An introduction to the common processing challenges associated with pharmaceutical powders, why powder behaviour can vary during manufacture and how objective powder testing can help scientists compare materials, investigate variability and better understand process performance.
Pharmaceutical powders are handled at many stages of manufacture, from raw materials and intermediates through to final dosage forms. Along the way, they may need to be stored, transported, transferred, blended, fed and filled.
The challenge is that powders do not always behave consistently as they move through these different stages. A material that handles well during development may behave differently after storage or transport. A new batch of raw material may require unexpected process adjustments. Two materials that appear similar may not necessarily pack or flow in the same way.
Objective powder testing provides a way to characterise and compare relevant material properties under defined conditions, helping analysts investigate potential reasons why materials behave differently during manufacture.
This is the first in a three-part series exploring pharmaceutical powder testing. We begin with the manufacturing challenges that create a need to understand powder behaviour, before looking in Parts 2 and 3 at the measurements available and how comparative powder profiles can be used throughout the product lifecycle.
In this blog, we cover:
- Why powder behaviour matters during pharmaceutical manufacturing
- How powder properties can affect filling, transfer and discharge
- How settling and consolidation can change powder volume
- Why powder behaviour can vary between batches
- What USP <1174> and <616> tell us about powder testing
- How objective powder testing can support material comparison and troubleshooting
Reading time: 12 minutes
Why does powder behaviour matter in pharmaceutical manufacturing?
A pharmaceutical powder can experience very different conditions during manufacture. It may be stored for a period of time, transported between locations, transferred into processing equipment, discharged from a hopper, blended with other materials or filled by mass or volume.
Each stage places different demands on the material. Storage may expose a powder to changing environmental conditions or allow its physical state to change over time, while transport can subject it to vibration and repeated movement. Transfer, feeding and filling require the material to flow under particular conditions and within specific equipment. Processing operations such as milling, granulation, drying and blending may also alter physical characteristics, including particle size and shape, bulk density and powder-bed structure.
Powder handling through the manufacturing lifecycle. Powders encounter different conditions at each stage, which can affect their behaviour.
This matters because pharmaceutical powder behaviour is complex.
USP <1174> Powder Flow describes powder flow as multifaceted and recognises that no single simple test can adequately characterise the flow properties of pharmaceutical powders. Instead, the chapter describes several approaches because different methods examine different aspects of behaviour.
For analysts, this is an important starting point. There is no single result that tells you whether a powder is simply ‘good’ or ‘bad’.
The more useful question is: Which aspect of the powder’s behaviour are we trying to understand?
How can powder properties affect filling consistency?
Many pharmaceutical processes depend on placing a controlled quantity of powder into a defined space. That might mean filling a tablet die, capsule, sachet or other container. Although the filling mechanism varies between processes, consistent delivery is essential for reproducible filling.
Two aspects of powder behaviour can be particularly relevant: flow and bulk density
The powder needs to reach and enter the filling system consistently, while bulk density affects the mass associated with a given volume of powder.
In practice, filling problems may appear as:
- variation in tablet, capsule, sachet or container fill mass
- incomplete or inconsistent filling
- repeated adjustment of filling equipment
- reduced production speed
- interruptions to production
- increased rejection rates.
If a material begins filling differently from a previous batch, density and flow measurements can provide objective information for comparison. They should not be treated as direct simulations of a filling process. Filling performance also depends on the design and operating conditions of the manufacturing equipment.
Powder properties can affect filling consistency.
The value of powder testing is that it gives the analyst a controlled way to determine whether relevant characteristics of the material itself have changed.
Why can pharmaceutical powders be difficult to transfer or discharge?
Powders need to move between stages of manufacture. They may be discharged from a container, transferred into a hopper, passed through an outlet or supplied to downstream equipment. When that movement becomes inconsistent, the effects can include:
- intermittent or incomplete discharge
- variable transfer times
- difficulty maintaining a consistent powder supply
- increased operator intervention
- reduced process throughput.
Two terms commonly associated with discharge problems are bridging and ratholing.
Bridging occurs when material forms a stable structure above an outlet and prevents normal discharge. Ratholing describes a situation in which material flows through a channel while surrounding powder remains relatively stationary.
These problems also show why powder testing needs to be interpreted carefully. Whether a powder bridges, ratholes or discharges successfully does not depend on the powder alone. Equipment geometry, outlet dimensions and operating conditions can also affect what happens in practice.
Why powders can be difficult to transfer or discharge.
Measurements such as angle of repose and flow through an orifice can be used to characterise aspects of powder flow under defined test conditions, but they should not be treated as direct predictors of hopper or process performance.
USP <1174> includes both among the approaches used to characterise powder flow. It also recognises limitations within individual methods. For example, an angle of repose measurement is not appropriate if a symmetrical powder cone cannot be prepared successfully and reproducibly.
For troubleshooting, the value of these measurements is comparative. If a material that was previously processed successfully begins to behave differently in a standardised flow test, that change provides additional evidence for investigation.
How do settling an consolidation affect powder volume?
A powder does not necessarily occupy the same volume throughout its lifecycle. A powder bed contains particles as well as spaces between those particles. The way the particles are arranged therefore contributes to the overall volume of the material.
USP <616> Bulk Density of Powders reflects this directly. Bulk density depends on both the density of the powder particles and their packing arrangement within the powder bed. The chapter also states that the bulking properties of a powder depend on the preparation, treatment and storage of the sample.
If that packing arrangement changes, the volume occupied by a given mass of powder may also change.
This may become noticeable as:
- a reduction in occupied powder volume
- unexpected headspace in a container
- differences in the mass of powder held within a defined volume
- changes in filling or discharge behaviour after storage or handling.
Settling and consolidation may chnage the volume occupied by a powder.
Vibration during transport is one condition that may change how particles are arranged within the powder bed. Storage and handling can also affect packing. Bulk and tapped density measurements provide standardised ways of examining powder packing under specified conditions.
Bulk density is the ratio of powder mass to its untapped bulk volume. Tapped density is the increased bulk density obtained after the sample has undergone a specified mechanical tapping procedure.
Comparing the two provides information about the change in packing produced under the conditions of the test.
A tapped density test does not simulate transport or storage. It does not reproduce all the forces a container or batch of powder may experience in practice. Its value lies in providing a controlled and repeatable basis for comparison.
Why can powder behaviour vary between batches?
A common manufacturing observation is: ‘This batch is behaving differently.’
The reason may not be immediately obvious. A manufacturer might be working with:
- a new batch of raw material
- a different material grade
- material from another supplier
- a formulation produced at a different scale.
The material may also have undergone processes such as:
- milling
- granulation
- drying
- blending
- storage
- transport or other handling.
These operations can alter physical characteristics of the powder or its packing state. The material may still appear normal and may still meet its existing specification, yet behave differently during a particular manufacturing operation.
The difference might appear as a change in:
- filling behaviour
- discharge
- occupied volume
- process speed
- frequency of equipment adjustment
- overall throughput.
At this point, the analytical question is not necessarily whether the material has passed or failed one individual powder test.
A more useful question is: What has changed about the way this material behaves?
Comparative powder testing can help investigate that question. A change in bulk density may show that the material is packing differently. Tapped density provides a second, defined packing condition for comparison. Flow measurements can show whether the material behaves differently under their respective test conditions.
No single result can identify every possible cause of a manufacturing problem. Several complementary measurements can, however, make differences between materials easier to identify and investigate.
What does USP say about pharmaceutical powder testing?
The pharmacopoeia provides standardised methods for measuring aspects of powder behaviour, but it does not reduce powder flow to one universal test or acceptance value. USP <1174> Powder Flow discusses several approaches to powder-flow characterisation, including:
- angle of repose
- flow through an orifice
- compressibility index and Hausner ratio
- shear-cell methods.
These methods do not all measure the same thing. USP <1174> does not therefore provide one universal result that defines acceptable flow for every pharmaceutical powder. Its purpose is to describe and standardise approaches that may be useful in pharmaceutical development.
USP <616>, meanwhile, provides standardised procedures for bulk and tapped density measurements.
The distinction is important. A standardised method defines how a measurement is generated. It does not automatically determine what that result means for every material or manufacturing process.
Interpretation still requires context.
Useful questions include:
- What material is being tested?
- How has the sample been prepared, stored and handled?
- What manufacturing issue is being investigated?
- Is the result being compared with previous batches?
- Is a material or batch known to process successfully available as a reference?
- Has a formulation, supplier, grade or process step changed?
This is where powder testing moves from simply generating a number to helping explain material behaviour.
Can a powder test predict manufacturing performance?
Not on its own.
Laboratory tests characterise powder behaviour under defined conditions. Manufacturing performance also depends on the process and equipment in which the powder is being handled.
For example, flow through an orifice can provide comparative information about powder flow under the conditions of that test. It does not recreate every outlet, hopper or feeder that might be encountered during manufacture.
The same principle applies to angle of repose and density measurements. Their value is in producing standardised, objective data that can be compared between materials, batches or stages of development. When combined with process knowledge, equipment information and relevant manufacturing experience, powder test results can contribute to an assessment of likely performance.
Some tests can support predictions when used with appropriate process knowledge, models or historical data.
How can pharmaceutical powder testing support manufacturing?
Standardised powder testing provides objective, comparable information about particular aspects of powder behaviour under controlled conditions.
Broadly, the measurements considered in this series address two areas.
How does the powder pack?
Bulk and tapped density measurements provide information about the relationship between powder mass and occupied volume, and about changes in packing under defined test conditions.
How does the powder flow?
Methods such as angle of repose and flow through an orifice examine different aspects of powder movement under specified conditions. Considering several measurements together can provide a fuller basis for comparing one material with another.
Powder testing can therefore provide supporting information for:
- raw-material and batch comparison
- formulation and process development
- investigation of material changes
- comparison of development- and production-scale materials
- troubleshooting unexpected manufacturing behaviour
- establishment of reference data for materials known to process successfully.
The important point is that powder testing provides supporting evidence rather than a direct prediction of what will happen during manufacture. A comment such as ‘this powder seems harder to handle’ is subjective. A set of standardised measurements can show whether a measurable aspect of the material has changed and where that difference appears.
Use complementary measurements to build a fuller picture of powder behaviour.
Building a clearer picture of powder behaviour
Copley’s powder testing range brings together complementary methods for assessing powder packing and flow behaviour.
- The Powder Testing Workstation™ PTW supports established powder testing methods including bulk density, angle of repose and flow through an orifice.
- The JVi Tapped Density Series supports pharmacopoeial bulk and tapped density testing.
- The Powder Testing Assistant™ PTA 100i supports analysts in carrying out compatible powder testing workflows consistently, including associated calculations and data handling.
Together, these systems allow laboratories to compare several aspects of powder behaviour rather than relying on a single measurement.
Copley’s Powder Testing Suite (Powder Testing Workstation™ PTW and Powder Testing Assistant™ PTA 100i)
That is particularly useful when materials appear similar but behave differently during manufacture.
Looking at the measurements in more detail
Different measurements reveal different aspects of powder behaviour. Bulk density and tapped density provide information about packing, while angle of repose and flow through an orifice examine aspects of flow under their respective test conditions.
The value comes from choosing measurements that are relevant to the question being asked and considering the results together.
In Part 2, we will look more closely at bulk density, tapped density, angle of repose and flow through an orifice, including what each measurement reveals, its limitations and how the results complement one another to create a fuller powder profile.
