Particle Size Methods and Solid State

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What is a valuable indicator of quality of performance?
Particle size (influences many properties of materials)
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Which processes in the Pharmacy Industry are affected by particle size?
Content uniformity, flow and mixing. The release and dissolution of a drug. Absorption and therapeutic effect. Final dosage form
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Which four factors does choosing a method for particle size analysis depend on?
Nature of the material to be sized. Cost. Specification requirements. Time restrictions
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Describe features of nature of the material to be sized?
Estimated particle size range, solubility, ease of handling, toxicity, flowability, intended use
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Describe features of cost for particle size analysis
Capital (fixed one-time expenses incurred on the purchase of new equipment). Operational (expense required for the day to day functioning of a business)
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What are the five main methods for determining particle size?
Size distribution, microscopy, sedimentation, electrical sensing zone and laser light scattering
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Describe the process of sieving
Stack of sieves each with a smaller aperture size than that above it. Can be performed wet or dry, by machine or by band, for fixed time/constant low rate. Vibrations added or use of air-jet or ultrasonics. Fill - seal - agitate - weigh
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Which sieving machine is used for sieving fine powders?
Air-jet sieving - prevents particles aggregating
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What does sieving measure?
The sieve equivalent diameter - the size of a sphere that will just pass through the aperture of a particular sieve (2D value)
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Describe the process of air-jet sieving
Vacuum switched on. Narrow slot for incoming high speed air. Particles dispersed before being drawn backwards through sieve apertures by suction, Coarse material remains on sieve, re-weighed at the end
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Why is the air-jet sieving method reproducible?
Due to having an automatic under pressure controller
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Which method is specified for regulatory approval and is most widely used?
The cascade impaction (looks at inhalation of particles and focuses on aerodynamic particle size as a key parameter which influences regional deposition in lungs and respiratory tract - measurement critical during product development/quality control)
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Describe how the cascade impactor works
The impactor is connected to suction to mimic inhalation. It measures the reach range of particles as it moves through the opening of the aerosol
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The cascade impactor is suitable for which aerosolised particle sizes?
0.4-10 microns
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What are the advantages of sieving as a size distribution method?
Easy to perform, wide size range and inexpensive
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What are the disadvantages of sieving as a size distribution method?
Known problems of reproducibility. Wear/damage in use or cleaning. Irregular/agglomerated particles. Rod-like particles (overestimate of undersize). Labour intensive
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What is microscopy?
The technical field of using microscopes to view objects and areas of objects that cannot be seen with the naked eye (objects that are not within the resolution range of the normal eye)
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What are the three types of microscopy?
Optical, electron and scanning probe microscopy
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What are the accept diameters in microscopy (2D image of particle)?
Martin's diameter (dm), Feret's diameter (dF) and projected area diameter (da)
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What is Martin's diameter?
The length of the line which bisects the image of particle
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What is Feret's diameter?
The distance between two tangents on opposite sides of the particle, parallel to some fixed direction
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What is the projected area diameter?
The diameter of a circle having the same area as the particle viewed normally to a plane surface on which the particle is at rest in a stable position
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Describe features of automated, digitalised microscopy
High throughput, statistically significant numbers, true shape, no shape factors, sizing of mixed particle populations possible
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What are the factors which influence the correct determination of particle sizing using microscopy?
Inter-individual differences in sample preparation. Non-representative selection of particles. Resolution limit of microscope.
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Why are particles increasingly oversized as their size approaches the resolution limit?
The diffraction image they produce is larger than the particle
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What are the advantages of the manual optical microscope?
Relatively inexpensive. Each particle individually examined - detect aggregates, 2D shape, colour, melting point (hot stage microscopy). Permanent record (photograph). Small sample sized required
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What are the disadvantages of manual optical microscopy?
Time consuming - high operator fatigue - few particles examined (overcome which semi-automated image analysis systems). Very low throughput. No information on 3D shape. Certain amount of subjectivity associated with sizing - operator bias
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What are the advantages of electron microscopy?
Particles are individually examined. Visual means to see sub-micron specimens. Particle shape can be measured
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What are the disadvantages of electron microscopy?
Very expensive. Time consuming sample preparation. Materials such as emulsions difficult/impossible to prepare (EM requires dry samples). Low throughput - not for routine use
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What do sedimentation methods depend on?
The fact that the terminal velocity of a particle in a fluid increases with size. The particle size distribution of fine powder can be determined by examining a sedimenting suspension of powder
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What is Stoke's diameter (dst)?
The diameter of the sphere that would settle at the same rate as the particle
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What is Stoke's Law used to determine?
Stoke's diameter of particles in a suspended powder
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What is used to speed up measurement time?
Centrifugal settling velocity (now a common particle sizing technique)
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Describe how an Andreasen pipette is used (1)
Suspend sample (0.1-1%) in suitable liquid (water). Add dispersing agent to prevent aggregation if needed. Fill the Andreasen pipette with homogeneous suspension. Remove samples at intervals (starting at 2 mins)
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Describe how an Andreasen pipette is used (2)
Determine sample weight using gravimetric analysis of dried sample or chemical analysis. Calculate radius using Stoke's Law (convert r to d). Plot cumulative undersize curve and determine statistical parameters
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What are the advantages of sedimentation?
Equipment required can be relatively simple and inexpensive. Can measure a wide range of sizes with accuracy and reproducibility
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What are the disadvantages of sedimentation? (1)
Large particles created turbulence (slows and recorded undersize). Careful temperature control is necessary to suppress convection currents. Lower limit of particle size is set by increasing importance of Brownian motion for smaller particles.
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What are the disadvantages of sedimentation? (2)
Particle re-aggregation during extended measurements. Particles have to be completely insoluble in the suspending liquid
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Describe how electrical sensing zone methods are used
As particles pass through the aperture opening, they bend the current flux lines around the particles. Thus causes a longer length for the current to pass and a higher resistance to the current
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The amplitude of current pulse is directly proportional to what?
The volume of the particle that produced it (volume diameter, dV)
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Which electrical sensing zone method is used for particles 1-1000 microns?
Coulter Counter
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Which electrical sensing zone method is used for particles 1-1000 nm?
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What are the advantages of electrical sensing zone methods?
True volume distribution. High resolution. Wide range of measurement - particle diameter from approx. 0.5-400 microns
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What are the disadvantages of electrical sensing zone methods?
Needs calibration. Medium must be an electrolyte. Low particle concentration. Errors with porous particles. Orfice blocking troublesome. Particles below minimum detectable size go unnoticed. Difficult with high density materials
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What are the two types of laser light scattering techniques?
Laser diffraction particle size analysis (0.02-2000 microns or 0.01-3500 microns) and photon correlation spectroscopy (1 nm - 5 microns)
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How does a laser diffractometer work?
Particles pass through laser beam and light is scattered. Amount of light hitting outer circles of bull's eye detector is used to calculate amount of diffracted light and then mean particle size
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What is the Fraunhofer approximation of diffraction?
Spherical, non-porous and opaque particles. Diameter d > wavelength l (particle size > 50 microns). Particles distant enough from each other. Random motion. All particles diffract light with same deficiency
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What are the advantages of laser diffraction particle size analysis?
Non-intrusive (uses a low power laser beam). Fast (3 mins to take measurement and analysis). Absolute measurement (no calibration, instrument based on fundamental physical properties). Simple to use. Highly versatile
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What is the disadvantages of laser diffraction particle size analysis?
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How does Photon Correlation Spectroscopy (PCS) work? (1)
Large particles move more slowly than small particles so rate of fluctuation of light scattered from them is slower. PCS uses rate of change of light fluctuations to determine size distribution of particles scattering light
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How does Photon Correlation Spectroscopy (PCS) work? (2)
Light scattering experiment. Statistical fluctuations in the intensity of light scattered through a 90 degree angle is measured against time. Fluctuations in intensity of scattered light- due to Brownian motion of particles in suspending medium
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What is Brownian motion?
The random movement of particles in a suspension due to constant bombardment by surrounding solvent molecules
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What are the advantages of photon correlation spectroscopy?
Non-intrusive, fast, nanometre size range
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What are the disadvantages of photon correlation spectroscopy?
Expensive. Vibration, temperature fluctuations can interfere with analysis. Restricted to sold in liquid or liquid in liquid samples. Need to know additional properties e.g. viscosity
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What is surface area?
The surface area of a solid object is a measure of the total area that the surface of the object occupies (see lecture notes for equations table)
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What is specific surface area per weight unit (Sw)?
A property of solids defined as the total surface area of a material per unit of mass (e.g. m^2/kg)
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What is the BET method?
Brunauer-Emmett and Teller Theory. Explains physical adsorption of gas molecules on a solid surface.
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The BET method applies to which systems?
Systems of multilayer adsorption utilising probing gases that do not chemically react with material surfaces to quantify specific surface area
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Describe the BET method
Powder filled in a vacuum sealed chamber. Small amounts of N2 gas added to chamber. N2 molecules adsorb to surface of powder until entire surface (pores) are covered. Pressure transducers sense amount of gas adsorbed and specific SA can be calculated
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Describe four features of polymorphs
Thermodynamically most stable (less soluble). Metastable polymorph more soluble/less stable. Most thermodynamically stable form is normally preferred. A metastable polymorph has a balance between processability and stability
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Polymorphs affect which processes in the manufacturing of drugs?
Milling, flowability and compactability (form I and form II of polymorphs)
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Describe the stability and reactivity of polymorphs
Less stable forms are called metastable. There could be two different forms of polymorphs e.g. one stable the other reactive
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Describe the solubility of polymorphs
Metastable polymorphs have a higher solubility than stable forms
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Describe the dissolution rate of polymorphs
The polymorph with the higher melting temperature has a greater lattice strength (more difficult to remove molecule from lattice, slower dissolution rate)
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What are the effects of polymorphism on bioavailability?
Very stable polymorphs result in a low bioavailability but metastable polymorphs have a high bioavailability
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What is the difference between a hydrate and a solvate?
Hydrate involved solvent being water and solvate involves the solvent in other solvents
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Describe features of hydrates
Organic compounds form hydrates in the presence of water due to small molecular size of water and multidimensional H bonding capability of water. Anhydrous form favoured over hydrates
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Can stable hydrates have an acceptable bioavailability?
Yes - can be developed to have better physicochemical properties and may be the only crystalline form of an API
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Describe features of Theophylline
Used to treat respiratory diseases e.g. asthma and COPD. Hydrated forms are obtained by recrystallisation of anhydrous form of water
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What is a pharmaceutical salt?
Parent drug exists with physicochemical properties - not always optimal for dissolution or absorption into the body. Drug converted into salt to improve properties (choice of drug depends)
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What are crystalline salts and co-crystals?
They both contain two or more components in the same lattice
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List the properties which can be modified?
Dissolution rate, chemical and physical stability, crystallinity, hygroscopicity, bulk properties (density, particle size, flowability), manufacturing (drying)
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Give real example of salts
Diclofenac sodium or potassium is used in tablets but diclofenac diethylammonium is used in a gel
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Describe features of amorphous based products
Amorphous drug is dispersed in biologically inert matrix (e.g Rosuvastatin, Lopinavir, Ritonavir)
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What is a big challenge in the formulation of medicines?
Amorphous powders, polymorphic crystals and polymorphic phase transformation
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What is dissolution?
The process of releasing the active pharmaceutical ingredient (API) from the dosage form - disintegration, disaggregation, dissolution
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What is absolute bioavailability?
The fraction of administered dose of unchanged drug that reaches systemic circulation
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What is relative bioavailability?
A systemic availability of a drug from a dosage form as compared to a reference standard given by the same route of administration
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What is bioequivalence?
Relative bioavailability study
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Which route of administration has a bioavailability of 100%?
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Which routes of administration have the lowest bioavailability?
Oral and inhalation (due to first pass metabolism)
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What does the Noyes-Whitney equation describe?
The rate of dissolution of spherical particles when dissolution process is diffusion controlled and involves no chemical reaction. Relates to rate of dissolution of solids and properties of solid and dissolution medium
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Describe each aspect of the Noyes-Whitney equation
dC/dt (rate of dissolution. D (diffusion coefficient - temp/state dependent). A (SA of drug particle). Cs (saturation solubility of drug in solution is diffusion layer). C (concentration of drug in dissolution media). h (thickness of diffusion layer)
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According to the Noyes-Whitney equation, how does the total surface area affect dissolution?
Increase in total SA (smaller particle size) leads to an increase in dissolution rate
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What does particle size reduction lead to?
Increased bioavailability, provided the absorption of the drug is dissolution-rate limited
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What is comminution?
The reduction of solid materials from one average particle size to a smaller average particle size
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What is pulverisation?
The reduction of a substance to a powder
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What is trituration?
Particle size reduction of a substance by rubbing it in a pestle with mortar. Intimate mixing of two or more powders together, the rubbing of light, fluffy powders into heavier denser and more compact composition
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Describe pharmaceutically relevant particle size classes
0.5-10 microns (suspensions). 10-50 microns (coarse particles). 50-100 microns (fine powder). 150-1000 microns (coarse powder). 1000-3360 microns (granules)
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Why are some materials readily prone to size reduction than others?
Material properties (solid state, brittle/tough, surface hardness, elasticity/plasticity), environmental factors (moisture)
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Describe features of brittleness
A material which is easily broken or fractured by an impact. Decrease in temperature leads to increase in brittleness. Brittle materials are easy to comminute
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Describe features of toughness
Ability of a material to withstand an impact. Tough materials require a large impact to fracture of break. Tough materials are difficult to comminute
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What is hardness?
The ability of a material to withstand scratching or penetration (e.g. diamonds). Classified on Mohs' scale. Difficult to comminute (lead to abrasive wear of milling parts)
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What is elasticity?
Material returns to its original shape after it has been stretched
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What is plasticity?
Material is stretched or formed into another shape and then holds that shape without breaking or fracturing
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How does temperature affect elasticity or plasticity?
Decrease in temperature decreases elasticity/plasticity
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Why are elastic and plastic materials difficult to comminute?
They both absorb high amounts of energy through elastic or plastic deformation before fractures occur
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Which factors of solid state are affected by milling?
Shear forces from milling cause powder to exhibit amorphous state. Affects: dissolution profile, hygroscopicity, chemical stability, powder flow properties, compressibility
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Why is careful monitoring of milling time and shear stress required?
To avoid batch to batch variability that may arise from amorphous content during milling - evaluate milling method, milling time, switch to dry or wet milling, add stabilising excipients
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Which processes in the Pharmacy Industry are affected by particle size?


Content uniformity, flow and mixing. The release and dissolution of a drug. Absorption and therapeutic effect. Final dosage form

Card 3


Which four factors does choosing a method for particle size analysis depend on?


Preview of the front of card 3

Card 4


Describe features of nature of the material to be sized?


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Card 5


Describe features of cost for particle size analysis


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