Particle Size and Shape PDF

**Why is particle size important?** - Particles produced from crystallisation and size reduction - Need to know particle size of a powder during formation, manufacture and use of dosage forms - Why? - Choice of appropriate excipients for powders mixtures (avoid segregation) -...

**Why is particle size important?** - Particles produced from crystallisation and size reduction - Need to know particle size of a powder during formation, manufacture and use of dosage forms - Why? - Choice of appropriate excipients for powders mixtures (avoid segregation) - uniform! Powder flow related to particle size - Uniformity of content of low dose drugs in a powder mixture - For suspensions of particles; use fine particles to avoid 'scratchy' feeling on skin and to avoid rapid settling (Stoke's law) ⇒ size range (ideally colloidal size) - For lung delivery, only fine particles will reach deep lung areas - Drug release and bioavailability how much drugs get into blood are influenced by available surface area of drug i.e. particle size -- increased surface area with smaller particles improves dissolution and absorption rates. - Particle size is a critical material attribute when manufacturing many dosage forms - It will influence the processing operations & performance of the product (and therefore the quality) so it needs to be very carefully controlled **Considerations before size measurement** - The starting point in sizing is by using visual techniques -- optical light microscopy - How the size data are used -- does the measurement control one particular aspect of particle behaviour? Statistics? - The medium in which the sample is presented - The formulation type / Particle shape - The size distribution to be measured, e.g. is the distribution submicron or very broad? - The amount of material available - Safety considerations -- materials which have a low OEL (occupational exposure limit) need to be adequately contained; this may restrict the use of some particle size techniques unless adequate controls are put in place **Factors to consider before conducting a sampling scheme 🌟** - Nature of the powder -- physical properties e.g. packing, flow properties, tendency to segregate large particles float/small particles sediment, friability -- strength (break or not) - Quantity of powder and sample size - Associated assay techniques - Convenience - Degree of precision required - Avoidance of precision required e.g. selection of sample does not affect the selection of another sample. Randomisation helps avoid bias, but rigorous procedures must be used **Equivalent sphere** - An equivalent sphere is a sphere which is equal to the real particle in the physical parameter which we are measuring A diagram of a rock Description automatically generated **Particle Size and Shape** - Information on particle size and shape needed to characterise a particle - Regular geometric figures, one or more dimensions needed in addition to identification of shape. For sphere, cube and regular tetrahedron only one dimension needed  - **α-lactose monohydrate** (63-90 μm) size fraction mixed with **1.5% w/w ipratropium bromide** (micronized) A close-up of a microscope Description automatically generated - **Length, breadth & thickness**  - **Particle size grades** A white paper with black text Description automatically generated - **Statistical particle diameters** a. b. **Feret's diameter**: distance between 2 tangents on opposite sides of the particle c. **Martin's diameter**: distance between opposite sides of the particle measured crosswise of the particle and on a line **bisecting** the projected area  d. **Equivalent particle diameter** - **Equivalent circle** (or **projected area**) diameter is the diameter of a circle with the same area as the particle profile. Commonest equivalent diameter - **Equivalent volume diameter** is the diameter of a sphere with a volume equal to that of the particle A diagram of a circle and a circle with text Description automatically generated with medium confidence  **Particle shape 🌟** - Fundamental property of powder particles - British Pharmacopoeia gives descriptive terms to use for shape (**qualitative**) e.g. acicular, angular, round, fibrous, flaky, cubic -- **Qualitative description of shape** A collage of different types of objects Description automatically generated - **Quantitative characterisation** using microscopy/image analysis - Two-dimensional shape factors - Three-dimensional shape factors  - Method chosen should represent a particle property relevant to the process of powder handling studied e.g. -- if making spherical pellets; sphericity / if studying powder packing -- general geometric shape **Shape factors** 1. 2. **Projected area ratio** 3. **Circularity** 4. 5. **Image analysis** 6. **Conductivity** (old-fashioned) **Particle Size Distribution** - Typically, the number of fine particles exceeds the number of coarser particles -- **positive skew** A graph with text and numbers Description automatically generated with medium confidence - **Size distribution** - **Number vs weight distribution** Ex) Optical microscopy, 100 particles, equivalent area diameter -- **eyepiece graticule**  A diagram of a grid with circles and circles Description automatically generated with medium confidence **% Cumulative Undersize Distribution** A yellow paper with numbers and a percentage Description automatically generated with medium confidence - **% cumulative oversize?** - Plot % undersize/oversizew vs size (μm) - 50% = median size - 25 and 75% = lower and upper quartile Ex) (not using data from previous slide) of Plot of percent cumulative undersize for α-lactose monohydratre sieve fraction (63-90 μm) **Measurement techniques** - Liquid dispersion is nearly always possible - Dilution will not change the distribution if the dispersing fluid mimics the host fluid - Highly water-soluble materials can be dispersed in oil - Particle size is often measured using a technique which **does not measure size** - What is the technique actually measuring? - How good is the correlation? -- acicular drugs? - Can we compare results from different techniques? - Real particles are not spheres - Particle size methods have a different concept of **accuracy** compared with other analytical methodologies 1. **Sieve analysis -- weight distribution** A diagram of a dinosaur\'s head Description automatically generated - Lowest sieve diameter of 45 μm, and maximum diameter of 1000 μm - Use a **series, stack** or **'nest'** of sieves, which has the smallest mesh above a collection tray, above which are meshes that become progressively coarser towards the top - Sieve stack usually comprises six to eight with an **aperture progression** based on [\$\\sqrt{}2\$]{.math.inline} change in area between adjacent sieves 1. Powder is loaded onto the coarsest sieve at the top of the assembled stack -- subjected to mechanical agitation 2. After a suitable time, the sieve diameter of particles pass the minimum square aperture 3. The weight material collected on each stage is determined and used to plot a cumulative-undersize plot - Rarely complete as some particles can take a long time to orient themselves -- recommended to continue until the mass on any sieve does not change by more than 5% or 1 g of the previous mass on that sieve 2. **Liquid dispersion mechanisms** - Surface tension reduction -- By lowering the surface tension, surfactants allow the liquid to displace air or other contaminants from the particle surfaces, promoting better dispersion - Change of ionic species (pH change) -- Adjusting the pH of the liquid medium can influence the ionic environment around the particles, altering the surface charge and inter-particle interactions 1. Particles often carry a surface charge, which creates an electric double layer around them. The thickness and stability of this layer are influenced by pH 2. By changing the pH, **the zeta potential** (a measure of surface charge) can be adjusted to **maximize repulsion** between particles, **preventing aggregation** 3. This mechanism works well with particles prone to flocculation in neutral or suboptimal pH conditions - Shear stress via ultrasound waves -- high localised pressures over small distances are important for small particle dispersion (micron/sub-micron) 1. When ultrasonic waves pass through a liquid medium, they cause **rapid pressure changes**. This **results** in: **Cavitation**: Bubbles form and collapse violently, releasing energy **Shear Forces**: The rapid motion and turbulence break apart particle agglomerates 2. This mechanism is particularly important for **dispersing small particles** (micron or sub-micron scale), as it **overcomes strong van der Waals forces** 3. **Coulter counter (Electrical sensing zone method)** - Particles dispersed in electrolyte to form a very diluted suspension -- subjected to ultrasonic agitation -- to break up any particle aggregates (**dispersant** may also be added to aid particle **deaggregation**) - Particle sucked through orifice -- changes electrical conductivity -- electrical resistance increases - This gives voltage pulse proportional to volume of particle - Number of particles = number of pulses - Gives equivalent volume diameter - Calibrate with monosize particles - Lower limit 0.3 mm - Problems: particles may be too large (coarser particles block a small-diameter orifice) or too small (below noise limit); two particles may enter orifice at the same time **Dispersion** must be sufficiently dilute to avoid the occurrence -- more than one particle may be present in the orifice at any one time -- may **result** in: 1. A loss of count (i.e. two particles counted as one) 2. Inaccurate measurement -- as the equivalent sphere diameter calculated is based on the volume of two particles, rather than one) 4. **Laser light scattering (Laser diffraction)** - High speed, versatile, high reproducibility - Laser light source (e.g. helium-neon laser), suitable detector, flow through cell and stirrer for dispersing particles, data processing unit - Particles (in dilute suspension) hit by laser beam and scatter light at angle inversely proportional to particle size i.e. large particles scatter at small angle - Scattered light picked up by series of photodetectors and gives an equivalent volume diameter - Assume every particle scatters light with same efficiency and particles are spherical and opaque to light (do not transmit light) A diagram of a laser light scattering Description automatically generated **Selection of a particle size analysis method**