The appropriate size of particulate solids is important to achieve the optimal formulation and production of safe and effective medicines. When a drug is synthesized and formulated, the particle size of the drug and other powders in the formulation is determined. This will ultimately impact the physical performance of the drug product (medicine) and the subsequent pharmacological effects of the drug.

The Impact of Particle Size on Production

Particle size influences the production of many formulated medicines. For instance, both tablets and capsules are manufactured with use of equipment that controls the mass of drug (and other solid excipients) by volumetric filling. Therefore any interference with the uniformity of fill volumes may alter the mass of drug incorporated into the tablet or capsule, adversely affecting the content uniformity of the product. Powders with different particle sizes have different flow and packing properties, which alter the volumes of powder during each encapsulation or tablet compression event. To avoid such problems, the particle sizes of drugs and other powders may be defined, and controlled, during formulation so that problems during production are avoided.

The Impact of Particle Size on Dissolution Rate

Following administration of the medicine, the dosage form should release the drug into solution at the optimal rate. This depends on several factors, one of which will be the dissolution rate of the drug, which is inversely related to particle size as described by the Noyes–Whitney equation. Thus reducing the size of particles will generally increase the rate of dissolution, which can have a direct impact on bioavailability and subsequent drug handling by the body.

For example, the drug griseofulvin has a low solubility by oral administration, but is rapidly distributed following absorption; reducing the particle size increases the rate of dissolution and consequently the amount of drug absorbed. However, a reduction in particle size to improve the dissolution rate and hence bioavailability is not always beneficial. For example, reducing the particle size of nitrofurantoin increases its dissolution rate, which may consequently produce adverse effects because of its more rapid absorption.

Mean particle sizes

Suppose we have conducted a microscopic examination of a sample of a powder and recorded the number of particles lying within various size ranges. To compare these values with those from, say, a second batch of the same material, we usually compute an average or mean diameter as our basis for comparison.

The equation for the average particle size, whether it is an arithmetic, geometric, or harmonic mean diameter, is:

$$ d_{mean}=(\frac{∑nd^{p+f}}{∑nd^f})^{\frac{1}{p}} $$

In this equation, n is the number of particles in a size range whose midpoint, d, is one of the equivalent diameters mentioned previously. The term p is an index related to the size of an individual particle, because d raised to the power p = 1, p = 2, or p = 3 represents the particle’s length, surface area, or volume, respectively. The value of the index p also determines whether the mean is arithmetic (p is positive), geometric (p is zero), or harmonic (p is negative). For a collection of particles, the frequency with which a particle in a certain size range occurs is expressed by nd^f. When the frequency index f has values of 0, 1, 2, or 3, the size frequency distribution is expressed in terms of the total number, length, surface area, or volume of the particles, respectively.

Classification of Powders by Particle Size

In practice, the pharmaceutical scientist may not need to know the precise size of particles intended for a particular purpose, rather a size range may be sufficient, and consequently powders are frequently graded on the basis of the size of the particles of which they comprise. The size or ‘fineness’ of a powder may be expressed by reference to the passage/ nonpassage of the powder through sieves of defined mesh size, or to specific descriptive terms, for instance:

• coarse powder: median size (X₅₀): greater than 355 µm;
• moderately fine powder: median size (X₅₀): 180 µm to 355 µm;
• fine powder: median size (X₅₀): 125 µm to 180 µm;
• very fine powder: median size (X₅₀): 125 µm or less; and
• micronized powder: median size (X₅₀): less than 10 µm (most <5 µm).

Reference:

• Aulton, M. (2018). Aulton’s pharmaceutics, the design and manufacture of medicines. Edinburgh. : Elsevier
• Sinko, P. (2011). Martin’s Physical Pharmacy and Pharmaceutical Sciences. Baltimore, : Lippincott Williams & Wilkins, a Wolters Kluwer business.