Pharmaceutical Powders

What is a powder?

Pool of solid particles where the solid particles have

• The same chemical composition e.g. lactose powder

• Multiple chemical compositions = powder blend e.g. ibuprofen, lactose, starch powder blend

• An individual diameter, 1000 micrometers beyond this we will refer to granules (2-4,000 micrometers)

Powders are complex heterogeneous systems:

• They can flow

• Can resits deformation to a point

• Can be compressed

Powders as dosage forms: oral administration

1. Effervescent powders:

• Release CO₂ when dispersed in water

• Source of acid - citric acid and/or tartaric acid

• Source of CO₂ - sodium bicarbonate or calcium carbonate

• Protect from moisture - packed in individual dose units, airtight

2. Powder for reconstitution

Powders as dosage forms: other RoA

1. Dusting powders

• Applied on the skin

• Well-controlled particle size

• Good/excellent properties needed

• Packaged in bottle with sifter top

• Quality assessment:

  • Fineness

  • Uniformity of dosage units

  • Sterility

• Label - to mention if powder is sterile

2. Nasal/pulmonary

• Powders for inhalation - DPIs

• Nasal powders - fine powders

What is particle size and what does it affect?

Particle size describes the characteristic dimensions of individual powder particles

It is important because particle size affects:

• Powder flow

• Surface area

• Dissolution rate

• Mixing and segregation

• Packing and bulk density

• Content uniformity

• Dose uniformity

Why is particle size important in pharmaceutical powders?

Particle size can affect the physical and pharmaceutical properties of a powder

Smaller particles generally have:

• Greater surface area

• Greater surface energy

• Potentially poorer flow

• Faster dissolution

• Greater tendency to agglomerate

Particle size analysis

Pharmaceutical powders tend to be:

• Irregular and heterogeneous

Equivalent sphere:

• Concept devised to simplify particle size analysis for powders

• Particle size obtained will depend on the method used

Approximation - the actual size may be different

Particle size analysis - microscopy-based methods

Projected perimeter and area diameters

• Independent of particle orientation and shape

1. Martin’s diameter - length of a line that bisects the particle

2. Feret’s diameter - distance between drawn tangents

Particle size analysis - sieving-based methods

Dry sieving and air-jet sieve

• Sieving diameter undersize vs oversize

Particle size analysis - sieving-based classes table

Particle size analysis - alternative classification table

What is particle size distribution?

Describes the range and proportion of different particle sizes present in a powder sample

What is a monodisperse powder?

A monodisperse powder contains particles that are approximately the same size - has a narrow particle size distribution

What is a polydisperse powder?

A polydisperse powder contains particles with a range of different sizes

Most pharmaceutical powders are polydisperse

Why is particle size distribution important?

PSD affects:

• Powder flow

• Packing efficiency

• Bulk density

• Mixing

• Segregation

• Dissolution

• Dose uniformity

What generally happens when particle size decreases?

Surface area ↑ → surface energy ↑ → interparticle forces ↑

This can cause:

• Increased cohesion

• Increased agglomeration

• Poorer flow

However, the increased surface area can also increase the dissolution rate

What happens when light hits a particle?

• Scattering

• Absorption

• Refraction

• Diffraction

Light scattering - laser diffraction

Laser diffraction:

• Size range: 1-1000 micrometers

• Measurement performed on dry suspended solids

Particle size>> wavelength of light

• Light scattered (forward) with a small change in angle

• The angle of diffraction varied with particle size

  • Fraunhofer diffraction

Light scattering - dynamic light scattering

Hydrodynamic diameter

• Measurement performed on suspended solids

• The intensity of scattered light is measured as a function of time

Size range: 2nm-2 micrometers

• Particle subjected to Brownian motion

Particle size distribution

Different types of size distribution

• Number distribution e.g. microscopy - from counting particles in each range

• Weight distribution - from determining the weight of particles in each range

• Length, area, volume distributions

Normal size distribution graph

Skewed size distribution graph

You can determine only the mode directly from a skewed frequency curve or histrogram

Log-normal distribution graph

Frequency is plotted v particle diameter on a log scale

Multimodal distribution graph

Cumulative distributions graph

From a cumulative frequency graph:

• You can get the median NOT the mean - unless the distribution is normal

What are the forces that balance powder flow?

1. Forces that drive flow (flow-promoting)

• Gravity

• Particle mass (related to true density)

• Inclination

• Mechanical force

2. Forces that resist flow (drag forces)

• Adhesion - changes with particle size and moisture content

• Cohesion - changes with particle size and moisture content

• Electrostatic interactions

• Surface forces

A powder will flow if flow-promoting forced > drag forces

Impact of particle size on powder flow diagram

Impact of particle shape on powder flow table

Packing and flow

Study of packing geometry

How solid particles are arranged in a powder blend

How particles are packed in a powder bed will also affect the volume the powder bed occupies

Packing, porosity, density and powder flow

Consider a single solid particle - it occupies a volume which can be used to calculate density

• That volume is the true volume and that density is the true density

A given particle can have only 1 true volume and density

Packing, density and flow - powder bed

Consider a powder bed - it occupies a volume which can be used to calculate its density

• That volume is the bulk volume and that density is the bulk density

A powder bed can have multiple bulk volumes and densities

Packing, density and flow - porosity

Can be calculated knowing the bulk and true volumes:

• Bulk Volume (V_bulk) = true particle volume + volume of void spaces

• True volume (V) = volume of occupied by a solid particle - measured by displacement methods e.g. helium

Porosity is the ratio of the void volume vs bulk volume

Packing, density and flow - bulk density

Bulk volume considers intra and inter particular voids - measured using a graduated cylinder

Bulk density can be calculated knowing the weight

Packing, density and flow - light and heavy powders

For the same material i.e. same true density

‘Light’ powders:

• Large bulk volume

• Low bulk density

• Loose packing

‘Heavy’ powders

• Small bulk volume

• High bulk density

• Tight packing

Change in bulk density/porosity may not be enough to counteract the influence of particle size

Factor affecting flow through an opening

1. Size of the opening

• Flow is independent of the size of the powder bed

• Allow filling of powders at a constant rate

2. Wall angle

3. Design of the hopper

• Hopper width

• Height activated in the hopper

Troubleshooting

1. Look at particle size and size distribution

• Remove small particles through sieving (size separation) or adsorption

• Granulate the powder

2. Change the shape, control roughness

• Spray-drying to produce more regular-shaped particles

3. Dry the powder

• Cohesiveness increased by moisture

• Include magnesium oxide to absorb excess moisture

• Use silicon treated powder if hygroscopic

4. Add a flow-promoting excipient

• Glidants, lubricants, antiadherents

Use mechanical assistance

Measuring adhesive/cohesive forces

Shear strength/shear cell

• Measures resistance to flow depends on flow preventing forces

Tensile strength

• Powder on a plate change the angle detect angle that induces flow

Change the angle

• Good correlation with AOR

Powder flow analysis table and equation

What is the angle of repose?

The angle of repose is the maximum angle formed between a pile of powder and the horizontal surface

It is used as an indicator of powder flowability

• Lower angle → generally better flow

What does a high angle of repose suggest?

A high angle of repose indicates greater resistance to particle movement

Therefore, the powder generally has poorer flowability

A low angle indicates easier flow

What is bulk density?

Bulk density is the mass of powder divided by its bulk volume, including the spaces between particles

What is tapped density?

Density of a powder after mechanically tapping the container until the volume reaches a relatively stable minimum

• Tapping causes particles to rearrange and pack more closely

What does Carr's compressibility index measure?

Carr's index estimates powder flowability from bulk and tapped density

• A lower value generally indicates better flow

Why does Carr's index relate to powder flow?

A powder that undergoes a large reduction in volume during tapping is likely to have:

• Poor packing initially

• Greater interparticle interactions

• Greater cohesiveness

Therefore, a large difference between bulk and tapped density generally indicates poorer flow

Additional methods - critical orifice and hopper flow rate

Critical orifice method

• Based on finding out the smallest hole through which powder will flow

Hopper flow rate

• Direct measurement of flow properties

• Directly relevant to the set-up used in production of solid dosage forms

• Allow troubleshooting of manufacture issues

Advantages and disadvantages of powders as dosage forms

Advantages:

• Higher stability - shelf-life, powder reconstitution

• Convenience - high doses

• Faster dissolution - soluble drugs

Disadvantages:

• Inconvenient to carry - bulk formats vs sachets

• Organoleptic properties

• Limited to non-potent drugs

• Drug degredation

Granules as dosage forms

Powders as dosage forms

Special cases - hygroscopic, deliquescent and efflorescent powders

1. Hygroscopic powders - these powders can absorb moisture from air

2. Deliquescent powders - these hydroscopic powders can liquefy following moisture absorption

3. Efflorescent powders - powders which contain hydration or crystallisation water, can release water when exposed to low-humidity environments or during handling e.g. trituration

How to handle these powders:

• Package in an air-tight container

• Store in dry place in tightly closed container +/- desiccant (hygroscopic/deliquescent)

• Use excipients that can preferentially absorb humidity (hygroscopic/deliquescent)

• Use the anhydrous from (efflorescent)

Special cases - eutectic mixtures

Specific combination of 2 ingredients

• Starts as solids but can liquefy during processing at room temperature

How to handle these powders:

• Force the mixture, then, adsorb on inert solid

  • Magnesium carbonate, calcium phosphate, starch, light/heavy magnesium oxide

• Mix each ingredient separately with an inert powder

• Use a spatula and glass tile rather than mortar and pestle

Quality assessment of powder dosage forms

1. Uniformity of dosage form

• Uniformity of mass or uniformity of content

2. Uniformity of delivered dose

• Multidose container

3. Disintegration and dissolution

• Effervescent powders/granules

• Coated, modified released or gastro-resistant granules

4. Sterility

• Depending on use