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dosage forms

procedures for four simple methods,which are examined here.

Success or failure in many pharmaoperations can be linked directly to theflow properties of the powder beingprocessed. Flowability is clearly impor-tant when assessing how materialmoves around the plant, particularlyfrom storage bins and hoppers.

Much work has gone into developinglinks between powder properties anddischarge behaviour, to provide designmethods that reduce the likelihood ofproblems such as flooding and rat-holing. Ratholes and arches formwithin a hopper when the strength thatthe powder bed develops is sufficientto form a stable structure that preventsfurther flow. Flooding, the uncontrolledflow of material, occurs with powdersthat flow too easily once mobile.

Other process steps affected by flow properties include blending andtableting. Manufacturing pharma-ceuticals often involves mixing a relatively small amount of active ingre-

dient into a much larger excipient bulk.Homogeneity in the final formulation isessential and easier to achieve if thepowders have appropriate flow charac-teristics. Research has shown a directcorrelation between both the rate anddegree of mixing and flowability.4

Tablet making provides a good example of the many ways in whichflowability can influence process performance. The goal is to produce aconsistent dosage form that alwaysbehaves the same in vivo. A high degreeof powder flowability ensures:■ Smooth powder flow into the press.This discourages the formation of airpockets in the die for improved weightconsistency and tablet stability.■ Accurate filling of the dosage chamber. This decreases weight variability and creates even pressureduring compression, lessening wear onmachine parts. ■ Improved reproducibility of feedparameters. This results in more consistent tablet hardness, friability,dissolution rates, and ultimately blooddrug levels. ■ Rapid air release during com-pression. Free-flowing powders tend tobe highly permeable so air is readilyreleased during the compression step,reducing problems such as capping andsplitting.■ High production speeds. Throughputhas increased with the maturation �

Powders are the starting pointfor many processes in thepharmaceutical industry,including capsules, granules,inhaled products and tablets,

and their flow characteristics are critical-to-quality parameters in theproduction process.

Current regulatory thinking (European Medicines Agency and theUS Food & Drug Administration) isbased on the concept of Quality-by-Design (QbD) and places heavyemphasis on the application of ProcessAnalytical Technology (PAT) duringmanufacturing. The exact nature of thePAT techniques to be used is normallydetermined during the pharmaceuticaldevelopment process1 through the useof ‘Design of Experiments’.

Historically, a variety of methodshave been used to test powders, and inan effort to rationalise the situation thePharmacopoeias recently introduced anew harmonised chapter on PowderFlow.2,3 This gives recommended

Measuring a powder’s flow characteristics is key toestablishing Quality-by-Design in powder-handling facilities.Mark Copley, of Copley Scientific, reviews currentmethods for powder flowability testing

A test of quality

The new powderflowability tester BEP2

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of tableting technology; however,very fast production rates demandexcellent flow characteristics.

It is clear then that the pharmaceuti-cal industry needs the ability todevelop formulations with tailoredflow properties, and the first step isidentifying suitable techniques forpowder characterisation.

Many factors influence the flowbehaviour of powders, making charac-terisation a significant challenge. Thesefactors can be grouped under three general headings:■ physical properties of the particle ■ properties of the bulk powder ■ processing environment.

This dependence on so many differ-ent variables explains why the powdercharacterisation community is still along way from being able to predictprocessing behaviour from particledescriptors.5 It also highlights the diffi-culties inherent in trying to develop asingle test that will accurately define apowder.

In fact, no single test can adequatelycharacterise the flow properties of powders, so most scientists advocateusing multiple standardised test methods.

Over many years an array of testingtechniques has been developed. Some,such as angle of repose and compress-ibility index, are relatively simple andwell-established within the pharmaindustry. Their advantages and limita-tions are understood and there is muchexperience linking results with aspectsof manufacturing practice. More recenttechniques, such as powder rheometryand avalanche testing, bring new capa-bilities that complement traditionalmethods. All are valuable in providinginformation about different aspects ofpowder behaviour.

The new harmonised pharma-copoeia chapter on the testing of powder flow2,3 is a move towards standardisation. It reviews four of themost commonly used techniques –angle of repose, compressibilityindex/Hausner ratio, flow through anorifice and shear cell analysis – recommending instrumentation andmethodologies for each. Organicgrowth of characterisation techniqueshas produced many variants of similartests and the new guidance outlinesbest practice with the aim of improving consistency of approach.

pharmacopoeial methods In developing guidance, the pharma-copoeial bodies have extensivelyreviewed literature relating to each ofthe four powder flowability tests covered and assessed the impact ofvariations in method. Equipment

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manufacturers have responded bydeveloping instruments that providetesting in accordance with the newadvice. The powder flowability testermodel BEP 2 from Copley Scientific,for example, provides flow through anorifice, angle of repose and shear cell ina single instrument.

angle of reposeAngle of repose is ‘the constant three-dimensional angle assumed by a cone-like pile of material’ formed as powderflows onto a surface.2,3 It is a function ofthe strength of interparticle forces, flatter cones being formed when theseare weak. The more acute the angle ofrepose, the better the flowability of thematerial (see table 1). The literaturesuggests that formulations with an

angle of repose as high as 40 - 50° willprocess satisfactorily but above thislevel flow will be problematic.

The pharmacopoeia chapter recom-mends that testing is carried out using acommon fixed base with a retaining lip.This avoids the variability introducedby using different surfaces and byallowing the powder to spread in anuncontrolled way. A similar method isalso described in an ISO standard dating back to 1977.6

compressibility index Compressibility Index and Hausnerratio are closely related: both are basedon the comparison of ‘as poured’ andtapped bulk density. These techniqueshave existed for some time and arewell established. Both the US andEuropean Pharmacopoeia already haveseparate monographs that define methods for determining Bulk Densityand Tapped Density.7,8 CompressibilityIndex is defined as the percentagechange in volume induced by tapping asample of fixed mass. Hausner ratio issimply the unsettled volume dividedby the tapped volume.

Compressibility Index =

100 x (V°-Vf)/Vf

Where V° = unsettled volume and Vf= tapped volume.

Hausner ratio = V°/Vf

These two parameters are influencedby variables such as particle size andshape, and cohesivity, since they essen-tially reflect the impact of tapping onthe particle packing. These are primaryfactors in determining flow behaviourthat can therefore be inferred directlyfrom values of Compressibility Index

�

The impact of Quality by DesignThe FDA’s Guidance for Industry Q8 Pharmaceutical Development1 emphasises the importance of product and process knowledge for the implementation of Quality by Design (QbD). The basic premiseof QbD is that quality should be designed into the product and manufacturing process rather than simply tested for prior to release. It demands the identification of critical-to-quality variables – those thatdirectly affect product performance – and the development of a robust manufacturing process that effectively controls these parameters.

The realisation of QbD requires enhanced knowledge of product performance over a range of material attributes, manufacturing process options and process parameters. The guidance emphasisesthe importance of building scientific understanding to support the establishment of the ‘design space’,specifications and manufacturing controls that define operating conditions for the production of material that meets the defined specification. Changes within the design space are not subject to furtherregulatory approval, providing a strong incentive for developers to ensure that it is optimally defined.

QbD is not compulsory but its adoption ultimately offers manufacturers greater flexibility with respectto regulation than has previously been afforded. The concept is therefore generating significant interestwithin the industry. Since powder flowability is frequently a critical process parameter, the focus on greaterprocess knowledge is likely to increase the need for testing. The pharmacopoeias release of new guidance relating to powder flow is, therefore, timely since it highlights the most widely used characterisation techniques and the best ways of implementing them.

Table 2: The relationship between CompressibilityIndex/Hausner ratio and flowabilityCompressibility Index (%) Flow character Hausner ratio<10 Excellent 1.00-1.1111-15 Good 1.12-1.1816-20 Fair 1.19-1.2521-25 Passable 1.26-1.3426-31 Poor 1.35-1.4532-37 Very poor 1.46-1.59>38 Very, very poor >1.60

Table 1: The relationship between angle of reposeand flowabilityFlow property Angle of repose (degrees)Excellent 25–30Good 31-35Fair – aid not needed 36-40Passable – may hang up 41-45Poor – must agitate, vibrate 46-55Very poor 56-65Very, very poor >66

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and Hausner Ratio (see table 2). In general, powders that are less affectedby tapping have better flow properties.

The pharmacopoeias recommend100g sample in a 250ml volumetriccylinder for this test and point out thatboth rotation of the sample during tapping and the number of taps willaffect results. Sample should be tappeduntil there are no further changes involume. Scott Bulk Density testers andTapped Density testers are widely usedfor this test, appearing in ASTM standards dating back as far as 1958,originally produced for the metal powder manufacturing industries.9,10

powder flowAssessing how a powder flows throughan orifice is an intuitively sensible wayof investigating flowability and is apopular test for basic assessment. However, there is no established scalethat allows behaviour to be inferredfrom results because there is such variability in the way tests are performed. Results depend on: diameter and shape of the orifice; wallfriction of the container material; anddiameter and height of the powder bed.

The technique’s main value is forcomparative study, although it alsoallows direct observation of flowbehaviour. Pulsating flow patterns andchanges in flow rate induced by chang-ing the bed height are two phenomenamost frequently detected. Only free-flowing powders can be studied.

Tests are conducted using either acylinder or hopper as the powder container. Cylinders have advantagesbecause particle-wall interactions areminimised, so the results are lessdependent on the construction materialof the instrument. However, a hoppermay more closely simulate productionconditions. Conventionally shaped funnels are not recommended becauseflow rate will be dictated by the lengthand size of the stem, and by particlestem material interactions.

Orifice shape and the method ofmeasuring powder flow rate (in particular whether mass or volume isrecorded) are additional test variables.In an effort to create a degree of standardisation, the European Pharma-copoeia had previously generated aprecisely defined funnel arrangement,through the creation of a dedicatedpowder flowability monograph.11

Equipment based around this funnelarrangement, with three nozzle sizes(10, 15 and 25mm), is now widelyused. The powder flowability testermodel BEP 2 from Copley Scientific issuch an example.

To account for the wide range ofmethods already in existence, the newharmonised pharmacopoeia chapter2,3

simply recommends using an orificewith a diameter six times greater thanthat of the particles and a cylinder witha diameter twice that of the opening.While a circular orifice is preferred,other geometries are acceptable. Theavailability of orifices of different diameter allows testing to be carriedout on the basis of the minimum orificethrough which a powder will flow satisfactorily, and also facilitates optimal tailoring of the instrument tothe test material.

shear testShear cell testing involves applyingforce to a powder sample to shear itacross a plane. The methodology ismore involved and time-consumingthan the test described above, but theclose control of degree of consolidationand environmental conditions permitsa more precise and detailed investiga-tion of flow behaviour. Shear cell test-ing closely defines the cohesive natureof powders, generating parameters suchas the angle of internal friction, uncon-fined yield strength, tensile strength,flow factor and flowability indices.These data can be used directly indesign methods for hoppers and bins.

Shear cells can be annular, vertical orplate – each offers benefits and disad-vantages. The new guidance offers nospecific recommendations but endorsesthe value of the technique.

References1 ICH Q8 (Pharmaceutical Development) – Manufacturing ProcessDevelopment (2.3)2 European Pharmacopoeia Chapter 2.9.36. Powder Flow3 US Pharmacopoeia Chapter <1174> Powder Flow4 ‘Evaluating flow property of powder by Carr’s flowability method using thepowder characteristics tester’ I Sato. Technical Data Sheet. Hosokawa EuropeLimited.5 ‘Developments in powder flow testing’ M Rios Pharmaceutical TechnologyFeb 20066 ISO 4324:1977 Surface Active Agents – Powders and Granules –Measurement of the Angle of Repose7 US Pharmacopeia Chapter <616> Bulk Density and Tapped Density8 European Pharmacopoeia Chapter 2.9.15. Apparent Volume9 ASTM B 329 – 98 (Re-approved 2003) Standard Test Method for ApparentDensity of Metal Powders and Compounds Using the Scott Volumeter10 ASTM B 527 – 06 Standard Test Method for Determination of Tap Densityof Metallic Powders and Compounds11 European Pharmacopoeia Chapter 2.9.17. Powder Flowability

The new harmonised pharma-copoeia chapter2,3 on powder flowbrings some standardisation to thecomplex area of flowability testing. Itdescribes optimal methods for the fourmost commonly used measurement

techniques, providing valuableguidance. As pharma manufac-turers get to grips with QbD,better understanding of criticalparameters such as powderflowability is increasinglyimportant. As the analyticalburden increases, well-designed cost-effective instru-ments that provide testing inaccordance with the new guid-ance are to be welcomed. ■

contact Mark CopleyTechnical sales managerCopley Scientific LimitedColwick Quays Business ParkPrivate Road No. 2, ColwickNottingham NG4 2JYUKT +44 115 961 6229 F +44 115 961 7637m.copley@copleyscientific.co.ukwww.copleyscientific.com

Typical powder discharge problems include arching (a) and (b) ratholing

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