Preformulation - mixing Flashcards
What is the definition of mixing?
- Mixing is a unit operation in which a uniform mixture is obtained from two or more components, by dispersing one within the other.
- It is a process that involves manipulating a heterogeneous
physical system, with the intent to make it more homogeneous
What is the importance of mixing?
- To obtain homogeneity and dose uniformity = efficacious & safe
- To produce dispersion.
- To achieve reproducibility during manufacture.
- To achieve efficiency and cost-effectiveness.
What are the three types of mixture?
- Positive mixture
- Negative mixture
- Neutral mixture
Describe positive mixture.
– Mixes spontaneously, energy input required to separate components.
– Miscible fluids (e.g. ethanol + water, gases).
Describe negative mixture.
– Segregates spontaneously, energy input required to mix and keep mixed.
– Immiscible phases (e.g. oil + water, suspensions).
Describe neutral mixture.
– Components neither mix nor segregate spontaneously, energy input
required to mix or segregate components.
– Once mixed, mixture remains stable (e.g. powders, pastes)
What are the three mechanisms of mixing solids?
- Convective mixing
- Shear mixing
- Diffusive mixing
Describe convective mixing.
– Redistribution of large groups of particles.
– Large degree of mixing in short period of time.
Describe diffusive mixing.
– Powder bed dilation, air introduced into powder bed during mixing.
– Particles move into air spaces under gravity or mechanical forces
Describe shear mixing.
– Velocity differences between layers of particles, layers of particles slide over one another.
– Mixing at interface between layers
Which mechanism predominates and the extent of which each occurs depends on what?
o Mixer type
o Mixing process conditions (e.g mixer load, speed)
o Particles characteristics
o Flowability of the components
As perfect mixing is unattainable what are the other alternatives?
- Random mixing
- Ordered mixing
Describe a random mixture.
A mixture in which the
probability of finding a particle of any component is
the same at all locations and equal to the proportion
of that component in the mixture as a whole
Describe an ordered mixture.
- When micronized particle become adsorbed on surface of larger carrier
particles. - Adsorbed and carrier particles move inter-dependently.
- Minimal segregation.
- Useful for mixing potent drugs.
What are the main challenges with mixing powders?
Homogeneity difficult to achieve - especially when mixing small amounts into large bulk.
Demixing - segregation of components due exceeded blending times.
Overmixing - prolonged mixing degrades material properties (e.g. particle size, charge, surface texture).
State the two types solids are divided into.
- Cohesive materials
- Noncohesive materials
Describe cohesive materials.
These are characterized by their resistance to flow through openings for e.g. wet clay.
Fine particles are more cohesive.
Mixing of cohesive materials is more difficult due to formation of aggregates and lumps
Describe non cohesive materials.
These materials flow readily such as grain, dry sand etc.
Describe which physical properties affect mixing.
- Material density: Denser material will sink through the lighter one
- Particle size: Differences in particle size is the main cause of segregation
- Particle shape: ideal particle is spherical - greater flowability
- Particle attraction: influence aggregation
Describe segregation.
- Reverse process of mixing.
- Vibrations during manufacturing can demix fine particles by diffusion
When is segregation likely to happen?
– Particle size non-uniform.
– Particle density non-uniform.
– Spherical shape (free-flowing).
– Powders are not free flowing
How can we minimise segregation?
- Uniform particle size.
- Ordered mixture (e.g. granulation).
- Select excipients of similar density.
- Use premixing.
- Avoid mixer overfilling.
- Choose particles that are geometrically similar.
- Reduce vibration.
- Use appropriate mixer.
- Single-station operation (i.e. multiple processes in same equipment).
What are the three mechanisms of segregation?
- Percolation separation
- Trajectory segregation
- Elutriation segregation
Describe percolation separation.
Small particles fall through voids (e.g. in cereal box).
Percolation segregation is
often observed in cereal packets where
the smaller particles congregate towards
the bottom of the container
Describe trajectory segregation.
Larger particles go further as they have more mass based inertia.
Describe elutriation segregation.
‘Dusting out’—fine particles
settle on top after motion
has ceased
