Particle Sizing Techniques

There are many particle-sizing methods as summarized in Table 21.4. Each method has advantages and disadvantages. The method of choice depends on the specific type of powder or dispersion sample to be characterized. The main criteria for evaluating the quality of the particle size results are accuracy, precision, reproducibility, and speed of analysis. 

Method Abbreviation Principle Applicable size range (pm) 

LASER diffraction, LASER light scattering (Fraunhofer diffraction, Mie scattering) LAS Electromagnetic wave interaction 0,1- 100 

Small angle neutron scattering. Ultrasmall angle neutron scattering SANS, USANS Wave interaction 0,001-10 

Small angle X-ray scattering Ultrasmall angle X-ray scattering SAXS USAXS Electromagnetic wave Interaction 0.001-31 

---

One of the newest particle sizing techniques is light scattering. This technique is used to measure particle size distribution, colloid behavior, particle size growth, aerosol research, clean room monitoring, and pollution monitoring. 

Suspensions contain micronized drug for proper delivery to and absorption in the respiratory system. Typical particle size of the micronized drug is from 2 to 5 microns [5], Aerodynamic mean particle size as measured by cascade impactor or direct method of microscopic analysis is usually from 0.5 to 4 microns [5], Additional particle-sizing techniques such as light scattering can be used [6],... 

In this chapter, the basic definitions of the equivalent diameter for an individual particle of irregular shape and its corresponding particle sizing techniques are presented. Typical density functions characterizing the particle size distribution for polydispersed particle systems are introduced. Several formulae expressing the particle size averaging methods are given. Basic characteristics of various material properties are illustrated. 

The book contains two parts each part comprises six chapters. Part I deals with basic relationships and phenomena of gas-solid flows while Part II is concerned with the characteristics of selected gas-solid flow systems. Specifically, the geometric features (size and size distributions) and material properties of particles are presented in Chapter 1. Basic particle sizing techniques associated with various definitions of equivalent diameters of particles are also included in the chapter. In Chapter 2, the collisional mechanics of solids, based primarily on elastic deformation theories, is introduced. The contact time, area, and... 

System conditions often allow for the measurement of magma density, and in such cases is should be used as a constraint in evaluating nucleation and growth kinetics from measured population densities. This approach is especially useful in instances of uncertainty in the determination of population densities from sieving or other particle sizing techniques. 

Third, in selecting a particle sizing technique, one must consider the size of the material itself. Most techniques have effective upper and lower limits of detection. Laser diffraction, for example, can measure particles from approximately 0.01 pm to several millimeters. With optical microscopy and image analysis, it becomes very difficult to resolve features that are smaller than a 0.3 pm because of the wavelength of light used in conventional optical microscopes.1... 

TABLE 13.1 Comparison of Particle Sizing Techniques for Active Pharmaceutical Ingredients... 

This paper describes the development of a particle sizing technique utilizing the visibility parameter and the Mie scattering theory for spherical particles. The technique allows the measurement of size and velocity of individual particles and was tested in fuel sprays under both burning and non burning conditions. 

The mass versus particle size distribution of several polymer latices with diameters in the range of 30 nm to 1500 nm was determined in less than 20 minutes using an integrated hydrodynamic chromatograph. Distributions obtained were compared with those found by other particle sizing techniques such as electron microscopy to verify validity of the technique. The instrument employed was able to analyze latices re-producibly with different optical properties, even though some of the injected particles may have been trapped within the column. Latex properties were correlated with particle size distribution data to illustrate the benefit of this particle sizing technique. 

Hydrodynamic chromatography was originally described by Small (7) in 1974. A number of publications have appeared since then which describe the separation mechanism and sample detection methods used with HDC (5, 8-18). In addition, Van Gilder, et. al. (19) used HDC as the primary particle sizing technique in research on the particle size versus viscosity relationship of high solids paper coating latices. 

Fairs (1943) has criticized the method of linear measurements above described. He points out that the diameter so measured does not correspond with the Stokes or effective diameter det but is usually greater. The importance of avoiding some shape factor to convert d to de is obvious but over and above this lies the fact that a linear measure is of statistical interest only, as already inferred. A diameter to be useful must be related to measures of mass or surface. Schweyer (1942) in his comprehensive analysis of particle size techniques (about which more will be said later) has dealt with this subject in detail. 

Microscopy is the only widely used particle sizing technique in which individual particles are observed and measured. A single particle can have an infinite number of linear dimensions and it is only when these are averaged that a meaningful value results. 

In making a decision on which particle sizing technique to us, the analyst must consider the purpose of the analysis. What is generally required is not the size of the particles, but the value of some property that is size dependent. In such circumstances it is important whenever possible to measure the size dependent property, rather than to measure the size by some other method and then deduce the required property. For example, in determining the size of boiler (fly) ash with a view to predicting atmospheric pollution the terminal velocities of the particles should be measured in measuring the size of catalyst particles, the surface area should be measured, since this is the property that determines the reactivity. The cost of the equipment as well as the ease and the speed with which the analysis can be carried out have then to be considered. The final criteria are that the method shall measure the appropriate property of the particles, with accuracy sufficient for the particular application at an acceptable cost, in a time that will allow the result to be used. 

The author of these recommendations added that the validation of particle sizing technique cannot be completed with the first batch of a sample, as data are insufficient to fully validate the procedure at this stage. It is not always important to know the absolute particle size of the first batch manufactured, but it is important to know how the second and subsequent batches compare with it. The validation of a particle size method should be in phases, with parts completed when the first sample is analyzed and other data completed or added later, for example, prior to the regulatory filing. Calibration or verification of an instrument being used is assumed to be normal part of GMP and may be used as a suitability assessment. " ... 

Microscopy is a widely used particle sizing technique in which individual particles are observed and measured. Optical microscopy is used for examination of particles from about 150—0.8 microns. For smaller particles an electron microscope is needed. A single particle has an infinite number of linear dimensions and it is only when they are averaged that a meaningful value is yielded. When a linear dimension is measured parallel to some fixed direction, the size distribution of these measurements reflects the size distribution of the projected areas of the particles [3]. ... 

There is much debate about these particular tests and their appropriateness. However, the concept of the use of aerodynamic particle size testing as a compendial test is now well established. Both impactor testing and impingers testing have a role in the development of MDIs, because they are useful tools in studying aerosol clouds and can provide information that leads to formulation optimization (at least in terms of respirable dose). It should be emphasized that these data should not be taken in isolation, and other appropriate particle-sizing techniques should also be used. A more complete discussion of this topic can be found in Chapter 11. 

Table 6.2 Particle size techniques and size range. ...

Tayali, N. E. and Bates, C. J., Particle sizing techniques in multiphase flows A review. Flow Meas. Instrum., 1, 77-105 (1990)... 

Holographic diagnostic of sprays eliminates the depth of field correction problem of conventional photographic particle sizing techniques by acquiring... 

Before choosing a particle sizing technique, examination of the samples under a microscope is usually wise becau.se the range of sizes and shapes present can then he estimated. Most particle size methods are sensitive to particle shape and all are limited with respect to the particle size range. Particles with approximately spherical shapes are measured most accurately. Needles and other shapes that differ significantly from spherical are often analyzed by microscopy. 

Regarding N, it has been reported [116] that this parameter reaches a maximum during the nucleation stage if the polymerization is performed below the CMC, because the low availability of surfactant causes limited coagulation. On the other hand, N tends to increase in this stage when the surfactant concentration is above the CMC. During interval II, N is typically assumed to be constant, but some authors have reported that this parameter increases in this period [138, 150-152]. The subject is still a matter of debate due to the limitations of certain particle sizing techniques [125, 129, 130]. 

Sampling is by far the most important part of particle size analysis by microscopy (and probably all particle size techniques). A kilogram of drug substance will contain many millions of particles. Since, at most, the particle size analysis samples a few thousand particles, the measured particles must be selected with care. Allen [20] presents an extensive discussion of bulk sampling issues relevant to all particle size analysis, irrespective of the particular technique. Our interest, though, is primarily directed toward sampling as it relates to the specimen used for particle size analysis by microscopy. We will assume that the 50 mg or so of sample dehvered to the laboratory is truly representative of the bulk powder. 

The validity of the label as assessed by in vitro testing, using particle sizing techniques to ensure that the distribution of drug and label are the same, thus indicating that the label provides a useful surrogate for drug distribution... 

---