the effects of particle size distribution on the properties of medical materials with license

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The Effects of Particle Size Distributionon the Properties of Medical Materials

Author: Matthew Cantelo

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Introduction

As so many 3-D products are created from powder particles, the shape and size ofthese particulates can have a great impact on the physical and chemical properties ofthe final product. Analysis of the size distribution and shape of the particles can also

give useful information concerning the processes they go through in manufacturing,and can help make these processes more efficient as well as, of course, helping tosolve problems. This is of particular importance in the field of medical materials anddevices, as processing control for materials that enter the body is vital. This whitepaper will discuss laser diffraction, a well-known method for measuring particle sizedistribution (PSD). As well as describing the theory behind it, the paper will focus onhow important laser diffraction can be to the field of medical materials.

The Importance of PSD Measurements

The distribution of particle sizes in glass, ceramic, metal and polymer powders is ofvital importance to many industries, ranging from the medical to aerospace andconstruction sectors. Many raw material producers, and their clients also, employprocesses like milling to create a target powder size or shape. Given that powdersoften represent the starting point in production, it is important to ensure that both thepowder supplier and user are confident that a desired size distribution is beingconsistently achieved. There are two aspects to this: consistent processing andconsistent measurement of particle size. Both require the definition and compliancewith SOPs (Standard Operating Procedures). If this has not been achieved, thepowders will not perform as expected, causing (a) time wasted in supplier-end-userdisputes concerning the nature of powder supplied and/or (b) poor yields/increasedwaste at different process steps and/or (c) variable end-product performance and therisk of customer dissatisfaction or even legal action.

There are several different methods available for measuring the size of particles.These range from simple techniques such as sieve analysis or use of opticalmicroscopes through to techniques based on sedimentation rates as a function ofparticle size. At Ceram we tend to rely on using the Malvern Mastersizer 3000 ® tomeasure sizes using a laser diffraction technique. This method is suitable for a widevariety of materials in the particle size range <10µm to more than 100µm, and Ceramhas experience with characterising everything from sand and clays to medical-gradeimplant coatings. The theory behind this measurement method, and the practicalaspects of the technique, will now be discussed.

Figure 1 – A Typical Particle Size Distribution Curve



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The Experimental Procedure

The powder sample under investigation is mixed to obtain a representative sample.This can be done, for example, by a method called ‘cone and quarter’, where the

sample is shaped into a cone, flattened, and divided into four equal sections. One ofthese sections is taken and the process is repeated until only 1/16 th of the originalvolume is left. Other techniques include riffling and scoop sampling2.

The apparatus can now be filled with the dispersant – a liquid that will not affect thephysical or chemical properties of the powder, but simply allow it to be transportedfrom the reservoir cell into the detector apparatus. For example, hydroxyapatitewould be dispersed in water as it is insoluble in it, but certain silicate-based glasseswould be dispersed in ethanol as these would dissolve in the water. It should benoted that the term ‘dispersant’ should not be confused with surfactants - in this case,it is just a liquid medium to transport the suspended particles. The apparatus must beflushed through with the clean dispersant of choice before any experiments areperformed, and the detector window aligned and the background measured.Measuring the background greatly improves the signal-to-noise ratio, making themeasurements as accurate as possible. This is all done with constant stirring of thedispersant, and the system should be allowed to settle and thermally equilibratebefore any background measurements and alignment takes place3.

The system pre-sets now need to be set up using the PC software. Each dispersanthas a pre-set refractive index, and this is used in conjunction with the particle’srefractive index to calculate the distributions. Most substances have a value alreadyin the database, but if necessary values can be allocated from data in the literature.For almost all wet samples, the pre-sets for non-spherical particles can be used, and

measurements are programmed to be taken at set time intervals (usually a fewseconds apart), alternating between the blue and the red lasers. The differentwavelengths of light give different scattering from the particles, to obtain a full rangeof values from the detectors in the Mastersizer (see later). An acceptable obscurationrange is also programmed, and a suitable analysis model is chosen to fit with thetype of particle.

The representative powder sample is now added, small amounts at a time, until theobscuration is in a suitable range. Finer particles need a lower obscuration toproduce accurate results compared to more coarse particles, but an obscuration inthe range 4 – 15% will give more accurate results as this reduces the signal-to-noiseratio. When considering how the powder sample is introduced, the following is worthy

of note: Direct addition of powder may mean the introduction of agglomerates thattake a long time to break down. As an alternative, powders can be pre-dispersed inthe dispersant. However, if the resulting dispersion is dilute, using a pipette tosubsequently add sample can mean coarser particles are left behind as a sediment(leading to a spurious PSD with a misleadingly high contribution from finer particles).Therefore creation of a homogeneous paste may be the best approach.Measurements can now be taken, and will be produced as a report in the software. Agood practice is to take two sets of measurements several minutes apart, as this canhighlight any de-agglomeration or agglomeration that may be taking place in thesystem. Ultrasonics can be employed to break up any agglomerations, and so a truemeasurement of the PSD can be obtained, rather than an inaccurate one. Alternatively surfactants can help ensure deflocculation and so give a true measure

of primary particle size distribution.

The data is presented as a distribution curve, an example is shown in figure 1. Thekey values from the report are the size value at the highest point of the curve – the



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modal particle size, and the d10, d50 and d90 values. These values represent thesizes (in microns) at which 10%, 50% and 90% of the total particles has a smallersize, and are often used as standards in QC work. The second green line is thecumulative volume, which shows the amount of particles in total that are under anygiven size. It is important to appreciate that these curves can also take the form ofvolume or number distributions, and care needs to be taken when selecting whichto use. If particle size is small, e.g. sub-micron level, then a number distribution willprovide more accurate information as each particle’s contribution to the overallvolume is small. Conversely for larger particles, a volume distribution would givemore accurate results4.

Laser Diffraction – The Theory

Measuring particle size with laser diffraction typically employs two differentwavelengths of light – a red laser, in the region of 700nm, and a blue laser in theregion of 470nm. When the particles are brought through the laser beams with thedispersant, the light is scattered by the particles and picked up by a range ofdetectors around the measuring cell. Smaller particles have a larger scattering angle,whereas larger particles have a smaller scattering angle.

Ceram’s apparatus has a ring of 63 detectors around the measuring cell, withdetector 1 being in front of the sample and detector 63 effectively behind the sample,for those particles with the widest scattering angles. These can be viewed in real timeusing the PC software. As mentioned above, a large particle will give a smallscattering angle and this will be picked up by the lower number detectors, and smallparticles with the larger scattering angles will be picked up by the higher numberdetectors.

Figure 2 – Particle Size and Scattering Angle

Incident LightSmall Particle – LargeScattering Angle

Incident LightLarge Particle – Small

Scattering Angle



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Once the measurements have been taken, a mathematical process based on the Mietheory takes these values and predicts the scattering of light at all possible angles. According to ISO13320-1, this is the best method for particle sizes less than 50µm(below sieve measuring limits). Another theory that was widely used, the Fraunhoferapproximation, only accounts for classical diffraction around the particles andassumes that they are opaque, whereas the Mie theory takes the refractive index ofthe particle into account. The Mie theory requires knowledge of the particle anddispersant refractive indices, as well as the imaginary particle refractive index, all ofwhich can be obtained from the apparatus’s database. If a material’s RI values arenot listed, the values can be estimated and then edited later on depending on their fitwith the data. There needs to be good agreement between the so-called residualvalues, the difference between the actual measurement and the predicted data.However, it must be noted that a good data fit does not necessarily give a correctresult4.

Variability in PSD Investigations

The importance of having a thorough protocol for measuring PSDs and ensuring allthe relevant information needed for the processing of the values was highlighted in around robin study performed by the National Physical Laboratory (NPL) inconjunction with Ceram and Leeds University5. Samples of crystalline silica were sentto different laboratories, one with a known median particle size of <10µm (A) and onewith a known size of <100µm (B). Minimal information was provided with the samplesbut partner labs were encouraged to answer questions concerning the methodologythey had selected in undertaking the analysis. This was repeated a year later, thedifference being that partner labs were additionally supplied with more thoroughprocedures and methods to use. Unknown to the labs, the same samples (labelled C

and D this time) were sent.

The results of this investigation show clearly that once the procedures and thoroughprotocols have been put in place, the agreement between the measurements madeat different labs improved and the coefficient of variation was greatly reduced innearly all of the cases. This coefficient decreased more for the larger silica particlesize. The standard deviation for the A samples was also larger than that of B,indicating that free reign over the method used, without questioning, does notnecessarily give an accurate result (comparing A and B against C and D). This studyhighlights the importance of using thorough methods and strict sampling protocols toobtain accurate results, but also that measurements can vary significantly betweenlaboratories depending on the protocols they use. The results may be accurate

according to their standards, but not necessarily the correct results2

.

It is very common for clients to come to Ceram asking for particle size distributiontests to be performed on a powder with no prior information on test protocolsprovided, which can lead to discussions around the results, despite themeasurements being performed as accurately as possible according to a standard in-house protocol. This highlights the importance of working with clients to develop aprotocol specific to their materials, something Ceram is very capable of. We haveextensive experience in the fields of powder processing and characterisation, andthis expertise can help provide the most accurate and reproducible data betweenlaboratories. Very relevant to this process is understanding how powder samplesbehave in water: many problems arise from the fact that powders have a low surface

charge in water and so a strong tendency to agglomerate. Particle sizemeasurements then often reveal additional coarse peaks that are not representativeof the primary particles. This can be rectified through changes to suspension pH orthe use of surfactants. The interested reader is encouraged to read this white paper



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in conjunction with previous ones - ‘The Role of Zeta Potential in the Manufacture ofHealthcare Materials’ and ‘The Applications of Zeta Potential in Process Control’ onthe Ceram website.

An example of the link between zeta potential and PSD is shown in some testingwork carried out for a client on titania powders. The initial experiments showed thatthe titania particles were flocculating and giving a misleading merged bi-modaldistribution. After conducting zeta potential vs pH measurements and then mixing ina small amount of a suitable anionic surfactant, PSD measurements gave adistribution with one, much sharper peak at the lower particle size rather than two.The surfactant had the effect of increasing the surface charge of the particles, andsubsequently their zeta potential. This meant that the particles possessed enhancedelectrostatic repulsions (versus Van Der Waals forces) leading to no flocculation6.

PSD Measurements and the Medical Sector

PSD measurements are important to many industry sectors, but become even moreimportant when applied to materials that have medical applications and will be usedin the body. The processing of these materials must be even more tightly controlledthan in other industries, as they are subject to a huge range of regulations (e.g. theFood and Drug Administration, FDA). Two very important classes of biomaterials thatCeram has experience in manufacturing are hydroxyapatites (HA) and bioactiveglasses.

Both of these materials are widely used as implant coatings, conferring increasedbioactivity, solubility, or releasing ions or organic molecules to the body fortherapeutic purposes or to promote integration with existing bone. These materials

can be coated onto an implant - usually made from a titanium alloy - by plasmaspraying of a spray-dried granulate form of HA or bioactive glass. During spraying,where the coating is subjected to very high temperatures as it passes through thespray gun. This ensures it assumes a plasticity so that it “splats” onto the metalsubstrate. Returning to the start of the process, obtaining the correct particle sizedistribution in the primary HA powder is crucial for this process: particle sizedistribution will impact on the rheology of the slurry and therefore the solids loading.This, in turn will alter the granulate morphology and size distribution after subsequentspray drying. If the particles are too small in the primary powder suspension, they willremain this way during the spray-drying process as well. They will have a tendency tomove closer together and the resulting static effects will result in intermittentspraying. If the particles are too large then there is the possibility of blocking the

spray drying nozzle. The ideal situation therefore is a very narrow particle sizedistribution around a specific size range, typically 50-70µm, and this will give asuitably even and consistent coating7, 8.

Conclusion

While it may seem initially like a relatively simple routine characterisation test,measuring the particle size distribution of a solid powder can be challenging. Whenperformed correctly however, it can give a lot of information that informs powderprocessing and so end-product performance. This is vital for a wide range of

industries, and Ceram can help ensure that clients’ materials are of the rightspecification for their needs.



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References

1. Work done at Ceram in 2013 for a client, investigating the particle sizedistribution of a range of different biomaterials.

2. Good Practice Guide for Improving the Consistency of Particle SizeMeasurement, K Mingard, R Morrell, P Jackson, S Lawson, S Patel and RBuxton, National Physical Laboratory Publications (2009)

3. Malvern Instruments MS3000 Customer Training Course, Part 1 – BasicPrinciples and Data Quality (2012)

4. Malvern Instruments MS3000 Customer Training Course, Part 2 – Obtaining andUnderstanding the Size Distribution (2012)

5. Malvern Instruments MS3000 Customer Training Course, Part 3 – MethodScreening, Wet Measurements (2012)

6. Work done at Ceram in 2012 for a client, investigating the particle size

distribution of titania suspensions.7. P. Chean and K.A. Khor, Biomaterials 17 (1996) 537-544

8. M. Monsalve, H. Ageorges, E. Lopez, F. Vargas, F. Bolivar, Surface andCoatings Technology 220 (2013) 60 –66



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by Ceram

About Ceram

Ceram is an independent expert in innovation, sustainability and quality assurance of

materials.

With a long history in the ceramics industry, Ceram has diversified into othermaterials and other markets including aerospace and defence, medical andhealthcare, minerals, electronics and energy and environment.

Partnership is central to how we do business; we work with our clients to understandtheir needs so that we can help them overcome materials challenges, develop newproducts, processes and technologies and gain real, tangible results.

Headquartered in Staffordshire, UK, Ceram has approved laboratories around theworld.

About the Author

Matthew CanteloLaboratory Chemist Matthew Cantelo has a MChem (Hons) chemistry degree from Cardiff University. Hisfinal year research project was largely focused on inorganic synthesis withinhealthcare applications. This is an area that Matthew is continuing to concentrate onat Ceram, particularly with regards to hydroxyapatite synthesis.

the effects of particle size distribution on the properties of medical materials with license

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