Particle Characterization

GARY NICHOLS,1 STEPHEN BYARD,2 MARK J. BLOXHAM,3 JOANNE BOTTERILL,4 NEIL J. DAWSON,1

ANDREW DENNIS,5 VALERIE DIART,6 NIGEL C. NORTH,7 JOHN D. SHERWOOD8

1Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, England

2Sanofi-Synthelabo Research, Alnwick Research Centre, Willowburn Avenue, Alnwick, Northumberland NE66 2JH, England

3GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, England

4AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, England

5Bristol-Myers Squibb, Pharmaceutical Research Institute, Reeds Lane, Moreton, Wirral CH46 1QW, England

6Aventis Pharma, London Road, Holmes Chapel, Crewe, Cheshire CW4 8BE, England

7GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, England

8AstraZeneca, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, England

Received 4 December 2001; revised 25 February 2002; accepted 25 March 2002

ABSTRACT: The terms ‘‘agglomerate’’ and ‘‘aggregate’’ are widely used by powder tech-nologists to describe assemblages of particles that are found in dry powders and powdersin liquid suspensions. Each term has a specific meaning but, unfortunately, they arefrequently interchanged at will and this has resulted in universal confusion. Thisconfusion is perpetuated by conflicting definitions in national and international stan-dards and this presents problems when describing powder properties or communicatingresults in reports and research papers. This paper reviews the current status of thedefinitions, with particular emphasis on their use in the pharmaceutical industry. It isproposed that just one term, agglomerate, should be used to describe an assemblage ofparticles in a powder and that the term aggregate should be confined to pre-nucleationstructures. � 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci

91:2103–2109, 2002

Keywords: agglomerate; aggregate; nomenclature; particle assemblage; powdercharacterization; powder properties

INTRODUCTION

The terms ‘‘agglomerate’’ and ‘‘aggregate’’ arewidely used by powder technologists to describeassemblages of particles that are found in drypowders and powders in liquid suspensions. Each

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 10, OCTOBER 2002 2103

Correspondence to: Gary Nichols (Telephone 1304 643925;Fax: 1304 653909; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 91, 2103–2109 (2002)� 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

term has a specific meaning but, unfortunately,they are frequently interchanged at will and thishas resulted in universal confusion. This confu-sion presents problems when describing powderproperties or communicating results in reportsand research papers. Some powder technologistshave strong views about the use of these terms,whereas others (probably most) do not care oreven consider their correct use.

As will be shown in this paper, during the lastfew decades, many attempts have been made todefine agglomerates and aggregates so that aconsistent, universally accepted terminology isused. However, these attempts have been ignoredand, to complicate matters, there is even an in-consistency in the way that national and interna-tional standards organizations use the terms. Inthis paper, we review the current status of thedefinitions and propose that just one term shouldbe used to describe an assemblage of particles.

Although we are specifically interested andconcerned about the correct use of these terms inthe pharmaceutical industry, other manufactur-ing industries (e.g., pigments, coatings, cement,food, minerals, and agrochemicals) also use thenomenclature in an inconsistent manner. A majorreason for the confusion and indiscriminate use ofthe terms agglomerate and aggregate is probablythat scientists and technologists learn a definitionin one industry, then moving to another, applytheir existing knowledge. As a consequence, mostpharmaceutical companies will have their own‘‘in-house’’ preference for the use of the two terms.

In an attempt to harmonize particle nomencla-ture, especially within the pharmaceutical indus-try, members of the Particle Characterizationsubgroup of the Pharmaceutical AnalyticalSciences Group (PASG) in the UK have collabo-rated to prepare this paper and support itsrecommendations.

EXISTING DEFINITIONS OF AGGLOMERATEAND AGGREGATE

Any powder will generally consist of a complexmixture of primary particles (i.e., discrete parti-cles) and particle assemblages in the form ofagglomerates and aggregates. Some particleswill be single primary particles (possibly as well-formed crystals or irregular-shaped fragments)and others will be assemblages of primary par-ticles. The latter may behave like primaryparticles or, alternatively, they may disassembleto yield primary particles. Under some circum-

stances, they may fracture when stressed (e.g.,mechanical or sonication) to give particles havingshapes and sizes that are completely unrelated tothe primary particles. To fully understand thesedifferent particle behaviors and how they influ-ence the development of pharmaceutical pro-ducts, unambiguous definitions are essential.

The Oxford English Dictionary1 has the follow-ing definitions for the terms agglomerate andaggregate:

� Agglomerate [from the Latin agglomerare(glomus-meris ball)]. Gathered into a ball orcluster; collected into a mass.

� Aggregate [from the Latin aggregare herdtogether (grex gregis flock)]. A mass formedby the union of individual particles; an as-semblage, a collection.

These English dictionary definitions suggest thatan agglomerate consists of loosely coherent par-ticles, whereas an aggregate consists of particlesthat are united in a much stronger way. However,these definitions are not specific enough and aresubject to interpretation; hence the confusion thatprevails in their usage.

The Chambers Science and Technology Dic-tionary2 defines agglomerate and aggregate asfollows:

� Agglomerate¼ assemblage of particles rig-idly joined together, as by partial fusion(sintering) or by growing together.

� Aggregate¼ assemblage of particles whichare loosely coherent.

In 1966, Gerstner3 defined assemblages ofpigment particles as follows:

� A primary particle can exist as a single crys-tal or as a crystal composed of crystallites.

� An agglomerate is a loose arrangement ofprimary particles or aggregates or a mixtureof the two attached, for instance, at thecorners and edges. The total surface isidentical with the sum of the surfaces of theindividual particles.

� An aggregate consists of primary particlesattached at their surfaces. The surface ofsuch an aggregate is smaller than that of thesum of the surfaces of the primary particlesor, in other words, the inner surface of anaggregate is either completely inaccessible oronly partially accessible.

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Gerstner also included diagrams of primaryparticles, aggregates, and agglomerates, whichclearly distinguish between them.3 Gerstner’sdefinitions (which were also in accordance withthe nomenclature of a draft proposal of theGerman Standards Organisation during the1960s) are probably the most descriptive tobe published to date. From these definitions, ag-glomerates can be distinguished from aggregatesbased on the way that the constituent particlesarebound togetherandtheir relative surface areas.Many powder technologists have not adopted suchexplicit definitions and, as a consequence, we havethe current situation whereby the terms are poorlyunderstood and are interchanged.

To exacerbate the confusion in the use of theterms, the British Standards Institution4 usesthem in the opposite sense to the InternationalStandards Organisation:6

BS 2955:1993.� Agglomerate¼ an assembly of particles

rigidly joined together as by partial fusion,sintering or by growing together.

� Aggregate¼ an assembly of particles whichare loosely attached to each other.ISO 14887.

� Agglomerate¼ assemblage of particleswhich are loosely coherent.

� Aggregate¼ assemblage of particles rigidlyjoined together.

In ISO 14887, the following note is included:‘‘Because of the confusion which exists in the useof the above terms they are used sparinglythroughout the text.’’

To add more confusion, ISO 14887 has yetanother term that covers both agglomerate and

aggregate; that is, clump, which is defined asfollows:

� Clump¼ an assemblage of particles whichare either rigidly joined or loosely coherent.

Within the pharmaceutical industry, the onlypharmacopoeia to define particle assemblages isthe United States Pharmacopoeia (USP)6 and thisdefines the terms as follows:

USP 24 2000.� Agglomerate¼ fused or cemented particles.� Aggregate¼mass of adhered particles.

Clearly, the USP definitions are in accord withthose given in BS 2955:1993. The European Phar-macopoeia (Section 2.9.14 ‘‘Specific Surface Areaby Air Permeability’’) does not provide formaldefinitions.7 However, it is implied that agglo-merates are loosely bound assemblages that canbe readily dispersed.

Without a doubt, there is great confusion aboutthe terms, although individual sources are ada-mant that theirs is the correct usage! To compli-cate matters more, Van Hook8 even interchangesthe two terms within his book. Mullin,9 in hisclassic textbook on crystallization for chemicalengineers and industrial chemists, recognizes theconfusion and so avoids any distinction by onlyusing the term agglomeration to describe cluster-ing of small particles (in liquids). A summary ofthe use of the terms from seven literature sourcesis given in Table 1.

In addition to agglomeration and aggregation,the terms flocculation, coalescence, and coa-gulation can also be used to describe the statesof particle assemblage. However, these terms

Table 1. Summary of the Use of the Terms Agglomerate and Aggregate from Seven Literature Sources

Source

Assemblage of particles that isloosely bound with particles thatare loosely attached by contact

at their corners and edges.Readily dispersed

Assemblage of particles that isrigidly bound with particles thatare firmly attached at their faces

by fusion, sintering or growth.Not readily dispersed

BS 2955: 19934 Aggregate AgglomerateISO 148875 Agglomerate AggregateUSP 24 2000 (Monograph 776)6 Aggregate AgglomerateChambers Science and Technology

Dictionary (1988)2Aggregate Agglomerate

A. Van Hook (1961)9 Aggregate AgglomerateW. Gerstner (1966)3 Agglomerate AggregateJ.W. Mullin (1993)8 Agglomerate

USE OF TERMS AGGLOMERATE AND AGGREGATE 2105


tend to be used most frequently by colloid chemistswhen referring to charged species in a liquid andwill not be considered further in this paper.

The term aggregation is also used by chemiststo describe the process of supramolecular assem-bly in which molecules associate into pre-nuclea-tion structures that have the potential to growinto crystals.10

We should therefore consider confining the useof the term aggregation to those processes thatoccur prior to crystal nucleation and agglomera-tion to describe post-nucleation processes.

HOW DO PARTICLE ASSEMBLAGES OCCUR?

Primary particles can unite into assemblages as aresult of fusion, sintering, or interparticle bond-ing and growth (caking). They may combine dur-ing crystallization in the mother liquor, duringfiltration, during drying, during milling, or duringstorage of the finished bulk powder. The finalassemblages are polycrystalline (for crystallinesubstances), often with primary particles joined ina random array, but they may also be twins (i.e.,multiparticle assemblages that are not randomlyjoined but share definite crystal planes or crystal-lographic axes).

Postmilling changes can occur because milledparticles have highly energetic surfaces that canreadily adsorb small amounts of water. This ad-sorbed water can induce partial dissolution thatresults in recrystallization at the particle surfaceas it attempts to lower its high energy state.Alternatively, the plasticizing effect of the watermay lower the glass transition temperature ofamorphous material at the surface, also resultingin recrystallization. The latter is particularlyevident for some micronized drug powders whenparticles in direct contact with each other can fuseor sinter together to form larger lumps.11

AGGLOMERATES OR AGGREGATES,DOES IT MATTER WHAT THEY ARE CALLED?

The terms agglomerate and aggregate are quali-tative and have been interchanged by mostresearchers (without any thought as to what theyactually mean) for so long that it probably nolonger matters how they are used. If nationaland international standards organizations cannoteven agree amongst themselves, then there islittle hope or expectation for anyone else to agree!Unless there are ways to quantitatively measure

the degree of association of particles in an as-semblage, then it is difficult to establish if it is anagglomerate or an aggregate.

Is there a need to try and discriminate betweenagglomerates and aggregates and, if so, whatpractical benefit does it give us? There are noformal or unequivocal, universally adopted, defi-nitions of the terms ‘‘aggregate’’ and ‘‘agglomer-ate’’ that are suitable for use in distinguishingbetween different particle characteristics. It isevident that descriptors of particle behavior arerequired for manufacturing processes becauseof the downstream consequences of using parti-cles with different assemblages. The attempts byvarious groups to formalize definitions of agglom-erate and aggregate also reflect this need. How-ever, even with the availability of publishedformal definitions, it is likely that the terms agglo-merate and aggregate would be used interchange-ably because, intuitively, the words have a verysimilar meaning. There is also no real foundationto assign definitions to make the required distinc-tion between particle behaviors.

We therefore propose that for powders, use ofthe term ‘‘aggregate’’ is discontinued and the term‘‘agglomerate’’ is used exclusively. Where neces-sary, it may be useful to distinguish between ‘‘softagglomerates’’ and ‘‘hard agglomerates’’ and asimple microscopic test to do this is describedlater. Soft agglomerates are friable and readilydispersed, whereas hard agglomerates are non-friable, gritty, and not readily dispersed. In termsof the definitions used by Gerstner,3 a softagglomerate would be equivalent to an agglomer-ate and a hard agglomerate would be equivalentto an aggregate. Of course, most powders willcontain a mixture of these in varying proportions,so if it is not practical (or beneficial) to distinguishbetween them, then the term ‘‘agglomerate’’ alonewill suffice.

In this paper, we have made reference tothe situation where agglomerates (i.e., hard ag-glomerates) can fracture under applied stresses(mechanical or sonication) to yield fragments thatare unrelated to the shapes of the primaryparticles. Such particles could be referred to as‘‘brittle agglomerates.’’

By using just a single descriptive term, therecan be no confusion or uncertainty when describ-ing the nature of particle assemblages in a powder.As already mentioned, in ISO 14887, the term‘‘clump’’ is also defined and this single wordcaptures all aspects of aggregates and agglomer-ates. Therefore, we also suggest that the use of the

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word ‘‘clump’’ is discontinued and simply replacedwith ‘‘agglomerate.’’

IS IT IMPORTANT TO BE ABLE TODISTINGUISH BETWEEN SOFT ANDHARD AGGLOMERATES?

Soft agglomerates will not (in general) influencethe properties of a bulk powder because they willtend to be broken up by relatively mild forcesduring processing. Indeed, soft agglomeratesmay actually aid powder flow by making it morecohesive.

Hard agglomerates in a powder can behave asdiscrete, polycrystalline particles and will tendto be larger than primary particles. As a con-sequence, the presence of hard agglomerates canhave a profound, and possibly an adverse, effecton the behavior of a powder (e.g., lowering dis-solution rate, affecting flow, or reducing cohesive-ness). Hard agglomerates are unlikely to bedispersed during bulk powder processing (e.g.,powder transfer or blending) and so their pre-sence needs to be monitored to ensure that apowder has a controlled particle size distribution.Indeed, breakage of hard agglomerates may onlybe achieved by milling. Therefore, it may beimportant to be able to identify the presence ofhard agglomerates. In some industries, especiallypaint and ink manufacture, the presence of hardagglomerates above a certain size is a distinctdisadvantage because they can have an adverseeffect on the color strength and appearance of thedried paint or ink film.3

The presence of hard agglomerates in a drugproduct may ultimately change its bioavailabil-ity profile compared with that of an equivalentproduct comprising solely of soft agglomerates.This suggestion is based on the assumption thatsoft agglomerates will readily disintegrate intomany smaller particles to provide an increasedsurface area and, by implication, an increasedinstantaneous solubility.

The filling of a soft gelatin capsule with a drugproduct suspension requires that the solid parti-cles be less than a specified size related to thethickness of the capsule shell. This is important toensure that good contact is made between the twohalves of the shell during manufacture to providethe necessary containment and product protec-tion. In this case, the degree of particle disin-tegration during formulation, prior to capsule fill,needs to be assessed, and this should be includedas part of the particle characterization process.

HOW CAN WE ESTABLISH THE PRESENCEOF AGGLOMERATES IN A POWDER?

Methods used to distinguish between soft andhard agglomerates rely on the fact that softagglomerates will readily disperse into primaryparticles, whereas hard agglomerates may remainas gritty lumps even after considerable shearforces are applied. It may be a matter of monitor-ing the ease with which the particle size distribu-tion of a powder changes (i.e., an increase in finescontent) when it is subjected to a dispersion pro-cess (e.g., sonication, wetting, or the application ofmechanical shear). This method could, however,be misleading because a reduction in size couldbe due to the fracture and breakage of primaryparticles themselves. As with paint and ink, theoptimal particle size is achieved when the colorstrength is greatest.3 However, these are indirectmonitoring methods because it is not the particlesthemselves that are being measured, but a bulkproperty of the final product.

Microscopy is an ideal technique to observe thenature of particles in a powder. If a prepared slideof a suspension of a powder is examined with atransmitted light microscope, valuable informa-tion about the nature of its particles and particleassemblages can be determined directly. Forexample, by applying a shear force to the suspen-sion (by pressing on the cover glass and moving itsideways), soft agglomerates are seen to dispersewith ease, whereas hard agglomerates remainintact. Only by applying a ‘‘considerable’’ forcewill the hard agglomerates be dispersed orshattered. This method is qualitative, but willyield useful information about the nature of anyparticle assemblages present.

Four photomicrographs (all at the same mag-nification with a scale bar that represents 250 mm)illustrating how such a microscopic test can beapplied to a pharmaceutical powder are shown inFigure 1. The dry powder consists predominantlyof agglomerates that are up to 700 mm across(Figure 1a). As soon as this powder is added to aliquid (silicone oil) on a microscope slide (withouta cover glass), it begins to spontaneously disperse(Figure 1b). When a cover glass is gently loweredonto the preparation, the shear forces producedby the moving oil are sufficient to enhance thedispersion (Figure 1c). If light pressure is thenapplied to the top of the cover glass with a gentlesideways force (using a needle probe), the softagglomerates are dispersed even more (Figure 1d).The particles shown in Figure 1d consist of a



mixture of hard agglomerates that are up to 50 mmacross, some smaller soft agglomerates, and manyprimary particles (that are typically< 10 mmacross). Just by applying this simple and rapidmicroscopic test, it was established that thepowder comprises a mixture of both soft and hardagglomerates.

CONCLUSION

We have reviewed some of the many conflictinguses and definitions for the terms agglomerateand aggregate as applied to understanding thecharacteristics and behavior of powder particle as-

semblages. The two terms are currently usedinterchangeably without any apparent consider-ation for their meanings. To overcome thisunacceptable situation, a single term that isuniversally understood and accepted to describean assemblage of powder particles is needed. Wetherefore propose that when particle assemblagesare described, the term agglomerate is usedexclusively. Where specifically required, hardand soft agglomerates can be distinguished, withbrittle agglomerates being used to describe hardagglomerates that can only be fractured byapplying considerable force. The term aggregateshould be confined to prenucleation structuresthat arise from the association of molecules into

Figure 1. Photomicrographs showing qualitativetest for assessment of agglomeration in a powder (scalebar in each represents 250 mm): (a) Agglomerated drugpowder mounted dry on a microscope slide. (b) Softagglomerates disperse when added to silicone oil with

no additional shear forces applied. (c) Enhanced dis-persion of the powder after a cover glass is placed on thedrug–silicone oil mixture. (d) Powder dispersed byapplying gentle shear forces on cover glass liberatingprimary particles and exposing hard agglomerates.

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supramolecular structures, which in turn maydevelop into agglomerates.

REFERENCES

1. Simpson JA, Weiner ESC, editors. The OxfordEnglish Dictionary, 2nd ed.; Oxford, England:Clarendon Press. 1989.

2. Chambers Science and Technology Dictionary.Chambers Harrap Publishers: New PenderelHouse, 283-288 High Holborn, London, WC1V7HZ, UK, 1988.

3. Gerstner W. 1966. Crystal form and particle size oforganic pigments in printing inks and paints. J OilCol Chem Assoc 49:954–973.

4. BS 2955: 1993. Glossary of Terms Relating toParticle Technology. British Standards Institution,389 Chiswick High Road, London, W4 4AL, UK.

5. ISO 14887:2000 (E). Sample Preparation—Dispers-ing procedures for powders in liquids. Available inthe UK from British Standards Institution, 389Chiswick High Road, London, W4 4AL, UK.

6. USP 24 2000. The United States Pharmacopoeia.Monograph 776 (Optical Microscopy). UnitedStates Pharmacopoeia Convention: Rockville,MD.

7. European Pharmacopoeia. Third Edition (Supple-ment 2001). European Directorate for the Qualityof Medicines, 226, Avenue de Colmar, B.P. 907,F67029 Strasbourg, CEDEX 1, France.

8. Mullin JW. 1993. Woburn MA, editor. Crystal-lization, 3rd ed. Butterworth-Heinemann.

9. Van Hook A. 1961. Crystallization: Theory andPractice. American Chemical Society MonographNo.152. New York: Reinhold Publishing Corpora-tion.

10. Rodriguez-Hornendo N, Murphy D. 1999. Signifi-cance of controlling crystallization mechanismsand kinetics in pharmaceutical systems. J PharmSci 88:651–660.

11. Ticehurst MD, Basford PA, Dallman CI, Lukas TM,Marshall PV, Nichols G, Smith D. 2000. Character-isation of the influence of micronisation on thecrystallinity and physical stability of revatropatehydrobromide. Int J Pharm 193:247–259.



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