Powders in bulk form are commonly created and used by many industries, including the pharmaceutical industry.  Particle size is often part of the raw, in-process, or finished product specification.  It can be of considerable importance with respect to the downstream performance of the powder, as it can affect process behaviors such as dispersion, dilution, dissolution, and mixing, as well as affecting a final product in areas such as tablet hardness, content uniformity and dissolution. 
Particle size is not the sort of parameter that is“steered” in isolation.  Itis typically the result of manufacturing steps that form the material, such as crystallization, agglomeration, granulation or drying, as well as steps that are included for additional size control, such as milling, chopping, separating and screening.  However, simply stating an end goal of particle size may not be sufficient to ensure success.  The performance of the overall manufacturing process is often itself a strong function of particle size.  Issues can arise relating to yield, efficiency, excess labor, throughput, product loss (including dusting, as demonstrated in Figure 1), housekeeping, and product uniformity; all of which can be influenced by the particle size of the material being processed.  An understanding of how process characteristics are affected by particle size is an important part of the overall design effort for a manufacturing area, but is unfortunately one that is often overlooked.  By relating particle size to process performance, the design effort can avoid unwanted manufacturing problems.



Figure 1: Excessive dust loss due to fine particle size and inadequate process design.

One of the first steps in understanding the influence of particle size on process performance is to ensure that the measurement method for particle size is well understood.  Particle size can be effectively measured through a variety of methods, with sieving common for coarser materials and laser diffraction common for finer materials (with a dividing line for ease and resolution somewhere around 500 microns).  The user should bear in mind that different methods, and even different devices using the same method, can (and usually do) give different results.  It is therefore important to cite the exact device and conditions (both material and instrument) used when comparing particle size measurements. See example results in Figure 2.



Figure 2: Particle size distributions for various materials in comparison (as measured by a Malvern Mastersizer 2000, dry dispersion, 0.5 bar dispersion pressure)

In considering the results of a particle size analysis, mean values or quantities below a given size are often quoted for comparison or used as a specification.  However, “processability” can also be highly dependent on maximum/minimum size values, the breadth of the distribution, as well as any secondary peaks showing a concentration of fines or coarse.  Also, measured variations, or even the lack of variation, in particle size may be the result of an insufficient sampling program; the number of samples, the locations they are taken from, the method of collection, and post-collection sample handling should all be considered in terms of their potential contributions to error.
Once equivalency has been considered, bulk properties can be used to aid in the design of a powder manufacturing process.  One area of interest is powder flow.  Problems with arching and ratholing in bins and hoppers can lead to erratic flow or complete flow stoppages.  These problems can in turn result in undesirable consequences in terms of process efficiency (shutting a line down) and operator exposure (as they intervene to reinitiate flow).  The underlying bulk property of cohesive strength influences these types of flow problems, and is a property that can be affected by changes in particle size; often finer sized materials (with all other properties being consistent – a caveat for other comparisons made in this article) will have higher cohesive strength than coarser ones [1].
An additional powder flow behavior of interest has to do with achievable discharge rates.  Two-phase (air:solid) flow behaviors can result with fine particle size powders below a general threshold of 100 microns.  These behaviors can include air retention in powder beds, resulting in such problems as flushing of powders through handling equipment and long settling times needed to fit target masses in fixed volume containers.  Further two-phase flow issues can occur once powder beds settle, resulting in limited discharge rates through processing equipment, or secondary problems with packing or dosing weight uniformity.  These types of behaviors are almost always negatively influenced by reductions in particle size [2].  Fluidized processing (such as drying or milling) can be an exception, since finer materials generally fluidize more easily.  However, this trend has a limit; if the material is too fine, it may be too cohesive to fluidize.  These two-phase behaviors can be understood through the bulk property of permeability, which describes the resistance of airflow through a bed of powder as a function of its bulk density.
If there is a high coefficient of friction between the powder and a contact surface, the powder may stick to it.  This can result in problems with powder buildup, including ratholing and adhesion, which can lead to product loss or the need for frequent cleanings.  If a surface is sufficiently steep, be it a hopper or a chute, problems with buildup can be minimized or completely eliminated.  Measurements of wall friction can be used to assess the required steepness.  This bulk property can be influenced by particle size.  It will also be influenced by the wall surface itself – often smoother surfaces result in lower values of wall friction, allowing shallower surfaces (e.g., hoppers, chutes) to be used within handling equipment designs to promote powder reliable flow.  However, the exact interaction between material and wall surface can be hard to predict, and testing is often required to evaluate it.
Segregation, defined as the separation of a bulk material into regions of similar properties, can result in uniformity problems if encountered when handling a blend of ingredients, as well as size or density variations when handling an individual material.  Segregation behaviors are strongly influenced by particle size, with different mechanisms (or types) of segregation occurring over different size ranges.  For instance, sifting segregation will occur for free flowing materials, with a relatively small size range (ratio of large to small particles of 1.4) and a mean size approaching 500 microns, when offered an opportunity for inter-particle motion, such as forming a pile while dropping into a package during filling operations.  This effect generally lessens with decreases in particle size, but it can continue to occur with wider distributions down to a mean size of 100 microns, as demonstrated by Figure 3 [3].


Figure 3: One measure of the influence of particle size on sifting segregation

Other segregation mechanisms, such as fluidization anddusting, can occur with finer sized materials.  With a mean size below 100 microns, these mechanisms can become dominant over sifting. Opportunities for these types of segregation can occur during high flow rate transfer steps, when powder free falls, or in the presence of air injection as a flow aid, all of which result in the potential for air to interact with the powder and result in a migration or concentration of the finest particles.  Available test methods can be used to determine a material’s potential to segregate by either the sifting or fluidization mechanisms, and the results used as a justification for either handling equipment features that minimize segregation, or additional development efforts to arrive at a more robust final blend (if applicable) [4].
Apart from flow concerns, the performance of various process steps and equipment can be greatly influenced by changes in particle size.  Milling and sizing operations may encounter problems with buildup, blinding, and filtering (air/solids separation) when handling finer materials.  Blending behavior is a function of the particle size of key ingredients, as the ability to separate and comingle particles can change with variations in size.  Granulation and other powder-consuming processes can also be affected by shifts in particle size, resulting in differences in time required, wettability, viscosity, etc.The engineering decisions made regarding appropriateness and effectiveness for the equipment involved in these processing steps may not be a predictable function of particle size [5]. 
Understanding the impact of particle size on the design of a manufacturing system is essential, not only to ensure the desired final product is made, but also to ensure it can be delivered and successfully processed by each step along the way [6].

[1]    Craig, D.A. and Hossfeld, R.J., Measuring Powder Flow Properties, Chemical Engineering, September, 2002, pp. 41-46.
[2]    Baxter, T.J., Powder Flow – When Powders Flow Like Water: Addressing Two-phase Flow Effects in Tablet Feed Systems, Tablets & Capsules, March 2009, pp. 26-32.
[3]    Williams, J.C., and Kahn, M.I., The Mixing and Segregation of Particulate Solids of Different Particle Size; Chem. Eng., London, Vol. 19 (1973); p. 269.
[4]     Prescott, J. K. and Hossfeld, R. J., Maintaining Product Uniformity and Uninterrupted Flow to Direct Compression Tablet Presses,Pharmaceutical Technology, June 1994, pp. 99-114.
[5]    Clement, S.A. and Purutyan, H., Narrowing Down Equipment Choices for Particle Size Reduction, Chemical Engineering Progress, June 2002, pp. 50-54.
[6]    Barnum R.A. andKhambekar, J.V., Going with the Flow, Pharmaceutical Processing, March 2010, pp. 16-18.