Particle Size Analysis

Question 1

Particle size

Answer 1

• the most important physical property of particulate samples is particle size. Particle size measurement is routinely carried out across a wide range of industries, including the pharmaceutical industry.
• Measuring particle size and understanding how it affects your products and processes can be critical to the success of pharmaceutical manufacturing businesses.
• Particle size has a direct influence on material properties such as reactivity or dissolution rate, e.g. catalysts, tablets

Question 2

Dissolution rate

Answer 2

• The rate at which the drug dissolves is proportional to the surface area exposed to the solvent (Noyes–Whitney equation, Semester 2), which increases as the particle size is reduced. The larger surface exposed to the solvent significantly increases the dissolution rate of smaller particles.
• The dissolution rate influences the rate of absorption, the speed of onset of effect and the duration of therapeutic response of slightly soluble drugs.

Question 3

Uniformity of dosage of very potent drugs

Answer 3

Particle size influences the uniformity of dosage of very potent drugs formulated as a solid dosage form; this is greater with smaller particles because of the more significant number of particles constituting the dose.

Question 4

Powder flow

Answer 4

• Particle size also has essential effects on the bulk properties, particularly those that influence powder flow during manufacturing processing when large quantities of material are handled.
• The ability of powders to flow mainly because of its effect on the cohesivity of the particles, which increases as the particle size decreases. Particles larger than 250 µm are usually relatively free-flowing, but very fine particles (below 10 µm) are generally extremely cohesive and have a high resistance to flow.
• Pharmaceutical powders must flow freely into storage containers or hoppers of tablet and capsule-filling equipment so that a uniform packing of the particles and hence a uniform tablet or capsule weight is achieved. Uneven particle flow can also cause excessive entrapment of air within the powders, promoting the capping of tablets.

Question 5

Suspensions

Answer 5

• The particle size of the active agent plays a vital role in the physical stability and
  bioavailability of the suspension drug product.
• Diffusion will result in an improved, more homogeneous distribution of the
  particles throughout the system. There is an effective size range above which
  diffusion will be negligible, and for particles of radius greater than approximately
  1 μm to 2 μm, diffusion can be ignored
• Sedimentation is the downward movement of particles under gravity and is
  observed for particles with radii of approximately 0.5 μm or greater.
• Reducing the particle size will increase diffusion and reduce sedimentation, with
  a larger effect on the sedimentation rate. Particle size reduction would generally
  be regarded as beneficial because of these effects.
• However, particle size is a key parameter governing particulate interactions and
  so manipulation of particle size will have a direct effect on flocculation behaviour.
  Changing the particle size may lead to increased or lowered stability.

Question 6

Emulsions and particle size

Answer 6

• Emulsions are two-phase dispersion of liquids that are usually not miscible. The most common examples are oil in water and water in oil. It is essential to control droplet sizes as they influence emulsion stability, biopharmaceutical properties, and clinical use.
• The coalescence of fat globules in intravenous lipid emulsions (IVLEs) can cause
  pulmonary embolisms in small blood vessels with diameters ranging between 4 and 9 µm and larger blood vessels with diameters ~20 µm.
• The droplet size distribution influences the clearance kinetics of parenteral emulsions. Individual droplets should not exceed approximately 5 μm in diameter (the diameter of the smallest blood vessels) in intravenous emulsions because of
  the possibility of pulmonary embolism.
• Droplets smaller than 5 μm are rapidly cleared from the bloodstream by elements of the reticuloendothelial system, also known as the mononuclear phagocyte system (primarily by Kupffer cells of the liver).

Question 7

Creaming of emulsions

Answer 7

• Large droplets have a greater tendency to cream and coalesce, and a broad particle size
  distribution encourages an increase in droplet size. The most physically stable pharmaceutical emulsions generally have small droplets and narrow size distributions.
• Creaming is a process that occurs when the dispersed droplets separate under the
  influence of gravity to form a layer of more concentrated emulsion, the cream.
• Creaming occurs inevitably in any dilute emulsion containing relatively large droplets (~1 μm) if there is a density difference between the oil and water phases. The most effective way in practice to reduce creaming is to prepare emulsions with small droplet sizes and
  to thicken the external phase by the addition of viscosity modifiers.
• For oral emulsions, gastrointestinal absorption increases as droplet sizes decrease. Whilst this is desirable with oral formulations of nutrient oils alone or with drugs dissolved in them, it may give adverse clinical effects with laxative oils that are used for a local effect and are toxic if absorbed.

Question 8

Aerosols and Sprays

Answer 8

Pulmonary delivery of drugs because only very fine particles can remain dispersed and only very fine particles can penetrate the alveolar regions of the respiratory tract. But there is an optimum. Indeed, if the particle size is reduced too far, particles may be exhaled and not deposited.