Predicting Flowability and Characterizing Powders

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-01-01-2004, Volume 16, Issue 1

This article reflects on the challenges that predicting powder flowability currently pose to the pharmaceutical manufacturing industry and considers some of the benefits that can accrue when companies overcome these issues.

Pharmaceutical companies operate in a very sophisticated manner - innovation and quality are important elements. Workers in all areas - for example, scientists in discovery, formulation experts in development and analysts in manufacturing - work in close teams and enjoy the challenges they face. It is, therefore, very frustrating when, late in the development phase of a new drug candidate, the formulation starts to cause problems as it transfers to pilot production; or when an established production line faces continual delays because of the inconsistencies of powdered ingredients.

In today's pressurized environment, there is a major drive to manufacture at lower cost. Some companies have responded by moving plants to developing areas that offer a lower cost base, such as Eastern Europe, India and South America. Others are looking to streamline existing facilities or outsource manufacturing to one of a growing number of third party specialist suppliers. Some pharmaceutical manufacturers are doing all three. In addition, initiatives to supply drugs for key global diseases (such as HIV/AIDS) at lower cost and patent expiry issues - with many blockbuster drugs losing ground to emerging generics - are impacting these decisions as well as adding to the overall competitive pressure.

Figure 1: The flow energy of hydrous lactose as a function of packing condition.

The importance of powders and the need to measure

Almost all pharmaceutical products are in powder form at some point during their manufacture. The need to optimize formulation early (at laboratory and pilot scale) and the challenge of ensuring a smooth transition into full-scale manufacturing demand knowledge of the likely behaviour of the powdered components of a product.

Liquids, solids and gases are well characterized, and detailed information regarding their properties is well documented. Powders, however, are difficult to categorize, hard to describe and, in contrast to liquids, solids and gases, may be affected by a number of variables (for example, physical, chemical and, importantly, environmental).


This is logical because powders are a mixture of solid particles and air, and unlike other materials even a minor modification, such as simply moving a powder, can dramatically change its performance. Depending on the air content of a powder, rheological properties can typically change by a factor of 100 and in extreme cases by more than 1000 times (Figure 1).

Figure 2: Energy as a function of flow rate for various blends of lactose and magnesium stearate.

Many scientists think of powders as inherently 'good' or 'bad' in terms of flow properties. But, in practice, a particular powder may flow very well under aerating conditions. Yet, after containment in a hopper, the same powder may be altered and have extremely poor flowability. If the same powder is exposed to moisture, its rheology, even under aerating conditions, can be poor. On the whole, flowability depends on how powders are handled and processed, which makes measuring them and predicting their behaviour a significant challenge.

Traditionally, those who have tried to describe powder flow properties have used a single number; for example, angle of repose or shear strength. However, this approach does not reflect the complex nature of powders and the extent to which the rheological properties are affected by imposed environmental conditions such as flow rate, packing condition, humidity, temperature, charge, vibration and many other factors. For this reason, and against tradition, a range of parameters is needed to describe the flow properties of a powder. The idea that a single number can describe these complex materials is no more valid than it would be for people to be described simply by their age or height.

Positive performance gains

A new approach, using a powder rheometer, gives sensitive and reproducible results, and can evaluate each of the many factors that affect powder flowability. A comprehensive profile of a powder is developed using just small amounts of material and the data generated add value at many stages of the development and production cycles.

Figure 3: Wet granules of haloperidol being tested in a rheometer.

Importantly, users have confirmed that this approach provides a real insight into increasingly important areas, such as how a formulation might interact with process machinery as it moves to scale-up and production. For example, magnesium stearate is commonly used as a die lubricant in tabletting. An investigation to determine its effect on the flow properties of spray-dried lactose was undertaken. Figure 2 shows how the flow energy measurement varies as a function of flow rate (blade tip speed) and the magnesium stearate content. The basic lactose sample with no additive exhibits the poorest flowability properties, with basic flowability energy and flow rate index being the highest of the test series. When 0.1% magnesium stearate was added, there were marginal improvements in flowability; but between 0.1–0.25%, there was a marked reduction in flow energy. Concentrations of magnesium stearate greater than 0.25% only had a small effect, suggesting that optimum flowability is achieved between 0.1–0.25%, where the resulting powder shows very good flow properties with a moderate basic flowability energy value and insensitivity to flow rate.

Recent research has demonstrated how accurately predicting the end-point of a granulation step is essential to optimizing the final dosage form. Figure 3 shows a photograph of wet granules of haloperidol being tested in a rheometer during this work. Energy profiles indicated that at low water content, more energy is required when mixing for shorter times; and as water content increased to 12% w/w, the energy requirement increased with longer mixing times. By using a rheometer, it was possible to discriminate between samples that differed by less than 1% water content w/w. It was concluded that the ability to quantify the end-point in this way would allow operators to easily assess the granulation process. End-product quality has improved as a result.

The bottom line

The need to understand in detail all aspects of a product and the processes that produce it has never been greater. Characterizing powders and powder flow is a small but significant area in which valuable improvements can be realized. It can impact many operations, such as in the early stages as a formulation is developed; matching materials to plant as a product transfers into full-scale manufacturing; and in ensuring the quality of raw materials, intermediates and final product. In addition, creating a database of standard flow characteristics of existing materials is assisting users to predict the impact of introducing a new material. In every case, failures, reworks and stoppages cause delays, cost money and adversely affect the bottom line, something that must be minimized.

On the whole, flowability depends on how powders are handled and processed, which makes measuring them and predicting their behaviour a significant challenge.