Particle shape and size - Analyses of powders

Particle shape and size - Analyses of powders

Defining particle shape and size

The size of a sphere can be defined in terms of its radius, or more com-monly, diameter. The size of a cube can be described in terms of the length of its side or diagonal. However, as shown in Figure 19.1, particles can have a diverse range of shapes from needle shape to irregular polygo-nal. Quantitatively measuring and defining the size of these particles can be a challenge. Nevertheless, the use of finely divided powders in phar-maceutical unit operations requires a numerical description of particle size, preferably as a single number, to enable comparison of different powder types and also of different batches of the same material. Using a one-dimensional property of a particle (such as its surface area or volume) and describing it in terms of an equivalent sphere allow the description of a three-dimensional object by a single number with respect to the property of interest. The criterion of equivalency of particle size to the size of a sphere is based on the powder’s intended use or application. For example, use of a powder for surface catalysis or comparison of dissolution rate of different batches would require surface area-based equivalency.

Figure 19.1 Examples of particle shapes commonly encountered for active pharmaceutical ingredients.

Irregular-shaped particles can be defined in terms of two parameters:

·           Diameter of an equivalent sphere. Powder processing technologies, such as milling and granulation, tend to change the shape of particles toward or closer to a spherical shape.

·           Aspect ratio, which is the ratio of longest to the smallest axis of a par-ticle. It would be one for a sphere and the largest for a needle-shaped particle. Aspect ratio helps define the deviation of a shape from a perfect sphere.

Many commonly used particle size measurement methods define the size of a particle in terms of the diameter of an equivalent sphere. There are several assumptions and/or limitations associated with this description. For exam-ple, defining particle size in terms of the diameter of an equivalent sphere requires a consideration of the criterion used to define equivalency. For example, two particles can be described as equivalent in terms of volume or surface area. Thus, size of a particle can be expressed as the diameter of a sphere of equivalent volume or surface area of the particle being analyzed.

Defining particle size distribution

Powders are a collection of particles of different sizes. Therefore, powders have a PSD rather than a single particle size. A single numeric descriptor of the PSD of a powder can be the mean particle size. The mean diameter of a set of particles in a powder sample can be described using either arith-metic mean or geometric mean. When using arithmetic mean diameter, the presence of fewer, larger diameter particles can skew the calculated average result toward the large particle size, which may not be truly representative of the batch. The distribution of particles of a powder often follows a unimodal (one peak) lognormal distribution (i.e., when log of particle size is plotted against the frequency of occurrence of the particles of each size—a Gaussian or normal distribution is obtained). Therefore, geometric mean diameter (GMD) is generally preferred to define the particle size of a powder.

The method for defining PSD needs to have the following properties:

·           Be independent of the statistical type of distribution in the sample, for example, normal or lognormal.

·           Be descriptive of the particle characteristics of interest to the intended application that is, expressing particle size as spheres of equivalent surface area or volume depending on the application.

The statistical measures listed in Table 19.1 are frequently used to charac-terize the PSD of a powder sample.

Table 19.1 Statistical measures used to define a particle size distribution

Desired particle shape and size

The desired particle size and shape of a powder is determined by its usage in the downstream unit operations. For example,

·           Uniform mixing of powders is greatly facilitated if they are of equiva-lent size by volume. Therefore, the mixing of two or more powders with similar particle size and shape is the most likely to produce uni-form distribution of each material in the mix.

·           Use of particles in inhalation devices requires particles to be of simi-lar sedimentation rate in the air. Particle size expressed as diameter of spheres with equivalent sedimentation rate in the air is called aero-dynamic diameter.

·           The surface area per unit weight or volume (specific surface area) of the powder determines the extent of physicochemical properties of a material that are of surface origin. For example, for crystal pack-ing structures that lead to the exposure of functional groups on the surface, a polymorphic form with greater specific surface area is more likely to show greater intensity of such surface phenomenon than another polymorphic form with lower specific surface area. Examples of such crystal surface-dependent physical properties include chemi-cal reactivity or surface adsorption in the solid state and the sticking tendency of a material to the stainless steel processing equipment dur-ing pharmaceutical manufacturing.

Notably, the spherical shape offers the least surface area per unit volume or weight of the material.

Factors determining particle shape

Particle shape is primarily determined by the intrinsic properties of the material and its manufacturing process. For example, crystal habits of a compound determine the crystal faces exposed to the surface of the solid. Solute–solvent interactions during crystallization determine which faces of a crystal grow faster than others. In general, faces of the crystal that inter-act more with the solvent grow at a slower pace than the faces that have less interaction with the solvent. Thus, crystal shape is a function of the solvent used during crystallization, and one can produce crystals of different shape having the same crystalline or polymorphic form.

Particle shape can be altered after crystallization. For example, milling of a drug substance results in smaller, irregular-shaped crystals that are closer to the spherical geometry. Also, pharmaceutical processes such as granula-tion, spheronization, and spray drying can produce larger particles that are closer to the spherical shape.

Techniques for quantifying particle shape and size

Particle size is commonly measured using one or more of the following techniques:

·           Sieve analysis: This is a conventional technique that involves mass fractionation of a powder sample on a set of sieves, or wire meshes, of defined size openings using mechanical vibration. Several sieves of increasing size openings are placed one over another. A powder sample is loaded on the top sieve. Mechanical vibration is applied to allow the powder to sift through as many sieves as it would until it reaches a state where powder particles do not move through the sieve openings any more. The amount of powder on each sieve is weighed and expressed as the size fraction is lower than sieve open-ing diameter above and is higher than the one below (on which the powder was retained). Thus, sieve analysis produces a weight distribution of particles in different sieve fractions. The sieve analy-sis data can be used to compare the PSD of two or more samples graphically, or by using the calculated mean particle diameter and/or the proportion of fines.

·           Laser diffraction analysis: Laser diffraction analysis is based on the size dependence of scattering of incident laser light by particulates in the sample. A powder sample is dispersed in an insoluble liquid or air and is passed through a beam of laser light. The scattered laser light intensity is recorded using a detector. The angle of light scattering decreases and the intensity of scattered light increases with the increasing particle size. Measuring the intensity of scat-tered light at a particular angle allows the estimation of size of the particle scattering the light. Cumulative plotting of size of all the particles in a powder sample produces a PSD of the sample.

·           Focused beam reflectance measurement: In situ measurement of particle or droplet size and size distribution in dispersed systems is often carried out using focused beam reflectance measurement (FBRM). This is an inline technique used to generate real-time data during chemical synthesis, such as crystallization, and phar-maceutical processing, such as granulation. A fast spinning laser beam is focused on the sample through a quartz lens in a conical pattern. The laser light that encounters a particle is reflected back to the lens, where a fiber optic collects the light and passes to a detector that quantifies the intensity. The time period between the incident and the reflected light, the speed of the rotating lens, and the speed of laser light are used to calculate the length of a par-ticle passing through the focus of the laser light. This is called the chord length. Collective plot of chord length of several particles produces a chord length distribution. Changes in the chord length distribution during processing are used as a fingerprint of the pro-cess dynamics.

·           Microscopy: Microscopy allows direct visual examination of powder particles. However, it provides only a two-dimensional image of a three-dimensional particle. Although this technique allows versatility with respect to sample types that can be examined, the sample prepa-ration process can introduce bias into the sample. It is a qualitative tool for most of the applications. Automated image analysis software is frequently used when quantitation is desired. Several commercial instruments are available that automate the process of image collec-tion and analysis, allowing the examination of several hundreds or thousands of particles in a sample.

·           Sedimentation: Sedimentation involves gravity or centrifugal force-assisted separation of the dispersed phase from the dispersion medium over time. The density difference between the dispersed phase and the dispersion medium leads to particle separation. Sedimentation is not a preferred method for the assessment of particle size and size distribution. It is more commonly used for the quality assessment of colloidal systems, such as suspensions and emulsions, functional-ity assessment of superdisintegrants, such as croscarmellose sodium, and separation of particles of extremely small size from the disper-sion medium.

·           Electrozone sensing: Changes in the electrical conductance through a small aperture with the flow of a fluid containing sus-pended particles are used to estimate the size and number of parti-cles in the dispersion medium. The electrical conductance changes when a particle flows through the aperture, with the change in conductance being proportional to the size of the particle. It is commonly used for counting biological cells and bacteria, using a coulter counter.

A comparison of these techniques with respect to their merits, demerits, range of particle size measured, and principle of operation is provided in Table 19.2.

Changing particle shape and size

Reduction in particle size of the API is frequently desired to improve the biopharmaceutical properties of the dosage form, such as its dissolution and absorption. Increase in particle size of the bulk powder is generally desired to improve its processability, such as flow properties. Particle size of the powders can be decreased by controlled crystallization or milling (also called comminution) of preformed particles. Particle size can be increased by controlled agglomeration through granulation.

Table 19.2 Techniques for measurement of particle size distribution

Processing steps to change the size of the particles invariably also results in changes in particle shape. Milling of odd-shaped particles, such as nee-dles, tends to reduce their aspect ratio and to change the shape toward spherical dimensions. Granulation is often accompanied by shear force and consolidation of particles into larger particles, which tend to have an irregular shape with low aspect ratios. Both milling and granulation tend to increase the sphericity of particles.