Mastersizer 2000 Application Note
may yield a representative sample.For slurries it is important to overcomesedimentation by re-suspending thesample. This can often be achievedby simple stirring. However, use ofcertain stirrers, such as magneticfleas, can lead to the large particlesbeing thrown to the outside of thecontainer (in a similar way tohydrocyclone separation) where theyare not sampled.
The PASG group defined samplepreparation as “the pre-treatment andthe presentation of the sample to themeasuring technique in a meaningfulmanner” . Selection of the correctmethod will therefore depend on theinterests of the user. Where, forexample, the primary particle size isimportant, correct dispersion of thesample will be important. This may bethe case when control of the solubilityof the powder is important in definingits functionality. If the naturalagglomerated state is of interest, as isthe case in some granulationprocesses, sample preparation shouldtake this into account in order to avoidthe break-up of agglomeratedparticles. In either case, thedispersion medium – whether air or aliquid – should not cause irreversiblechanges to the particle size throughprocesses such as dissolution, millingor aggregation.For both dry and wet measurements itwill be important to understand howthe dispersion energy affects thereported particle size. For wetmeasurements the addition ofsurfactants and additives and the useof sonication for dispersion must beinvestigated. Comparison of the stateof the powder before and afterdispersion using microscopy can thenbe used to assess if irreversibleparticle break-up has occurred. In thecase of dry powder measurementsthe effect of dispersion pressure mustbe ascertained, with the correctpressure being selected by comparingthe results against wet dispersion.Dispersion parameters are normallyassessed as part of methoddevelopment rather than as part of themethod validation process. Details ofthe method development process aregiven elsewhere
Detection Limit and Range
Assessment of the detection limit ofthe laser diffraction technique is notrequired as part of method validation.However, it is important that thedynamic range of the particle-sizinginstrument covers the size range ofthe sample being tested. Thisnormally does not present a problemfor most pharmaceutical samples asmodern laser diffractioninstrumentation can cover a sizerange from 20nm to 2000µm in asingle measurement. Olderinstrumentation, however, may haveto use many lenses in order to coverthe same dynamic range. Here thelens that covers the largest proportionof the particle size distribution shouldbe used. Alternatively the result fromtwo lenses can be blended together,although this is not recommendedsince the result depends on themathematical efficacy of the blendingroutines.
Specificity, in terms of whether or notthe technique is appropriate to thematerial under analysis, should beaddressed as part of methoddevelopment and does not have to berevisited for method validation. It is, ofcourse, true that different sizingtechniques display differentsensitivities and will therefore providedifferent results for the same sample.Selection of an appropriate techniquedepends on what is of interest – forinstance is the detection of a smallamount of over-sized materialrequired or does the technique needto differentiate between differentparticle types? Laser diffractionprovides a good method for assessingsmall changes in the size distributionin this regard. However, it is difficult todifferentiate between the different
0 2 4 6 8 10 12 14 16Measurement Time / sec19202122
D v 5 0 / m i c r o n s
Variation in the Dv50 as a function of measurement duration. Theerror bars represent the COV over ten measurements.