advanced mixing

Question 1

how are fine particles classified?

Answer 1

fine particles may be classified as < 50 micrometeres

Question 2

what size are the particles we deal with for the lungs?

Answer 2

1-10 micrometeres

Question 3

what will influence particle size in a powder?

Answer 3

particle properties such as nature, size, shape & surface roughness will influence forces

Question 4

what are ideal properties of particles?

Answer 4

• Uniform particles with mono-dispersion
• Uniform density
• Non-cohesive
• No agglomeration
• No compaction
• Excellent flowability
• Readily dispersed when delivered as an aerosol

Question 5

in reality what are the properties that fine particles pose as challenges?

Answer 5

• Polydispersity
• Particlesize range 0.5 –10 μm
• High energy input for micronisation
• Less integral crystalline surface -amorphous regions
• Particle shape
• Particle density/porosity• Cohesive
• Hygroscopicity
• Chemical instability
• Electrostatic charge
• Poor flow properties
• Batch-batch variability

Question 6

what is s used to reduce the size of the particles to micron level (1-10 mm)?

Answer 6

air jet mill

Question 7

what is micronisation not suitable for?

Answer 7

not suitable for thermolabile drug and induces electrostatic charges
•Creates a large surface area to mass ratio. Therefore, powder becomes cohesive, poorly flow a bleand produces difficulty in powder device filling and aerosolization
•Particle morphology, density and composition cannot be controlled during micronisation.

Question 8

how do you produce free flowing, less cohesive and more easily dispersed/aerosolized particles?

Answer 8

• Spray drying
• Large porous particles
• Supercritical fluids

Question 9

what is spray drying?

Answer 9

evaporation of drug solution/suspension droplets atomized into a hot air stream.
High yield, continuous and scalable manufacturing process.

Question 10

what would spray drying be suitable for?

Answer 10

•Ideal process for producing inhalation particles of labile macromolecules. •Suitable for processing hydrophilic (spray drying from the aqueous solution ) or hydrophobic (spray dry from the organic solvent solution) compounds

Question 11

how can spray drying be manipulated?

Answer 11

Particle size, density, morphology and surface properties can be manipulated by controlling the process conditions or co-spray drying with excipients

Question 12

what properties do large porous particles have?

Answer 12

The particles have a low density -large geometric size but small aerodynamic particle size distribution
•The particles exhibit superior aerosolization performance and handling due to the particle morphology

Question 13

what is a supercritical fluid?

Answer 13

•Supercritical CO2•Crystallisation from supercritical solutions –following supersaturationinduced by varying temperature and pressure. •Or if solid insoluble in SCF (anti-solvents) –gas dissolves in organic liquid and lowers ‘solvent power’ –causes precipitation•promotes nucleation and yields very small and regularly sized particles even down to 5-2000 nm.•Pure crystalline with no defects

Question 14

what Important particle properties that explain ordered mixing & DPI performance?

Answer 14

•bulk properties –true density , tapped density, packing fraction & porosity under different conditions
•electrostatic properties. Capacitance & resistivity (sensitive to method, degree of compaction & moisture). Literature full of contradictions –experimental results rarely reflect theory
•contact angle –if high, lower uptake, non-uniform wetting. At low RH (30 %) capillary interactions –hydrophilic and hydrophobic particles. If hydrophobic, may get stronger meniscus bridges due to poor wetting
•moisture content and uptake at selected RH. Ordered mix –parabolic relationship between adhesion strength and RH?
size & shape distribution
•surface area
•adhesion –interparticulate& contact surface
•SEMs –surface features inclevidence of dissolution
•surface roughness

Question 15

how does Adhesion/autoadhesion of solid particles occur?

Answer 15

• mechanisms –Rumpf
• solid bridges
• chemical reaction
• melting –pressure, friction (processing)
• deposition during drying –crystallisation
• Bonding due to moisture

Question 16

what happens in adsorbed moisture bonding?

Answer 16

• immobile liquids
• overlap of adsorption layers
• bond strength proportional to tensile strength of film & area of contact
• force between a flat surface and sphere is double the force between two equi-sized spheres
• shape & surface roughness important variables –surface irregularities will decrease area of contact

Question 17

what happens in liquified bridge bonding?

Answer 17

• mobile liquids
• at high humidity level the largest adhesion force is the capillary force
• capillary force is created by liquid condensation due to adsorbed moisture on powder surface#
• liquid bridges between adjacent powders results in capillary force
• RH reaches critical point (usually 65-80 %) where liquid bridges form –incremental increase in bond strength & powder will become cohesive

Question 18

what happens in van der Waals forces (short range between particles)?

Answer 18

•fluctuations in electron cloud –dipole moments•force between a flat surface and sphere is double the force between two equi-sized spheres•magnitude decreases with square of distance between surfaces (either particle-particle or particle-surface)•critical distance between particles when force will just support weight of one of the particles
i.e. the smaller the particle, the longer the range of attraction

Question 19

what happens in electrostatic force (long range)?

Answer 19

generally accepted that the mechanism of charge transfer is electron transfer between contacting surfaces•material transfer and ion transfer may have a role during contact electrification (particularly where no correlation between charge transfer and work function)

Question 20

what is the work function in elecrostatic force?

Answer 20

work functionis the minimum energy required at 0°K to cause an electron to escape from the material into free space

Question 21

what is triboelectrification?

Answer 21

contact electrification involving sliding/friction

Question 22

what is Coulomb’s law?

Answer 22

The magnitude of the electrostatic force between 2 charges is proportional to the product of the magnitudes of the charges and inversely proportional to the square of the distance between them•Note –like charges repel, unlike charges attract

Question 23

what is involved in inhaled dry powder mixing?

Answer 23

• high speed impellers etc
• for DPIs don’t want to alter particle size of excipient
• fine particles generally require greater energy to dislodge from carrier than agglomerate

Question 24

what do Impaction & high shear mixers do?

Answer 24

• increase in energy input into a mix
• impaction mixers have blades rotating at 2000-3000 rpm in static vessel
• blade may be introduced along axis of rotation of tumbling mixer