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Reviewing Current Practice in Powder Testing Jamie Clayton Freeman Technology Ltd., 1 Miller Court, Severn Drive, Tewkesbury, Gloucestershire, GL20 8DN United Kingdom ABSTRACT: The pharmaceutical industry is seeking to transform manufacturing efficiency through smarter process development and improved operational control. Implementation of the Process Analytical Technology (PAT) initiative, alongside Quality by Design, supports this transformation but draws attention to the relevance of traditional analytical techniques. This is especially the case for powder testing which underpins the success of many pharmaceutical manufacturing steps. Here, Jamie Clayton, Operations Director of Freeman Technology, reviews the strengths and weaknesses of a range of powder testing methods, including those set out in the U.S. Pharmacopoeia and assesses their role in supporting modern pharmaceutical manufacture. use of that understanding to “facilitate innovation and riskbased regulatory decisions by the industry and the Agency”. This focus of PAT is central when it comes to assessing the relevance of available powder testing techniques. The PAT initiative calls for powder testing methods that are not just sensitive or highly reproducible but that also generate information to advance process understanding and manufacturing control. It is these criteria that powder test methods must meet to be useful in transforming the manufacturing landscape. Closer examination of the questions that must be answered by analytical data across the pharmaceutical lifecycle provides greater insight into what “relevance” means within the context of powder characterisation. Such questions might include: • Which of these excipients will make the better formulation for tablet manufacture? • Is this blend prone to segregation? • What granulation conditions should be applied to make granules that will produce high quality tablets? • Can new suppliers of a raw ingredient be introduced without compromising manufacturing performance or product quality? • Why does formulation A aerosolise far more efficiently from this dry powder inhaler device than formulation B? Such questions demonstrate the need to characterise powders during formulation, throughout manufacture and during QC, in terms that relate to how they perform within a process.
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he pharmaceutical industry is currently undergoing a significant shift in terms of manufacturing practice. The Process Analytical Technology (PAT) initiative, along with Quality by Design (QbD) encourages smarter manufacturing methods based on the assessment and management of risk. From an economic perspective, transformation is becoming essential to compete in the price-sensitive generics marketplace,1 and the engineering of more efficient processes that consistently produce materials of the necessary quality is more critical than ever before. Improving batch processes, which have historically been employed for almost all pharmaceutical production, is an important goal, but continuous manufacture holds even greater potential.2 Continuous processing is associated with smaller, easier to manage plants, lower capital investment, and easier scale up.2,3 Powder processing lies at the heart of pharmaceutical manufacturing. As a result, current trends in manufacturing practice are leading to an increased emphasis on efficient, knowledgeable powder handling. Understanding and, more importantly, controlling powder behaviour is vital for the development of efficient processes and for ensuring that every step of the manufacturing process is fully optimized. This article reviews the powder-testing techniques available to meet this need for greater understanding and assesses their relevance in light of the PAT initiative and its requirements. All of the methods presented in USP 11744 are considered alongside the newer technique of dynamic powder measurement which has proven to have particular relevance for process-related studies.5,6
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FOCUSING ON TABLETING The requirement to characterise powders using properties that correlate directly with performance in a specific process makes it essential to consider the processing environment. Focusing on tableting is a useful way to explore this issue since tableting is so widely used within the pharmaceutical industry. Figure 1 shows a typical tableting process, which comprises a number of discrete steps. Each step subjects the powder to a different
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ASSESSING POWDER TESTING REQUIREMENTS FOR IMPLEMENTATION OF THE PAT INITIATIVE The United States Food and Drug Administration (FDA) described PAT as “a system for designing, analysing and controlling manufacturing through timely measurement”.7 This is an initiative primarily focused not on drug discovery, in which the pharmaceutical industry has always invested heavily, but on the conversion of raw materials to a consistent product of closely defined quality and well understood clinical efficacy. PAT is a framework founded on process understanding and the © XXXX American Chemical Society
Special Issue: Process Analytical Technologies (PAT) 14 Received: January 17, 2014
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Figure 1. Schematic showing a typical tableting process.
establishing successful discharge from the feed hopper into the feed frame within the tablet press. However, in the feed frame itself, where powder is swept into the dies to ensure a complete fill, the conditions under which the powder is required to flow are very different: The blend is more loosely packed, but is sheared at relatively high speeds as the blades of the frame rotate. The powder is flowing under gravity but, depending on the design of the blades, may be subjected to a significant element of “forced flow”. This type of forced flow regime may also prevail in mixing and granulation processes where screw extruders are used. Optimising the flow regime in the feed frame, or through an extruder, relies on understanding how a powder flows under forcing conditions. Shear testing (see below) is less representative of these conditions since it involves measuring consolidated powders, and many traditional powder flow testing methods are limited in terms of their ability to apply test conditions that simulate this processing environment. Dynamic testing (see below), in contrast, can generate Basic Flowability Energy (BFE) measurements that directly quantify how easily a loosely packed powder flows under forced conditions, providing valuable insight for this part of the process. At other points in the tableting process it becomes important to understand how the powder blend responds to air. For example, in a press a permeable blend that quickly releases entrained air will settle rapidly and will efficiently fill the die. However, air can provide lubrication and promote flow in the feed frame so a material that releases air too easily may flow inconsistently. Here, there is a need to understand how the inclusion, or loss, of air impacts powder flowability. This need can be met uniquely by dynamic testing, which, unlike other methods, enables testing under aerated conditions. This brief review of the processing conditions applied during tablet manufacture highlights the need to measure a range of
regime, in terms of the stresses imposed, and places different demands on the powder. Typically, the first step in the tableting process is wet or dry granulation. This converts fine, but often dissimilarly sized, excipient and API particles into a homogeneous, granulated mass, in order to avoid downstream component segregation and improve flowability through the process. When using wet granulation, the exiting mass is dried to remove excess moisture prior to milling. This is to ensure the production of uniform, optimally sized granules that will perform well in the tablet press. Flow additives are often added to the resulting granules, whether they are the result of dry or wet granulation, to ease flow through the tablet press and help ejection of the finished tablet. The tablet press itself is often considered as a single unit operation. However, closer analysis reveals that there are four distinct stages involved in the production of tablets from a blend: • discharge from the feed hopper • flow into and through the feed frame • die filling • compression, followed by ejection Analysing each of the steps required to manufacture tablets helps to establish what is needed in terms of powder testing in order to control and optimise the process. For example, raw ingredients are dispensed from feed hoppers, at a consistent, closely controlled flow rate, into the mixing stages that precede granulation. In the feed hopper, moderate stress is imposed by the weight of the stored powder. This can cause sufficient consolidation to inhibit flow, either because of interactions between the vessel and the powder or as a result of powder− powder interactions. Therefore, cohesivity, shear strength, and wall friction angle are all relevant parameters at this point in the process, making shear testing a useful approach. In an exactly analogous way, shear testing is a helpful measure for B
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• sensitively differentiating; able to detect even a subtle change if this is relevant to process performance Focusing on Powder Flowability. Powder flow characteristics are central to the assessment and rationalisation of inprocess behaviour and/or or final product performance. Powders must flow to ensure success in a number of processesfrom a hopper into a feed shoe and on into tablet dies during tableting, for example, or from an inhaler into a patient’s lungs during DPI usage. Furthermore, flowability has also been shown to impact other unit operations such as blending, fluidisation, and granulation.6,8 This importance of powder flowability is reflected in USP 1174,4 a chapter devoted to techniques for the measurement of powder flow within the context of pharmaceutical development. USP 1174 reflects the fact that “powder behaviour is multifaceted” and suggests that “no single and simple test method can adequately characterize the flow properties experienced in the pharmaceutical industry”. It includes a number of powder flow measurement techniques and advises their combined application during pharmaceutical development. With judgment criteria in place it becomes possible to review these methods, alongside dynamic powder flowability, a more modern test method, to determine their relative value within the context of PAT and the goal of enhanced manufacturing efficiency. Angle of Repose. The measurement of the angle of repose is one of the oldest and simplest methods for characterizing powders. Angle of repose measurement is based on the premise that the angle at which a pile of powder settles depends on the strength of the interparticulate forces. The technique correlates interparticle interaction, and hence flowability, with the angle between the horizontal surface and slope of a cone-like pile of settled powder. Powders with an angle of repose of 25−30° are classified as having excellent flow properties and those in excess of 66° as having extremely poor properties.4 Different techniques have been proposed based on this basic principle,9 but the most common approach is to measure the poured angle of repose, the value attained when a powder sample is simply poured from a vessel (Figure 3). This simple measurement may have value for preliminary screening and to provide a gross assessment of flow behaviour, and there are examples in the literature of angle of repose
process-relevant powder properties to understand the factors affecting flowability and to fully optimise in-process behaviour. Powders have unique characteristics that impart industrially useful behaviour. It is vital to measure those characteristics in a representative and relevant way when the goal is to advance process understanding and control.
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UNDERSTANDING THE UNIQUE CHARACTERISTICS OF POWDERS Powders are multicomponent systems made up of particulate solids, the gases between them, and liquids, often in the form of moisture (Figure 2). Interactions between these components
Figure 2. Powders are multiphase bulk assemblies consisting of solid particles, liquids, and gases.
lend powders their versatility and industrial value. They allow powders to flow, compress, consolidate, aerate, or indeed, fluidise. However, these same interactions also complicate both analysis and processing. The properties of each phase of a powder, and the interactions between them, define bulk powder behaviour which in turn impacts process and product performance. This behaviour is therefore influenced by a large number of variables and a vast array of complex interactions. Many, but not all, of these variables are distributive physical properties of the particles, such as size, shape, surface texture, and porosity. Others relate to the process or “external” influences acting on the powder such as air content, moisture levels, and the degree of consolidation. This multifactorial web of relationships is responsible for the vast majority of complications traditionally associated with powder handling. It makes consistent processing, and/or reproducible measurement, similarly dependent on the close control of a substantial number of variables, not just pressure, temperature, and composition, as is the case with gases and liquids. If a powder loses a little air on standing, for example, certain measurable properties will change. Most relevantly, it may flow differently, a change that is highly likely to translate into a change in process performance. Similarly, changes may be triggered by powders consolidating under their own weight: particle attrition during processing, moisture uptake during storage, or aeration during discharge from a bag to a hopper, for example. It is important to note that in each of these examples, there is no planned intention to change powder behaviour. The preceding discussions help define some criteria against which to judge the powder testing techniques currently available, relative to their ability to support better manufacturing practice and the implementation of PAT. To summarise, they suggest that powder testing techniques should be • relevant; providing data that directly correlates with how a powder will behave in a specific processing environment • sufficiently well-defined and controlled to secure good repeatability and reproducibility despite the high potential for variability inherent in powders
Figure 3. Measuring the angle of repose gives an indication of the interparticle interactions within the powder which correlate with its flowability; however, as these images illustrate, this can be difficult when the powder generates ambiguous or multiple angles.10 C
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measurements being used to assess likely process performance.11−14 However, angle of repose is not an intrinsic powder property, and its value is highly dependent on the measurement methods used.4 Poured angle of repose methodology is not consistently defined, despite the age of the technique, and is influenced by procedural variability. For example, the height of the vessel from which the powder is poured may vary relative to the base, and/or the pile may be formed on a base of fixed diameter or allowed to spread. Multiple planes within the powder pile can lead to the imprecise determination of the required angle. As a result this technique tends to suffer from poor repeatability and reproducibility,13,15 which, in part, can be ascribed to operator technique, equipment choice and/or methodology. In addition, angle of repose instrumentation and methodologies provide extremely limited control over packing behaviour in the feed vessel during measurement. Aeration, consolidation, and segregation of the feed sample can therefore all have an impact on the results obtained, complicating the application of the gathered data within a processing context. Powders that are very cohesive may not discharge at all, meaning that they often cannot be measured using this method. Flow through an Orifice. Flow through an orifice can be viewed as a logical progression of the concepts employed within angle of repose. The technique involves measuring the rate at which powder flows through a hole of closely defined dimensions, and instrumentation may be either manual or automated. Like angle of repose, flow through an orifice is an easily accessible technique with a simple measurement principle, associated with relatively inexpensive instrumentation. The ability to observe a powder flowing, as well as giving the technique intuitive appeal, has practical value, as variations in powder flow, such as pulsating flow patterns, can be visually detected,4 but quantifying such phenomena, using this method, is relatively difficult. Analysis can be based on measuring the mass or volume of powder that flows as a function of time or the time taken for a known quantity of powder to discharge. Alternatively, comparative assessments may be made on the basis of the minimum size of orifice that permits flow (see Figure 4).8,15 Flow through an orifice methods vary in terms of the type of container used to hold the powder, and the size and shape of the orifice, as well as the method (volumetric or mass-based measurement) adopted for measuring flow rate. Results measured with different setups can be difficult to compare, and there is no generally applicable scale for flow through an orifice measurements.4 As with angle of repose measurements, there is only limited ability to control the packing state of the powder in the feed vessel. Flow through an orifice measurements may therefore exhibit poor repeatability, depending on how consistently the sample is loaded prior to testing.15−17 Tapped Density: Carr’s Compressibility Index/Hausner Ratio. Tapped density powder testing techniques attempt to quantify the cohesiveness of a powder by measuring the extent to which the bulk density of a powder changes when subjected to vibrational consolidation. Cohesiveness is influenced by the strength of interparticulate forces, which in turn impact the flowability of a powder. Tapping a container holding a defined volume of powder causes the particles present to reposition and reorientate with respect to each other and occupy voids within the powder bed. A comparison of the “final tapped” powder volume, which is
Figure 4. Flow through an orifice measures the flow rate as a powder falls through an opening of a defined dimension.
taken as the point at which no further changes occur in the powder and the “unsettled” volume shows the extent to which a given powder is affected by this type of vibrational consolidation. Hausner Ratio is the ratio of tapped to initial density (or volume if the mass of sample is kept constant). Hausner Ratio and Carr’s Compressibility Index (CCI) are expressed in the equations below. ρt − ρp CCI = × 100 ρt HR =
ρt ρp
where CCI is Carr’s compressibility index, HR is Hausner Ratio, ρt is the tapped density, ρp is the poured density. Note: Hausner Ratio = 100/(100 − CCI). More cohesive powders tend to form agglomerates and therefore retain air between and within these agglomerates. Less cohesive powders release entrained air more readily. Vibrational consolidation disturbs the structure that entrains air within cohesive powders, encouraging particles to move into available voids, and thereby induces a relatively large change in bulk density or volume. Less cohesive materials, which are typically more efficiently packed, tend to exhibit a much less marked reduction in volume, as a result of tapping. A classification of flowability is included within USP 1174 for both CCI and Hausner Ratio. A powder with a CCI of less than 10, which equates to a Hausner Ratio of 1−1.11, is designated as being very free-flowing, while one with a CCI >38, Hausner Ratio >1.60 lies at the opposite end of the cohesivity spectrum and would be expected to exhibit very poor flow.4,18,19 Tapped density equipment and methodologies vary in terms of:4 • the diameter of the cylinder used to contain the sample • the amount of powder tested • the number of taps applied to achieve the final tapped density D
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Figure 5. Shear cells differ in terms of their design, but in each case characterisation relies on determining the force required to shear one powder surface relative to another.
• whether the cylinder is rotated during tapping
Shear cell analysis or shear testing involves measurement of the forces required to shear one consolidated powder plane relative to another.23,24 It is used widely for the analysis of pharmaceutical materials and delivers substantive information relating to flowability, or arguably more accurately, to the strength of frictional forces and the extent of mechanical interlocking in a sample.25 Derived parameters include the angle of internal friction and unconfined yield strength of the powder as well as flow function and other flowability indices. In the nonlinear evolution of powder testing, shear cell analysis stands out as one of the first attempts at a more scientific approach to powder flowability studies and brings a degree of experimental control that is not evident in alternative USP methods. Shear cell analysis can also be applied to the investigation of certain process-relevant characteristics, such as the effect of consolidation load, storage time, and environmental conditions.26,23 The application of shear cell analysis has become prevalent within industry, partly due to the precision it can offer. Over several decades, a number of different shear cell designs and methodologies have proliferated around the central design principle, reflecting efforts to extend the application of shear cell analysis as far as possible (see Figure 5). A modern, wellengineered and automated shear cell can deliver excellent reproducibility and provide valuable information, particularly in relation to hopper performance, and more generally regarding the behaviour of cohesive powders in moderate to high stress environments. However, there are limits to the application of shear cell analysis that are becoming increasingly apparent against the backdrop of PAT and the goal of more efficient powder processing. When shear cell analysis is applied to cohesive powders, the forces measured during testing are relatively large, but for more free-flowing powders measurements are very small in absolute terms, and the technique begins to lose accuracy.27 Most importantly, however, the technique is far more suitable for predicting how a powder will behave under moderate to high stress, and most specifically when transitioning from the static to dynamic state, than when
These variations complicate data comparison in the broadest sense although the scale provided in USP 1174 is generally applied. In most test laboratories, the tapping process is automated and may be noisy; however, the frequency and amplitude of tapping can vary even between USP methods. Data accuracy is limited by the precision with which volume, both initial and final, can be measured, a task made more difficult by what can be an uneven powder surface, especially at the start of measurement. In addition, tapped density data can be influenced by parameters such as particle size, shape, and surface area in ways that conflict with and compromise the ability of the technique to assess flowability. For example, colloidal silica, an extremely fine, cohesive material with poor flowability, can exhibit a relatively small change in bulk density as a result of tapping, suggesting that it is relatively free-flowing. This is because the strength of interparticulate forces within the silica is so great that tapping fails to overcome the cohesion within the sample and induce substantial change. Similarly, in a free-flowing powder, particles are able to move readily with respect to each other and, therefore, an external force such as tapping may cause a considerable change in the packing structure and result in a large volume change typically associated with more cohesive materials.15,20,21 Shear Cell Analysis. Shear cell analysis was developed by Jenike in the 1960s to support a numerical methodology for the design of hoppers. Jenike based this design methodology on mathematical modelling of the flow/no flow condition that marks the boundary between acceptable and unacceptable hopper discharge.22,23 His focus was, therefore, the transition from stasis to flow, in a powder bed under some considerable stress, consolidated under its own weight. The test methodology he developed, shear cell analysis, very much reflects this application. Jenike’s work is widely recognized as a major breakthrough in the field of powder characterisation and transformed hopper design, and shear cell testing undoubtedly brings genuine value in this area. E
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flowing or being processed under the low stress conditions that prevail in many process environments. Extrapolating the data measured using shear cell analysis to infer behaviour under low stress, when a sample is aerated, or even into the fluidised regime that exists in, for example, pneumatic conveying and fluidised bed granulation, can be misleading. This brings into question the relevance of shear cell analysis for the advancement of process development and manufacturing control for many unit operations.28−30 Dynamic Powder Testing. Dynamic powder testing was developed in the 1990s in response to the need to measure powder flowability under conditions that more closely represent the process environment. Dynamic powder properties are determined from measurements of the torque and force acting on a helical blade at it rotates through a powder sample along a defined path (see Figure 6). As with some traditional
Dynamic powder testing, like shear cell analysis, is associated with more complex and expensive instrumentation than the simpler USP methods. Thoughtful interpretation of the data is required, but dynamic powder testing goes beyond the USP listed powder testing techniques in providing the capability to measure powders under conditions that directly simulate processing environments in order to produce highly relevant information. This is essential within the context of PAT. Direct correlation between dynamic powder properties, in-process behaviour, and product performance clearly demonstrate the technique’s potential to support better powder processing in areas5 where other available methods struggle to provide the required level of information. Case Study: Using Dynamic Testing to Assess the Performance of Dry Powder Inhaler Formulations. Formulating pharmaceutical blends for dry powder inhalers (DPI) is challenging since it relies on identifying a blend that will aerosolise efficiently when the inhaler is used by the patient. The active pharmaceutical ingredient (API) in a DPI formulation is usually a fine cohesive powder, which is often blended with a coarser carrier excipient to improve flow properties, thereby easing manufacture of the product. During inhalation, the API is stripped from the surface of the carrier and delivered to the lungs while the excipient is ingested. Most DPIs are passive, which means that the motive force for this aerosolisation/elutriation process is provided by the patient inhaling to activate the device. The inclusion of excipient fines in a DPI formulation has been shown to improve drug delivery.33 Experiments were carried out to investigate whether this effect can be correlated with measurements of powder flow properties. Blends of budesonide, sieved lactose (SV003), and micronized lactose (up to 20% w/w), were produced to assess the impact of fines on fluidisation behaviour and on DPI performance. The flow energy of each blend was measured using the FT4 powder rheometer from Freeman Technology, an instrument that enables dynamic, shear, and bulk property measurement. Flow energy was measured as a function of air velocity through the powder up to the point at which the powder samples fluidised.34 This analysis generated values of fluidisation energy, the energy required to induce flow in a fluidised powder sample. The fine particle dose (FPD) of each formulation was also measured using a next generation impactor (NGI) applying standard pharmacopoeial tests for DPI testing.35,36 Fine particle dose is defined as the mass of delivered drug lying in the sub-five micrometer fraction, the mass that, on the basis of size, might be expected to deposit in the lung. For these latter measurements the formulations were loaded into size 3 HPMC capsules and dispersed using the commercially available Cyclohaler device. The NGI was configured with a preseparator and operated at a test flow rate of 82 L/min. The results show (see Figure 7) that as the fines content is increased, fluidisation energy rises, as does FPD. A rationale for the observed results is that the increase in fines encourages greater cohesivity in the bed. The smaller particles create greater resistance to air flow, increasing the likelihood of channelling, and the magnitude of fluidisation energy. This in turn leads to more energetic failure of the powder bed during product use and more effective aerosolisation of the dose to a finer, respirable particle size.37 The observed changes in fluidisation energy exactly mirror the increase in FPD, indicating that fluidisation energy is a good
Figure 6. Schematic showing the operating principle that underpins dynamic powder testing.
techniques, dynamic powder testing has an easily comprehensible measurement principle, and the appeal of measuring powders in a way that can be intuitively related to flowability, since analysis is carried out on moving powders. Basic flowability energy (BFE), a dynamic flow property, is measured as the blade descends, forcing the powder against the base of the test vessel, and reflects how a powder will flow under forced conditions, such as through an extruder or into a semifilled tablet die.31,32 Specific energy (SE), in contrast, is measured during an upward traverse of the blade, which exerts a gentle lifting action. This parameter directly reflects behaviour in a low stress, unconfined environment, e.g. when a powder is flowing freely from a feed shoe, in a tablet press, for example.32 A defining difference between dynamic powder testing and other techniques discussed here is that powders can be measured in a consolidated, conditioned, aerated, or even fluidised state to directly quantify how the powder responds to varying stress and flow regimes. The test methodologies for dynamic powder testing are welldefined and also incorporate a sample conditioning step which ensures powders are tested in a consistent state. Conditioning involves gentle agitation of a received sample to ensure that excess air is released and any highly agglomerated material is gently broken up. This produces a homogeneous, loosely packed bed and a reliable baseline for measurement, overcoming a major source of poor reproducibility. Dynamic powder testing is highly repeatable and reproducible, and dynamic measurements can be used to differentiate powder properties that other techniques, such as shear cell testing, classify as identical.15,27 F
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AUTHOR INFORMATION
Corresponding Author
E-mail:
[email protected] Notes
The authors declare no competing financial interest.
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Figure 7. Correlation between fine particle dose and fluidisation energy for samples with increasing fines content. [Included by kind permission of Dr. R. Price, f rom a presentation given at Respiratory Drug Delivery 2010.]
predictor of DPI performance. linear, despite the fact that the fluidisation energy is not one highlights the potential role formulation.
REFERENCES
(1) Naegelen, J. Drugmakers warn of $140 billion patent cliff Reuters [online], May 2, 2007. http://uk.reuters.com/article/ idUKGRI22300720070502 (accessed Jan 14, 2014). (2) Pellek, A.; Arnum, V. Continuous flow: Moving with or against the manufacturing flow. Pharm. Technol. 2008, 9 (32), 52−58. (3) Clayton, J. The attraction and challenge of continuous manufacturing. Pharmaceutical Online Magazine, 2012. http://www. pharmaceuticalonline.com/doc/the-attraction-and-challenge-ofcontinuous-0001 (accessed Jan 14, 2014). (4) United States Pharmacopeia Powder Flow; USP 29/NF 24 ed.; U.S. Pharmacopoeial Convention: Rockville, MD, 2004. (5) Freeman, T.; Price, R. Dynamic powder characterisation for DPI formulations. Drug Delivery Technol. 2009, 9 (5), 50−55. (6) Armstrong, B.; Birkmire, A.; Freeman, T. A QbD Approach to Continuous Tablet Manufacture. Presented at the 28th International Forum and Exhibition Process Analytical Technology, Arlington, Virginia, January 22−24, 2014. (7) Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance; U.S. Department of Health and Human Services Food and Drug Administration: Rockville, MD, 2004. (8) Armstrong, B.;Freeman, T. Using powder characterisation methods to assess blending behaviour. Freeman Technol. [online] June 2007. http://www.freemantech.co.uk/en/literature-anddownloads/articles-and-white-papers.html (accessed Jan 14, 2014). (9) Fayed, M. E., Otten, L., Eds. Handbook of Powder Science and Technology; Van Nostrand Reinhold: New York, NY, 1984. (10) Zhou, Q. Surface modification of pharmaceutical powders. Ph.D. Thesis, Monash University: Melbourne Australia, 2011. (11) Abdullah, E. C.; Geldart, D.; Hassanpour, A.; Nwoke, L. C.; Wouters, I. Characterization of powder flowability using measurement of angle of repose. China Particuol. 2006, 3−4 (4), 104−107. (12) Geldart, D.; Abdullah, E. C.; Verlinden, A. Characterisation of dry powders. Powder Technol. 2009, 1−2 (190), 70−74. (13) Kalson, P. A.; Resnick, W. Angles of repose and drainage for granular materials in a wedge-shaped hopper. Powder Technol. 1985, 43 (2), 113−116. (14) Brockbank, K. M. Novel approaches to the assessment of pharmaceutical powder flow behaviour. Ph.D. Thesis, University of Bradford: Bradford, U.K., 2011. (15) Armstrong, B. study of pharmaceutical powder mixing through improved flow property characterisation and tomographic imaging of blend content uniformity. Ph.D. Thesis, University of Birmingham: Birmingham, U.K., 2010. (16) Lee, Y. S.; Poynter, R.; Podczeck, F.; Newton, J. M. Development of a dual approach to assess powder flow from avalanching behavior. AAPS PharmSciTech 2000, 1 (3), E21. (17) Taylor, M. K.; Ginsburg, J.; Hickey, A.; Gheyas, F. 2000. Composite method to quantify powder flow as a screening method in early tablet or capsule formulation development. AAPS PharmSciTech 2000, 1 (3), E18. (18) Hausner, H. H. Friction conditions in a mass of metal powder. Int. J. Powder Metall. 1967, 3 (7), 7−13. (19) Carr, R. L. Evaluating flow properties of solids. Chem. Eng. 1965, 72 (2), 163−168. (20) Armstrong, B.; Freeman, T. Consolidation of powders: How to evaluate the effect of vibration-induced powder compaction through flow property measurement. Presented at Particulate Systems Analysis Conference and Exhibition, Edinburgh, UK, Sep. 5−7, 2011.
This correlation is strong and relationship between fines and of direct proportionality, and of dynamic testing in DPI
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LOOKING AHEAD The implementation of the PAT initiative, alongside the adoption of QbD and a general drive for improved manufacturing efficiency, puts traditional analytical techniques under the spotlight. Nowhere more so than in the field of powder characterisation, which is critical to the success of so many pharmaceutical operations−both batch, and, increasingly, continuous. The understanding of powder behaviour needs to increase to meet the demands of more intelligent process development and more efficient process control. Analytical strategies are being redefined to realise this goal. The PAT initiative focuses on reducing risk by achieving greater control of every step of the pharmaceutical manufacturing cycle. Greater control requires more precise powder characterisation, using instruments and methodologies that can identify subtle differences in a way that is relevant to the process in question. When a process is tolerant of variability, the need to define an accurate specification may be low, and the relatively crude but inexpensive differentiation provided by simple techniques such as angle of repose, flow through an orifice and tapped density may be appropriate. If ever a time existed when this was all that was required to succeed in pharmaceutical manufacture, it would appear to be passing and newer methods are gaining prominence. Techniques such as shear cell analysis and dynamic powder characterisation enable the evaluation of powder characteristics in far greater detail. They can increase understanding and knowledge by an order of magnitude compared with other traditional techniques. Furthermore, these techniques enable test methods to be customised to investigate the intricacies of specific processes, implementing the essence of PAT. Embracing such technologies such as these in order to complement traditional methods, and using each according to its strengths, will help the pharmaceutical industry achieve the desired manufacturing transformation. G
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dx.doi.org/10.1021/op500019m | Org. Process Res. Dev. XXXX, XXX, XXX−XXX
