Powder Mixing

MPharm Programme: Powder Mixing

• Powder mixing is the treatment of two or more powder components so each particle of one component is in contact with one of each additional component.
• The aim is to achieve a homogenous distribution of components in the bulk powder.
• Components of a powder mix include different powders (drugs and excipients), different particle size fractions of the same powder.
• Powder mixing is crucial for granulation, tablet making, direct compression, capsule/sachet filling, and vial filling for injections.
• Different properties of drugs and excipients affect mixing, including homogeneity of drug distribution in dosage forms, mechanical properties (e.g. of tablets), and drug bioavailability.

Mixing Terminology

• Dry mixing: powders mixed without liquid additions
• Wet mixing: powder mixed with a liquid binder (granulation)
• Pre-mixing: used for mixtures with less than 5% w/w drug, followed by further deagglomeration (e.g., sieving).
• Post-mixing: adding an external phase (e.g., lubricant or glidant) with short mixing times (3-5 minutes).

Mixer Types

• Tumbler mixers: rotating vessels, prone to particle segregation, but internal impellers/prongs can reduce this. Useful for adding lubricants and glidants to granules.
• Cube, cone and V mixers: (illustrated)
• Turbula mixer: (illustrated)
• Double cone mixer: (illustrated)
• Convective mixers: fixed vessel with an internal impeller, less prone to fine particle segregation but have dead spaces, adhesion to blades, and shear forces that can shatter particles.
• Planetary mixing: (illustrated)
• Nautamixer: (illustrated)
• Impaction & high shear mixers: high-energy input, blades rotating at high speeds (2000-3000 rpm) in static vessels. Break up aggregates, often used after tumbling mixing.
• Impaction mixer: (illustrated)
• Fluidized bed mixers: powders subjected to a flowing gas stream; weight of particles is counterbalanced by buoyancy, increasing particle mobility and efficiency.

Choice of Mixer

• Physical Considerations: More space is needed, optimal loading ratio needed with respect to vessel volume (tumbling mixers – 25-35%, convective mixers – 50-80%, fluidised bed mixers – 20-30%). Need to consider particle distribution, limit particle attrition & overmixing, and temperature change.
• Economic and Safety Considerations: Energy consumption, mixing time, continuous vs. batch mixing, time to fill, empty, and clean, dust emission, explosion hazard (electrostatic charging), surfaces/mixer speed, relative humidity.

Mixing Mechanisms

• Expansion: Allows movement of particles
• Agitation: Ensures sufficient period for mix.
• Avoidance of segregation
• Maintenance of adequate mix
• Particle movement: Diffusion (random), convection (transfer of groups of particles), shear (sliding particle layers).
• Mixer design determines which mechanism is dominant (e.g., simple tumbling mixers - free flow, high shear mixers - cohesive powders).

Interactive Powder Mixtures ('Ordered Mixtures')

• Cohesive fine powders (<20 µm), coarse powders (coater/carrier units).
• Interparticulate forces, improves homogeneity.
• Ordered units have a definable size range.

Stable Powder Mixtures ('Ordered Mixtures')

• Vibrating on a sieve (seeding).
• Results: Segregation: ordered unit segregation (size difference), displacement segregation (3rd component), saturation segregation (limited surface sites).

Free-flowing Mixtures ('Random Mixtures')

• No interparticulate forces, particles move freely.
• Random distribution (governed by stochastic/statistical process).
• Complete random mixture only if all components are identical in size, shape, and density.
• Median size > 20 µm, used for direct compression.

Perfect/Random Mixtures

• Each particle in a 'perfect mix' lies adjacent to another particle from a different component.
• Random mix: maximum disorder - no way to predict particle type from neighbour.

Factors Affecting Segregation

• Particle size, density, shape
• Electrostatic charging, powder handling.

Particle Size Effects

• Large particles give poor distribution
• Particle size reduction gives good distribution.
• Particle agglomeration gives poor distribution.

Testing Drug Content Uniformity in Powder Mix

• Random samples, analysis of drug content.
• Inspection: standard deviation, coefficient of variation
• Comparing with pharmacopoeial tests.
• Effect of mixing variables.

Test your knowledge on the principles of powder mixing as part of the MPharm program. This quiz covers important concepts such as dry mixing, wet mixing, and the significance of homogenous distribution of components. Gain a better understanding of the role of powder mixing in pharmaceutical applications.