Particle Size & Shape PDF 2024-1

MPharm Programme Particle Size & Shape Dr Paul Carter Slide 1 of 30 MPharm Preformulation- Partical Size & Shape  Particle size...

MPharm Programme Particle Size & Shape Dr Paul Carter Slide 1 of 30 MPharm Preformulation- Partical Size & Shape  Particle size “… The size of the particles obtained depended on many variables and the particle size affected the burning characteristics significantly. Because the combustion of black powder occurs on the surfaces, fine grained powder burns much faster than powder made from large particles. Fine powder is more powerful, but it built too much pressure too fast for the guns of the day. The solution to slowing the rate of burn so that the cannon would not explode as frequently was to make powder with larger particles of consistent size…” Black Powder – the most important material discovery? ca. 1250 (Brian Stockton, Sirius-analytical.com) Slide 2 of 30 MPharm Preformulation- Particle Size  Photomicrograph for α-lactose monohydrate sieve fraction (63–90 µm) powder, magnification x 368 irregular, infinite number of dimensions Slide 2 of 30 MPharm Preformulation- Particle Size  Particle size analysis for α-lactose monohydrate sieve fraction (63–90 µm) using laser light diffraction after dispersed in butan-1-ol (with sonication for 4 min) Slide 3 of 30 MPharm Preformulation- Particle Size & Shape  Photomicrograph for α-lactose monohydrate sieve fraction (63–90 µm) powder, magnification x 733 Slide 4 of 30 MPharm Preformulation- Particle Size & Shape  Photomicrograph for salbutamol sulphate micronised powder, magnification x 5560 Salbutamol sulphate x 5560 Slide 5 of 30 MPharm Preformulation- Particle Size & Shape  Why is particle size important? particles produced from crystallisation and size reduction need to know particle size of a powder during formulation, manufacture and use of dosage forms Why? choice of appropriate excipients for powders mixtures (avoid segregation) 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 (Stokes’ law) for lung delivery, only fine particles will reach deep lung areas drug release and bioavailability are influenced by available surface area of drug i.e. particle size 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) and needs to be very carefully controlled. Slide 6 of 30 MPharm Preformulation- Particle Size & Shape  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 sub- micron or very broad? The amount of material available sampling/sample size 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 Slide 6 of 30 MPharm Preformulation- Particle Size & Shape  Factors to consider before conducting a sampling scheme Nature of the powder – physical properties e.g. packing, flow properties, tendency to segregate, friability Quantity of powder and sample size Associated assay techniques Convenience Degree of precision required Avoidance of bias e.g. selection of sample does not affect the selection of another sample. Randomisation helps avoid bias but rigorous procedures must be used Slide 3 WEEK 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 Liquid dispersion mechanisms Surface tension reduction Change of ionic species (pH change) Shear stress via ultrasound waves - high localised pressures over small distances are important for small particle dispersion (micron/sub-micron) Slide 6 of 30 Preformulation- Particle Size & Shape WEEK Measurement techniques Particle size is often measured using a technique which does not measure size – What is the technique actually measuring? – How good is the correlation? – 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 Slide 6 of 30 Preformulation- Particle Size & Shape WEEK Measurement techniques Slide 6 of 30 Preformulation- Particle Size & Shape WEEK Equivalent sphere An equivalent sphere is a sphere which is equal to the real particle in the physical parameter which we are measuring Slide 6 of 30 Preformulation- Particle Size & 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. Slide 7 of 30 MPharm Preformulation- Particle Size & Shape  α-lactose monohydrate (63-90 µm) size fraction mixed with 1.5 % w/w ipratropium bromide (micronised) Slide 8 of 30 MPharm Preformulation- Particle Size & Shape  Length, breadth & thickness Slide 9 of 30 MPharm Preformulation- Particle Size & Shape  Particle size grades Slide 10 of 30 MPharm Preformulation- Particle Size & Shape  Feret’s diameter: distance between 2 tangents on opposite sides of the particle Martin’s diameter: distance between opposite sides of the particle measured crosswise of the particle and on a line bisecting the projected area. Slide 11 of 30 MPharm Preformulation- Particle Size & Shape  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 Slide 12 of 30 MPharm Preformulation- Particle Size & Shape  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 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 Slide 13 of 30 MPharm Preformulation- Particle Size & Shape  Qualitative description of shape Slide 14 of 30 MPharm Preformulation- Particle Size & Shape  Quantitative determination of shape Slide 15 of 30 MPharm Preformulation- Particle Size & Shape  Shape factors – projected area ratio Slide 16 of 30 MPharm Preformulation- Particle Size & Shape  Shape factors - circularity Slide 17 of 30 MPharm Preformulation- Particle Size & Shape  Measurement of size - Image analysis Slide 18 of 30 MPharm Preformulation- Particle Size & Shape  Measurement of size - conductivity Slide 19 of 30 MPharm Preformulation- Particle Size & Shape  Coulter counter particles dispersed in electrolyte 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 (block orifice) or too small (below noise limit); two particles may enter orifice at same time Slide 20 of 30 MPharm Preformulation- Particle Size & Shape  Sieve analysis – weight distribution Slide 21 of 30 MPharm Preformulation- Particle Size & Shape  sieving Slide 22 of 30 MPharm Preformulation- Particle Size & Shape  Laser light scattering 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) Slide 23 of 30 MPharm Preformulation- Particle Size & Shape  Laser light scattering Slide 24 of 30 MPharm Preformulation- Particle Size & Shape  Particle size distribution Typically, the number of fine particles exceeds the number of coarser particles - positive skew Slide 25 of 30 MPharm Preformulation- Particle Size & Shape  Size distribution Slide 26 of 30 MPharm Preformulation- Particle Size & Shape  Number vs weight distribution Slide 27 of 30 MPharm Preformulation- Particle Size & Shape  Example Optical microscopy, 100 particles, equivalent area diameter - eyepiece graticule Slide 28 of 30 MPharm Preformulation- Particle Size & Shape  % cumulative undersize distribution Circle No. size (µm) % % cumul undersize 0-1 0 1-2 0 2-3 27 - 38 0 3-4 38 - 53 15 0 (< 38 µm) 4-5 53 - 75 20 15 (< 53 µm) 5-6 75 -106 25 35 (< 75 µm) 6-7 106 -150 30 60 (< 106 µm) >7 >150 10 90 (< 150 µm) % cumul oversize? Plot % undersize/oversize vs size (µm). 50 % = median size 25 and 75% = lower and upper quartile Slide 29 of 30 MPharm Preformulation- Particle Size & Shape  Example (not using data from previous slide) of Plot of percent cumulative undersize for α-lactose monohydrate sieve fraction (63–90 µm). 100 90 % Cumulative undersize 80 70 60 50 40 Sample1 30 Sample2 20 10 0 0 20 40 60 80 100 120 140 160 Particle size (µm) Slide 30 of 30 MPharm Preformulation- Particle Size & Shape