Powder processing and Excipients

Define Comminution.

The mechanical process of reducing the size of particles; reduction of solid materials from one average particle size to a smaller average particle size.

Define Micronization.

The process of reducing particle sizes to the micron or nanometre range.

Define Pulverization.

Reduction of a substance to a powder.

Define Trituration.

A pharmaceutical process that involves grinding, pulverizing, or rubbing a substance into fine particles or powder using a mortar and pestle.

What are the five key pharmaceutical impacts of milling?

1. Particle Size Control (impacts dissolution, bioavailability, effectiveness).

2. Solid-State Changes (affects stability, shelf life).

3. Blend Uniformity (achieves dose uniformity).

4. Micronization (improves bioavailability via increased surface area).

5. Impacts quality, efficacy, and safety.

What is the size range and example for Macroscopic particles?

500 μm; Tablets, capsules, suppositories.

What is the size range and example for Granules?

500 μm - 2000 μm; Granules for oral and topical formulations.

What is the size range and example for Coarse Powders?

250 μm - 1000 μm; Dry powder inhalers, effervescent tablets.

What is the size range and example for Medium Powders?

75 μm - 250 μm; Oral suspensions, wet granulation intermediates.

What is the size range and example for Fine Powders?

10 μm - 75 μm; Nasal sprays, topical creams and ointments.

What is the size range and example for Very Fine Powders?

1 μm - 10 μm; Inhalation powders, submicron emulsions.

What is the size range and example for Nanoparticles?

< 1 μm; Liposomes, nanoemulsions, targeted drug delivery systems.

Define Hardness in the context of material science.

A measure of resistance to permanent deformation, indentation, or scratching when subjected to an external force (e.g., Mohs Hardness Scale).

Define Brittleness.

The tendency of a material to fracture or break when subjected to stress or an external force without significant deformation (little or no plastic deformation).

How is brittleness measured?

Impact testing, hardness testing, tensile testing, and observational assessment.

Define Toughness.

The ability of a material to absorb energy without fracturing; it combines both strength and ductility. Tough materials withstand impact without breaking.

What is the key difference between Hardness and Toughness?

Hardness is resistance to deformation/scratching; Toughness is ability to absorb energy before fracturing.

Hardness ≠ Toughness.

How does Hardness affect milling and what is its application?

Influences energy/force needed for milling; impacts milling efficiency and equipment selection.

Application: Tablet manufacturing, solid dosage form milling.

How does Brittleness affect milling and what is its application?

Leads to easy fracturing during milling; contributes to effective size reduction.

Application: Milling of gelatin capsules, brittle tablet coatings.

How does Toughness affect milling and what is its application?

Affects energy absorption during milling; influences milling efficiency and particle size reduction. Application: Rubber stopper manufacturing, blister packaging.

Name two types of mills mentioned.

Jet Mill and Hammer Mill.

What happens to salbutamol sulfate with increased milling time?

Representative SEM images show changes at 6, 12, 18, and 24 minutes.

Shear forces cause 1-10% of the powder (predominantly the surface) to exhibit an amorphous state.

What four things does the amorphous state from milling affect?

1. Dissolution profile,

2. Hygroscopicity,

3. Chemical stability,

4. Powder flow properties and compressibility.

How does material density affect milling?

High-density materials require more energy to reduce particle size.

How can milling impact chemical stability?

Milling can introduce mechanical stress that may impact the chemical stability of some substances, especially APIs.

Define Adhesion vs. Cohesion in powder processing.

Adhesion occurs between two unlike surfaces (e.g., particle and equipment).

Cohesion occurs between like surfaces (e.g., between particles).

What problems do adhesive and cohesive particles cause during milling?

Adhesive particles stick to milling equipment.

Cohesive particles may form lumps or agglomerates.

How does excess moisture impact the milling process?

Causes agglomeration (issues in powder mixture) and stickiness (adherence to equipment = poor efficiency).

How is moisture content managed during milling?

Humidity control, monitoring, and drying techniques.

What are the three pharmaceutical impacts of mixing?

1. Homogeneity (uniform API distribution).

2. Content Uniformity (regulatory requirement).

3. Optimized blend time and equipment.

What four things depend on good powder mixing?

1. Content/dose uniformity (safety),

2. Uniformity of weight,

3. Uniform dissolution rate,

4. Uniform bioavailability.

When is a random mixture obtained?

If two different free-flowing powders of approximately the same particle size, density, and shape are mixed, and particles are not cohesive.

What happens if you reduce particle size too much?

Increased cohesion and particle aggregation, resulting in poor mixing and powder flow properties.

Define Segregation.

A separation of powder components depending on particle size, particle density, and particle shape.

Describe Percolation segregation.

Smaller particles fall through the voids between larger particles.

Describe Trajectory segregation.

Larger particles travel faster and further than smaller particles.

Describe Elutriation segregation.

'Dusting out' - small particles are blown into the air during mixing and settle as a layer on top of larger particles.

How does density cause segregation?

Separation occurs if particles exhibit different densities, even if they are the same size.

What are six strategies to prevent segregation?

1. Select specific particle size range (sieving).

2. Mix with excipients of similar density.

3. Granulation.

4. Reduce vibrations/movement.

5. Reduce powder residence time.

6. Production of an 'ordered' mix.

What is an 'Ordered' mix?

A mixture where sufficiently small (micronized) particles adsorb to the surface of larger 'carrier' particles (e.g., carrier lactose + micronized salbutamol sulphate for inhalable powder).

What is Ordered unit segregation?

Percolation separation of different sized carrier particles resulting in drug-enriched areas.

What is Displacement segregation?

Another particle component (e.g., Mg-stearate) competes for the same adsorption site on the carrier.

What is Saturation segregation?

There are insufficient carrier particles for the drug to adsorb to.

What are the Learning Outcomes for the Flowability section?

1. Describe factors influencing powder flow.

2. Discuss how flow affects pharmaceutical products.

3. Explain methods to evaluate flow.

4. Predict flow properties from bulk/tap volume.

5. Describe methods to improve flow.

What are four pharmaceutical impacts of flowability?

1. Tablet compression (consistent weight/quality).

2. Blend uniformity.

3. Capsule filling (accurate dosing).

4. Storage and handling (easier to handle).

How does particle size affect flow?

<10 μm = very cohesive, flow only as agglomerates.

<100 μm = cohesive flow (high frictional forces).

>250 μm = free flowing.

How does particle shape affect flow?

Spherical = free flowing (minimal contact areas).

Non-spherical (flakes/dendritic) = greater cohesion.

Define Bulk Density.

The apparent density; mass of loosely packed powder divided by total volume (includes all pores and inter-particle void space).

Define Tap Density.

The settled or packed volume of a given mass of particles under well-defined agitation (mass / tapped volume).

Define True Density.

The density of the solid phase of the particles; independent of porosity, compaction, or pre-treatment (mass / true volume).

How does humidity affect powder flow?

High RH = greater adsorbed water surface layer = greater surface tensional forces = poorer flow.

0% RH = absolutely dry air.

100% RH = saturation with moisture.

How does density affect flow?

Higher density particles flow under gravity; lower density particles are more cohesive.

What are indirect methods for measuring powder flow?

Angle of repose, Carr's Index, and Hausner Ratio (via bulk/tap density measurements).

What are direct methods for measuring powder flow?

Hopper flow rate and Recording flowmeter.

Define Angle of Repose.

The steepest angle at which a sloping surface formed of loose material is stable (tan a = h/r).

Provides info on frictional forces.

What angle of repose indicates Excellent flow?

25-30 degrees.

What angle of repose indicates Good flow?

31-35 degrees.

What angle of repose indicates Fair (aid not needed)?

36-40 degrees.

What angle of repose indicates Poor (must agitate/vibrate)?

46-55 degrees.

What angle of repose indicates Very, very poor flow?

66 degrees.

How many taps for free-flowing vs. poor flowing materials in tap density measurement?

Free flowing = 2000-3000 taps. Poor flowing = 7000 taps.

What is the formula for Carr's Index (Compressibility Index)?

Carr's Index = [(Tap density – Bulk density) / Tap density] × 100

What is the formula for Hausner Ratio?

H = Tap density / Bulk density (D_T / D_0)

What Hausner Ratio indicates Excellent flow?

1.00 - 1.11

What Hausner Ratio indicates Poor flow?

1.35 - 1.45

What Hausner ratio indicates a need for a glidant?

Between 1.25 - 1.45. (Note: H < 1.25 = good flow; H > 1.45 = poor flow).

How is Flow Through Hopper measured directly?

Time taken for a known amount of powder to flow through the hopper; Discharge = mass/time = flow rate.

What are five methods to improve powder flow?

1. Remove fine particles.

2. Adsorb fine particles onto larger particles.

3. Dry particles to reduce cohesiveness.

4. Add glidants (e.g., talc).

5. Increase particle size through granulation.

What are the Learning Outcomes for the Granulation section?

1. Determine when to implement granulation.

2. Select appropriate technology.

3. Describe excipients used and their effects.

4. Elucidate how granulation influences solid state.

Define Granulation (pharmaceutical).

The process in which primary powder particles are made to adhere to form larger, multi-particle entities called granules.

What seven things does granulation improve?

1. Prevents segregation.

2. Improves mixing properties.

3. Improves flow properties.

4. Avoids dustiness.

5. Improves compressibility.

6. Improves appearance.

7. Densifies material.

What is the first step of wet granulation ("Blend and Moisten")?

Solid components (Drug + Excipients) are blended with liquid components (Solvent + Binder).

What is the second step ("Sieve")?

The moist mass is pressed through a sieve or extruder to size the granules.

(Note: If too moist = strings form; too dry = granules fall apart).

What is the third step ("Dry")?

After drying, primary particles are held together by solid bridges (hardening binding agent bridges OR crystallized drug/excipient bridges, or a combination).

What are four limitations of wet granulation?

1. Stability concerns for moisture/heat-sensitive drugs.

2. Multiple steps add complexity.

3. Loss of material.

4. Expensive (labor, time, equipment, energy, space).

Name four types of granulation equipment/technologies.

1. High-speed shear mixer/granulators,

2. Fluidized-bed granulators,

3. Extrusion-spheronizers/pelletizers,

4. Spray-driers.

What are the advantages of High-speed Shear Mixer/Granulators?

1. Short processing time.

2. Less liquid binder required (compared to fluidized-bed).

3. Highly cohesive material can be granulated.

What are the advantages of Fluidized-bed Granulators?

1. Single step process.

2. Fine, homogenous particles.

3. Free flowing powders.

What are the advantages of Spray Dryers?

1. Rapid, one-step process.

2. Ability to be operated continuously.

3. Suitable for heat-sensitive products.

What are the advantages of Extrusion and Spheronization?

1. Incorporates higher levels of API without larger particles.

2. Applicable for immediate and controlled release.

What are the advantages of Dry Granulation (Compression/Slugging)?

1. Ideal for moisture/heat-sensitive material.

2. Ideal for improved disintegration (no binder).

What are the disadvantages of Dry Granulation?

1. Requires heavy duty tablet press.

2. Poor color distribution.

3. Creates dust (contamination risk).

4. High pressures/temperatures may cause polymorphisms.

Define Excipient.

An inactive substance that serves as the vehicle or medium for a drug or other active substance. (Note: Generic equivalents do not have to contain the same excipients as branded).

What are the main components in a solid dosage form?

Active ingredient (drug) + Fillers, Binders, Disintegrants, Lubricants, Anti-adherents, Glidants, Adsorbents, Dissolution retardants/enhancers, Wetting agents, Buffers, Chelating agents, Antioxidants, Preservatives, Coloring agents, Flavoring agents, Coating materials.

What is the function of Fillers (e.g., ethyl cellulose, lactose)?

Provide sufficient bulk volume for compression.

What are six ideal filler properties?

1. Chemically inert,

2. Biocompatible,

3. Water soluble/hydrophilic,

4. Good compatibility,

5. Good flow,

6. Acceptable taste, inexpensive.

Name six examples of fillers.

Lactose, Cellulose, Starch, Sucrose, Mannitol, Calcium phosphate.

What are the advantages and disadvantages of Lactose as a filler?

Advantages: Dissolves readily, pleasant taste, non-hygroscopic, fairly non-reactive.

Disadvantage: Poor tolerability for lactose-intolerant patients.

What are the advantages and disadvantages of Cellulose & Derivatives as fillers?

Advantages: Biocompatible, inert, high dilution potential, low bulk density, excellent binding, acts as disintegrant.

Disadvantage: Hygroscopic.

What is special about Microcrystalline Cellulose (MCC) (Avicel®)?

Highly compressible (hard tablets at low pressure), plastic deformation, fair flowability, binding properties, disintegrant activity, water insoluble.

What are the properties of Sorbitol as a filler?

Highly compressible, water soluble, hygroscopic, sweet/cooling taste, non-gritty, low caloric, non-cariogenic.

(Brands: Sorbifin®, Neosorb®).

What are the properties of Mannitol as a filler?

Poor flow (unless granular), requires high lubricant, most expensive sugar, water soluble, mild cooling, non-gritty.

(Brands: Parteck®M, Pearlitol®, Mannogem®).

What is the function of Binders (e.g., methyl cellulose, povidone)?

Added to the drug-filler mixture to provide cohesiveness (most are polymeric).

What three factors must be considered when choosing a binder?

1. Compatibility,

2. Sufficient cohesion for processing,

3. Must allow tablet to disintegrate and drug to dissolve.

What is the function of Disintegrating Agents (e.g., citric acid, powdered cellulose)?

Facilitate the breakup of a tablet after oral administration.

Name six mechanisms of tablet disintegration.

1. Capillary action (wicking),

2. Swelling,

3. Particle/particle repulsive forces,

4. Heat of wetting,

5. Deformation,

6. Release of gases.

How does wicking cause disintegration?

Water is pulled into pores by the disintegrant; physical adhesion between particles is disrupted.

How does swelling cause disintegration?

Disintegrant swells and breaks up the matrix from within.

What causes effervescent disintegration?

Bicarbonate and citric acid react to release gas.

How do fillers affect disintegration?

Water soluble fillers increase fluid viscosity and decrease effectiveness.

Water insoluble fillers promote disintegration.