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See all Premium member Presentation Transcript Particle Size Analysis : Particle Size Analysis PHARMACEUTICAL MATERIAL AND PRODUCT CHARACTERIZATION PHR553 August 2009 Dr Javad Sameni Reference: Aulton Outlines: : Outlines: Particle size definition Particle size distribution Particle size analysis methods Effect of Particle Size : Effect of Particle Size Processing blending, drying, tabletting Drug absorption in GIT rapid dissolution due to increased surface area with small particles Optimum particle size required in controlled release Particle Shape : Particle Shape Acicular – needle-shaped Angular – sharp-edged Crystalline – geometric shape Dendritic – branched crystalline shape Granular equidimensional irregular shape Spherical – global shape 1. Particle size definitions : 1. Particle size definitions Particle diameters Shape factors Particle size and shape A. Particle diameters : A. Particle diameters More than one sphere for a given irregular particle shape. The enclosed area of the image is measured and equated to the diameter of a circle with the same area. Mean particle diameters : Mean particle diameters Statistical diameters which are averaged over many different orientations to produce a mean value for each particle diameter. Feret’s and Martin’s diameter : Feret’s and Martin’s diameter Feret’s diameter is determined from the mean distance between two parallel tangent to the projected particle diameter. Martin’s diameter is the mean chord length of the projected particle perimeter, which can be considered as the boundary separating equal particle areas. Feret’s and Martin’s diameter (Cont…) : Feret’s and Martin’s diameter (Cont…) dF Feret’s diameter dM Martin’s diameter dM dM dM Comparison: Martin and Feret : Comparison: Martin and Feret B. Shape Factors : B. Shape Factors Shape factor refers to a value that is affected by an object's shape but is independent of its dimensions. Shape factors are calculated from measured dimensions, such as diameter, chord lengths, area, perimeter, etc. The dimensionless quantities often represent the degree of deviation from an ideal shape, such as a circle, sphere. Shape factors are often normalized, that is, the value ranges from zero to one. a. Aspect ratio : a. Aspect ratio Aspect ratio is a function of the largest diameter and the smallest diameter orthogonal to it. The normalized aspect ratio varies from approaching zero for a very elongated particle. b. Circularity : b. Circularity Circularity is a function of the perimeter P and the area A. Circle equivalent diameter: diameter of a circle that has the same area as the projected particle image. Calculation of circularity parameters : Calculation of circularity parameters Circularity and aspect ratio : Circularity and aspect ratio c. Particle size and shape : c. Particle size and shape Precise particle size is difficult to obtain due to the irregular shape of particles. Non-spherical shape : Non-spherical shape For spherical particles, defining particle size is easy, it is simply the diameter of the particle. For non-spherical particles, the term “diameter” is strictly inapplicable. For example what is the diameter of a fiber? Particle size diameters : Particle size diameters Sphere is the only shape that can be described by one unique number. Equivalent surface diameter : Equivalent surface diameter Equivalent volume/mass diameterD[4,3] : Equivalent volume/mass diameterD[4,3] Equivalent volume-surface diameterِD[3,2] : Equivalent volume-surface diameterِD[3,2] Slide 22: Different techniques give different means. Basic principle : Basic principle Imagine we have 3 spheres with diameters 1, 2 and 3 units. (1+2+3)/3 = 2 Number-length Mean D[1,0] = 2 (12+22+32)/3 = 4.67 Number-surface area Mean D[2,0] = 2.16 (13+23+33)/3 = 12 Number-Volume/Mass Mean D[3,0] = 2.29 Difficulty with counting particles Slide 24: Surface Area Moment Mean (Sauter Mean Diameter): D[3,2] Volume/Mass Moment Mean: D[4,3] (13+23+33)/(12+22+32)= 2.57 (14+24+34)/(13+23+33)= 2.72 Number and volume distributions : Number and volume distributions Number of man-made objects orbiting the earth in space. Sphericity : Sphericity Sphericity is a measure of how spherical (round) an object is. Sphericity : Sphericity Sphericity (Ψ) of a particle is the ratio of the surface area of a sphere (with the same volume as the given particle) to the surface area of the particle. where Vp is volume of the particle and Ap is the surface area of the particle Sphericity : Sphericity Schematic representation of difference in grain shape. Two parameters are shown: sphericity (vertical) and rounding (horizontal). 2. Particle size distribution : 2. Particle size distribution The particle size distribution ("PSD") of a powder, or granular material, or particles dispersed in fluid, is a list of values or a mathematical function that defines the relative amounts of particles present, sorted according to size. The method used to determine PSD is called Particle size analysis, and the apparatus a particle size analyzer. Significance of PSD : Significance of PSD The PSD of a material can be important in understanding its physical and chemical properties. It affects the reactivity of solids participating in chemical reactions, and needs to be tightly controlled in many industrial products such as the manufacture of printer toner, cosmetics, pharmaceutical, etc. Slide 31: It is unusual for particles to be completely monosized. Most powders contain particles with a large number of different diameters. The PSD may be expressed as a "range" analysis, in which the amount in each size range is listed in order. Histogram : Histogram The percentage of particles with equivalent diameter. Types of PSD : Types of PSD Skewed distribution Normal distribution Bimodal distribution Histogram and Frequency distribution curve : Histogram and Frequency distribution curve PSD - Liposome : PSD - Liposome Skewed to the right PSD – Colloidal silica : PSD – Colloidal silica Skewed to the left PSD - PVC Latex overlay of two sample distributions : PSD - PVC Latex overlay of two sample distributions High polydispersity index Almost monodisperse PSD - Polystyrene Latex Blend : PSD - Polystyrene Latex Blend Bimodal distribution Skewed distribution : Skewed distribution Bimodal distribution : Bimodal distribution Powder after milling Unbroken particles produce a mode towards the highest particle size Fractured particles appears lower down the size range. Frequency distribution data : Frequency distribution data Cumulative distribution : Cumulative distribution PSD may also be presented in "cumulative" form, in which the total of all sizes "retained" or "passed" by a single notional "sieve" is given for a range of sizes. Cumulative frequency distribution data : Cumulative frequency distribution data Cumulative frequency distribution data (undersize) : Cumulative frequency distribution data (undersize) Cumulative frequency distribution data (undersize) : Cumulative frequency distribution data (undersize) Powder (a) has a larger range or spread of equivalent diameters than the powder (b). Point a corresponds to the median diameter. b is the lower quartile point c is the upper quartile point Range and cumulative distribution : Range and cumulative distribution A volume distribution, showing the volume percentage of particles that have given the size. Undersize plot : Undersize plot Example : Example Example : Example Particle size analysis report : Particle size analysis report Span= [d(0.9)–d(0.1)] / d(0.5) Particle size distribution : Particle size distribution The median particle size is the particle diameter that divides the frequency distribution in half. Fifty percent of the mass has particles with a larger diameter, and fifty percent of the mass has particles with a smaller diameter. Histogram of a particle size distribution Lognormal Size Distribution : Lognormal Size Distribution When the particle diameters are plotted on a logarithmic scale against the frequency of occurrence, a bell-shaped curve is generated. Histogram of a lognormal particle size distribution MEAN : MEAN This is some arithmetic average of the data. There are a number of means that can be calculated for particles. MEDIAN : MEDIAN This is the value of the particle size which divides the population exactly into two equal halves i.e. there is 50% of the distribution above this value and 50% below. (Could be volume, surface , length or number) D[v,50]-Volume median D[s,50]-Surface median D50, D0.5 (without reference to the type of median) MODE : MODE This is the most common value of the frequency distribution i.e. the highest point of the frequency curve. Normal distribution : Normal distribution Bimodal distribution : Bimodal distribution Barium Titanate : Barium Titanate Average size = 70 nm Size 550nm : Size 550nm Size 76 nm : Size 76 nm Representing the size distribution : Representing the size distribution Volume distributions, as the name suggests, are based on the volume occupied by their constituent particles. One million 1µm spherical particles will occupy the same volume as one 100µm particle. This should be remembered if you ever compare volume distribution results with a number-based distribution. Conversion from one to another is often error prone! Representing the size distribution : Representing the size distribution Imagine we have 3 particles with diameters of 1,2,3 units. If these were measured by microscopy – a technique that produces a number distribution - then we would produce the following distribution… Representing the size distribution : Representing the size distribution Representing the size distribution : Representing the size distribution 3. PSD Measurement Techniques : 3. PSD Measurement Techniques Sieve analysis Optical counting methods Electrical counting methods Sedimentation techniques Laser diffraction methods Acoustic spectroscopy particle-sizing techniques : particle-sizing techniques The goal of all particle-sizing techniques is to provide a single number that is indicative of the particle size. Most sizing techniques therefore assume that the material being measured is spherical and report the particle size as the diameter of the “equivalent sphere”. The way the equivalent sphere approximation works is shown for an irregularly-shaped particle. The diameter reported for this particle will be dependent on the chosen technique. a. Sieve analysis : a. Sieve analysis This continues to be used for many measurements because of its simplicity, cheapness, and ease of interpretation. Methods may be simple shaking of the sample in sieves until the amount retained becomes more or less constant. Alternatively, the sample may be washed through with a non-reacting liquid (usually water) or blown through with an air current. The smallest practical sieve size is 20-40 µm. Sieve analyzer Sieves Disadvantages : Disadvantages A 20 μm sieve is exceedingly fragile, and it is very difficult to get material to pass through it. The longer the measurement, the smaller the answer . Insufficient energy fails to break down loose agglomerates. Sieve shaker b. Optical counting methods : b. Optical counting methods We can directly look at the particles and judge whether good dispersion, any agglomeration, particle shape and etc. PSDs can be measured microscopically by sizing against counting. For a statistically valid analysis, millions of particles must be measured. This is difficult when done manually, but automated analysis of electron micrographs is now commercially available. Optical microscope : Optical microscope 2D image of a 3D particle : 2D image of a 3D particle Describing a 3D particle is often a more complex matter than it first appears. Image analysis systems capture a 2D image of the 3D particle and calculate various particle size and particle shape parameters from this 2D image. Types of microscopes : Types of microscopes Optical theory microscopes (Light microscope) Electron microscopes (e.g., SEM) Scanning probe microscope (SPM) 1. Optical microscopes : 1. Optical microscopes Typical magnification of a light microscope is up to 1500x with a resolution of around 200nm. A stereo microscope is often used for lower-power magnification on large subjects. Many wavelengths of light are used to excite fluorescence emission from objects for viewing by eye or with sensitive cameras. New Digital microscope using optics and a camera to output a digital image to a monitor. 2. Electron microscopes : 2. Electron microscopes Scanning electron microscope (SEM): looks at the surface of bulk objects by scanning the surface with a fine electron beam and measuring reflection. Transmission electron microscope (TEM): passes electrons completely through the sample. This requires careful sample preparation, since electrons are scattered so strongly by most materials. SEM and TEM : SEM and TEM SEM image of a white blood cell, platelet and red blood cell. TEM image of cell organelles 3. Scanning probe microscopy : 3. Scanning probe microscopy Atomic Force Microscope (AFM) Contact AFM Non-contact AFM Dynamic contact AFM Tapping AFM Types of microscopes : Types of microscopes Disadvantages : Disadvantages Few particles are examined Need sample preparation Which dimension do we measure? c. Electrical counting methods(Coulter Counter) : c. Electrical counting methods(Coulter Counter) Coulter counter measures the momentary changes in the conductivity of a liquid passing through an orifice that take place when individual non-conducting particles pass through. The particle count is obtained by counting pulses, and the size is dependent on the size of each pulse. Principle of Coulter Counter : Principle of Coulter Counter The principle of operation is very simple. A glass vessel has a hole or orifice in it. Dilute suspension is made to flow through this orifice and a voltage applied across it. As particles flow through the orifice the capacitance alters and this is indicated by a voltage pulse or spike. Principle of Coulter Counter : Principle of Coulter Counter Disadvantages : Disadvantages Difficult to measure emulsions. Must measure in an electrolyte. For organic based materials this is difficult. For materials of relatively wide particle size distribution the method is slow. Dense materials or large materials are difficult to force through the orifice as they sediment before this stage. d. Sedimentation techniques : d. Sedimentation techniques These are based upon study of the terminal velocity acquired by particles suspended in a viscous liquid. Sedimentation time is longest for the finest particles, so this technique is useful for sizes below 10 μm, but sub-micrometer particles can't be reliably measured due to the effects of Brownian motion. Principle of Sedimentation : Principle of Sedimentation Typical apparatus disperses the sample in liquid, then measures the optical density of successive layers using visible light or x-rays. Andreasen pipette Disadvantages : Disadvantages Speed of measurement is slow. Not for emulsions. Accurate temperature control. (Viscosity) e. Laser diffraction methods : e. Laser diffraction methods These depend upon analysis of diffracted light produced when a laser beam passes through a dispersion of particles in air or in a liquid. The angle of diffraction increases as particle size decreases, so that this method is particularly good for measuring sizes below 1 μm. Laser diffraction methods (Cont …) : Laser diffraction methods (Cont …) In laser diffraction, particle size distributions are calculated by comparing a sample’s scattering pattern with an appropriate optical model using a mathematical inversion process. Two different models are used: the Fraunhofer Approximation and Mie Theory. Mie theory has been found to be more accurate over a wider range of sizes – particularly for particles less than 50 microns in size. Laser Diffraction – Light Scattering : Laser Diffraction – Light Scattering Laser Diffraction – Light Scattering : Laser Diffraction – Light Scattering 300 µm 30 µm 3 µm 0.3 µm Schematic diagram of laser diffraction pattern particle size : Schematic diagram of laser diffraction pattern particle size Different part of unit : Different part of unit Laser and detection system : Laser and detection system Blue light source : Blue light source The scattering intensity observed for sub-micron particles is increased by using 466nm blue light source. Detectors : Detectors Detectors 1-33: Small angle Detectors 34-42: Large angle Detectors 43-44: Extreme angle (Red) Detectors 45-46 : Extreme angle (Blue) Detectors 47-48: Backscatter (Red) Detectors 49-50: Backscatter (Blue) Detector 51- Extinction-Red Detector 52- Extinction-Blue Principle of Dynamic Light Scattering : Principle of Dynamic Light Scattering Emulsions and molecules in suspension undergo Brownian motion. If the particles or molecules are illuminated with a laser, the intensity of the scattered light fluctuates at a rate that is dependent upon the size of the particles. Analysis of these intensity fluctuations yields the velocity of the Brownian motion and hence the particle size using the Stokes-Einstein relationship. Dynamic Light Scattering (DLS) : Dynamic Light Scattering (DLS) The Zetasizer measures the size of particles in a fluid down to less than a nanometre by observing the Brownian motion of the particle. Submicron particle sizes are measured by observing the scattering of laser light from these particles, determining the diffusion speed and deriving the size from this, using the Stokes-Einstein relationship. Actually we are NOT measuring particle size. We are measuring diffusion coefficient. Stokes-Einstein equation : Stokes-Einstein equation d = diameter D = diffusion coefficient k = Boltzmann’s constant T = absolute temperature η = viscosity Dynamic Light Scattering (DLS) : Dynamic Light Scattering (DLS) As Dynamic Light Scattering is sensitive to the intensity of light scattered by particles, and larger particles scatter more light than small particles, then the DLS is very sensitive to the presence of aggregates, and hence this technique is an excellent basis for studying the stability of submicron particle dispersions. Dynamic Light Scattering (DLS) : Dynamic Light Scattering (DLS) DLS Distributions : DLS Distributions Intensity size Volume size Number Size Intensity, Volume And Number Distributions: A Real Example : Intensity, Volume And Number Distributions: A Real Example z-average diameter = 168nm Polydispersity index = 0.215 Recommended Distributions : Recommended Distributions Use the Intensity PSD for reporting the size of each peak in the distribution. Use the Volume or Number PSD for reporting the relative amounts of each peak in the distribution. Sample Requirements : Sample Requirements The sample should consist of well-dispersed particles in a liquid medium. The dispersant should be transparent. have a different refractive index from the particles be compatible with the particles (i.e. not cause swelling, dissolution or aggregation). have known refractive index and viscosity with an accuracy better than 0.5% be clean and filterable. f. Acoustic spectroscopy : f. Acoustic spectroscopy Instead of light, this method employs ultrasound for collecting information on the particles that are dispersed in fluid. Alternative term is ultrasound attenuation spectroscopy. Dispersed particles absorb and scatter ultrasound similarly to light. Instead of measuring scattered energy versus angle, as in case of light, in the case of ultrasound, measuring of transmitted energy versus frequency is a better choice. Range of analysis for different methods : Range of analysis for different methods Thank You : Thank You Slide 112: Words should be weighted and not counted. Polydispersity Index (PDI) : Polydispersity Index (PDI) An index that describes the variation in sizes The higher the PDI, the wider the PSD Range 0-1 0-0.1 0.1-0.2 Why is particle size distribution important? : Why is particle size distribution important? Determines the quality of final products. Establishes performance of processing. Determines the optimum size for separation. Determines the size range of loses. Example : Example Coulter Counter : A Coulter counter is an apparatus for counting and sizing particles and cells. It is used for Bactria or cells and particle size distributions. The counter detects change in electrical conductance of a small aperture as fluid containing cells is drawn through. Cells, being non-conducting particles, alter the effective cross-section of the conductive channel. Wallace H. Coulter designed the Coulter Counter. He first devised the theory behind its operation in 1947 while experimenting with electronics. Coulter determined that electrical charge could be used to determine the size and number of microscopic particles in a solution (Coulter Principle). The Coulter Counter is a vital constituent of today's hospital laboratory. Its primary function being the quick and accurate analysis of complete blood count(CBC). The CBC is used to determine the number or proportion of white and red blood cells in the body. Coulter Counters have a wide variety of applications including paint, ceramics, glass, and food manufacture. Coulter Counter Slide 118: A typical Coulter counter has one or more microchannels that separate two chambers containing electrolyte solutions. When a particle flows through one of the microchannels, it results in the electrical resistance change of the liquid filled microchannel. This resistance change can be recorded as electric current or voltage pulses, which can be correlated to size, mobility, surface charge and concentration of the particles. Range 100 nm -1000um Internet : Internet Light Scattering occurs when polarizable particles in a sample are bathed in the oscillating electric field of a beam of light. The varying field induces oscillating dipoles in the particles and these radiate light in all directions. This important and universal phenomena is the basis for explaining why the sky is blue, why fog and emulsions are opaque and other observations. It has been utilized in many areas of science to determine particle size, molecular weight, shape, diffusion coefficients etc. Slide 120: In a Coulter counter, a tube with a small aperture on the wall is immersed into a beaker that contains particles suspended in a low concentration electrolyte. Two electrodes, one inside the aperture tube and one outside the aperture tube but inside the beaker, are placed and a current path is provided by the electrolyte when an electric field is applied. The impedance between the electrodes is then measured. The aperture creates what is called a “sensing zone.” Particles in low concentration, suspended in the electrolyte, can be counted by passing them through the aperture. As a particle passes through the aperture, a volume of electrolyte equivalent to the immersed volume of the particle is displaced from the sensing zone. This causes a short-term change in the impedance across the aperture. This change can be measured as a voltage pulse or a current pulse. The pulse height is proportional to the volume of the sensed particle. If constant particle density is assumed, the pulse height is also proportional to the particle mass. This technology thus is also called aperture technology. Prediction of scattered lightFraunhofer v Mie : Prediction of scattered lightFraunhofer v Mie Laser diffraction requires a model that accurately defines the light scattering behaviour of all particles There are currently two popular choices available, Mie Theory and the Fraunhofer Approximation Prediction of scattered lightFraunhofer v Mie : Prediction of scattered lightFraunhofer v Mie Older instruments used the less accurate Fraunhofer Approximation. This was due to limited computer processing power. Since 1986 the preferred model has been Mie Theory which correctly predicts the scattering at all wavelengths of light at all angles. Fraunhofer v Mie - Mie theory : Fraunhofer v Mie - Mie theory Unlike Fraunhofer, Mie theory: Accounts for the interaction of light with matter Assumes that spherical particles are present Is valid for all wavelengths, scattering angles and sizes of particle Correctly predicts scattering intensities (Correctly predicts secondary scattering) Mie theory - Prediction of scattered light : Mie theory - Prediction of scattered light Incident light Scattered light Scattered light Absorption A basic laser diffraction system : A basic laser diffraction system The Mastersizer 2000 : The Mastersizer 2000 The angular scattering data is presented in real-time in the measurement window of the Mastersizer software. Detector numbers correspond to increasing scattering angle… Detectors 1-33: Small angle Detectors 34-42: Large angle Detectors 43-44: Extreme angle (Red) Detectors 45-46 : Extreme angle (Blue) Detectors 47-48: Backscatter (Red) Detectors 49-50: Backscatter (Blue) Detector 51- Extinction-Red Detector 52- Extinction-Blue Low Angle High Angle Slide 129: In dynamic light scattering one measures the time dependence of the light scattered from a very small region of solution, over a time range from tenths of a microsecond to milliseconds. These fluctuations in the intensity of the scattered light are related to the rate of diffusion of molecules in and out of the region being studied (Brownian motion), and the data can be analyzed to directly give the diffusion coefficients of the particles doing the scattering. Slide 130: Most proteins are certainly not spherical, and their apparent hydrodynamic size depends on their shape (conformation) as well as their molecular mass. Further, their diffusion is also affected by water molecules which are bound or entrapped by the protein. Therefore, this hydrodynamic size can differ significantly from the true physical size (e.g. that seen by NMR or x-ray crystallography), and this size is generally not a reliable measure of molecular mass. You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.