PSTT Vol. 3, No.

9 September 2000 research focus reviews

An engineering view of
pharmaceutical powder mixing
Norman Harnby

Can the pharmaceutical industry learn anything from other powder customer sensitive. Customer demands focus in
varying proportions on the mixture quality and
processing industries? Although essential regulatory processes have
the market appeal of the final product form. A
ensured that the pharmaceutical industry is a leader in quality ceramic component of a titan rocket is judged
assurance, they have also led to a conservative approach to process almost exclusively on its quality, in that the
intimacy and texture of the mixed powder before
technology. Conservatism is advantageous when the dosage form fusion will determine the reliability of the prod-
and profit margins are stable; however, for most other industries, uct; the appearance of the part has little signifi-
cance. By contrast, an eyeliner cosmetic faces a
form, price and quality of product are all subject to fickle customer
different customer demand, which is much more
requirements. Other powder industries have used a sequential orientated towards the presentational form or
questioning approach to elicit new technical responses to change. visual attraction of the final product. A package
of detergent lies somewhere between these two
Perhaps the time is ripe for this to be introduced to the
extremes: it is a relatively complex mixture that
pharmaceutical industry? requires quantifiable quality standards but at the
same time tries to meet a fickle public require-
ment for product forms, which could include
flakes, loose granules, dense granules, tablets
▼ The market for powder-based products is large and, the ultimate horror from a powder technol-
Norman Harnby
Department of Chemical and is growing. Products such as foodstuffs, cos- ogist’s point of view, the liquid form.
Engineering metics, ceramics, detergents, powdered metals, But where does the pharmaceutical industry
University of Bradford plastics and abrasives share many of the process- position itself in this spectrum of demands?
Bradford ing challenges faced by the pharmaceutical in- Quality is typically considered to be of para-
West Yorkshire
dustry and can frequently provide alternative mount importance and because the customer is
UK BD7 1DP
tel: 144 1274 233710
process outcomes. Over recent decades, all these considered to be incapable of judging the effi-
fax: 144 1274 235700 other industries have undergone a rapid tran- cacy and quality of a prescribed drug, a complex
e-mail: sition from a processing art to a processing regulatory system is enforced. Seemingly, drugs
[email protected] science. The art of manufacturing requires the are categorized with ceramics as quality domi-
acquisition of manufacturing skills based on ex- nated, with the product form being either irrel-
perience generated over a long period of time evant or at least of little significance. However,
and requires a stable, consistent market for its this scenario appears to be changing. Patients are
products. Intense competition in these industries no longer passive; increasingly, manufacturers
has led to the manufacturing process becoming are required to present the product in forms that
customer-led rather than technology-led and has are well accepted by patients. The customer-led
instigated the requirement that the process development of powder inhalants and skin pen-
should be flexible to meet changing customer etrants suggests that the slow succession of
demands. This requires a fundamental and quan- dosage forms from ‘shake the bottle’ prescrip-
titative understanding of the processing and tions through to rolled pills, capsules and the all-
packaging of the product. dominating tablet might not yet be finished
Powder mixing is a central operation associ- and might even gather further momentum in the
ated with all these industries, and has had to be future.

1461-5347/00/$ – see front matter ©2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00283-2 303
reviews research focus PSTT Vol. 3, No. 9 September 2000

energy input. Whatever the imposed

Mixture mixing mechanism, the ability of indi-
formulation vidual particles to move independently
within the bulk powder is evidently an
important characteristic and leads to a
broad division of powder-mixing pro-
Free-flowing and Cohesive and cesses into ‘free-flowing’ and ‘cohesive’
segregating structured (non-free-flowing) mixtures.
A division between the two regimes
is not easily defined. The bulk effect
can be seen by rolling the mixture in a
Generic mixer
bottle. The free-flowing powder moves
smoothly with well-defined planes of
movements whereas the cohesive pow-
der exhibits ‘stick-slip’ motion with
Quality Process irregular surface characteristics. Particle
requirements requirements
size is probably the dominant influence
on the type of flow regime. The gravi-
tational force associated with a large
Final mixer
selection particle is much larger than any restrain-
ing interparticulate force with the result
Pharmaceutical Science & Technology Today
that individual particles retain their free-
dom of movement. As the particle size
Figure 1. Issues to be addressed in mixer selection. decreases, various interparticulate forces
can potentially dominate and the par-
ticles attempt to retain a structured
But is there a general technological logic that can be applied arrangement. The actual transition size will be a function of
across all the powder process industries, which will allow a the nature of the interparticulate forces and other particle char-
flexible response to a changing customer requirement of qual- acteristics, but in general terms it can be stated that particles of
ity, form or both? Following a sequential questioning pro- nominal diameter greater than 50 mm tend to be free-flowing
cedure, a generic mixer selection can be made based on an whereas particles of nominal diameter less than 50 mm tend to
information input of the mixture formulation, the product be cohesive. But what effect has the flow property of a powder
quality requirements and the process limitations imposed by on the mixing process?
the nature of the product (Fig. 1).The procedure will highlight
any selection compromises that are needed to resolve conflicting Free-flowing mixtures
requirements from the three data inputs. From both a marketing and a processing perspective, free-flow-
This review will not detail a sequential questioning pro- ing powders have many desirable features, but the disadvantage
cedure but will explore the nature of the three information of these mixtures is that they can be subject to segregation or ‘un-
inputs and will reach conclusions relevant to the pharmaceutical mixing’ on a severe scale1.The same freedom that allows a parti-
industry on generic mixer selection. cle to move smoothly and independently of its neighbours en-
ables it to preferentially move in a particular direction. Even if a
Mixture formulation mass of free-flowing powder is ‘satisfactorily’ mixed, great care
Although the weight proportions of a formulation are usually has to be taken in subsequently handling the mixture. Storage and
fixed, there is considerable freedom at the formulation stage to handling processes can destroy the mixture quality that has been
vary the morphology of the ingredients and hence their flow so carefully created and only when the mixture has been ‘frozen’
characteristics. For mixing to occur, individual particles must at its final point of usage can the mixture be regarded as safe.
be given the opportunity to relocate themselves repeatedly
within the bulk of the mixture.To generate such movement the Cohesive mixtures
particles can be tumbled, kneaded, fluidized, sheared, scooped For the free-flowing mixture, the art of the process engineer
or impacted within a mixer with a variable level and type of is often to restrict the freedom of movement of individual

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PSTT Vol. 3, No. 9 September 2000 research focus reviews

particles; however, for the cohesive mixture the problem is re- Scale of scrutiny
versed. The cohesive system has a natural structure that must As the scale and intensity of segregation are reduced, the mix-
be repeatedly broken down in order to give individual parti- ture passes through a critical mixing state during which it
cles within that structure an opportunity to relocate them- changes from an ‘unsatisfactory’ to a ‘satisfactory’ mixture for a
selves. Problems of mixture quality can arise in processes that particular process. The identification of this critical quality or
demand a finely textured product. It is commonly found that scale of scrutiny is perhaps the most important step in the per-
although the scale of segregation of cohesive mixtures is small, formance analysis of a mixture. Any mixture will be unsatisfac-
the intensity of segregation can be high.This is caused by small tory if scrutinized closely enough because the scale of scrutiny
agglomerates of individual mixture ingredients retaining their will then approach the scale of individual elements. Thus, in
structure throughout the mixing process. The strength of these the case of the dispersion of a pigment in plastic, the scale of
agglomerates and the ability of different mixers to break them scrutiny on the plastic surface will normally be a small area
down to the scale of the individual particle is a central study of incapable of resolution by the human eye. Microscopic
cohesive mixtures. examination of the plastic places higher demands on the
mixture because the area examined, and hence the scale of
Ordered mixtures scrutiny, is reduced.The smaller the scale of scrutiny demanded
A subject of considerable industrial interest is the achievement by a product application, the greater the difficulty the mixer
of an ordered structural arrangement of particles, which could will have in achieving a satisfactory mixture. For meaningful
improve the typically limiting random particle arrangement. If results a mixture should be sampled at a size equal to or less
the shape and surface characteristics of the constituent particles than the scale of scrutiny required by the mixture application.
can be manipulated so that the particles prefer to adhere to a
dissimilar particle, an orderliness is introduced into the mixture Statistical assessment of mixture quality
that gives a better mixture quality than that for random mixing. The control of the mixture quality is then based on a statistical
Particularly attractive is the so-called ‘coating process’ wherein assessment of a selection of such samples3. It must be empha-
fine minor component mixture constituents adhere preferen- sized that such a quality assessment is only valid at that scale of
tially onto a relatively coarse carrier particle. Such a mixture scrutiny and should be scaled up or down with extreme caution.
carries the double advantage of having free-flow characteristics The variance of a component in several samples is a measure
for handling whereas still retaining a high mixture quality. of the consistency or quality of the product. The smaller the
variance, the better the mixture. Such a measure gives a graded
Mixture quality assessment of mixture quality, which enables process trends to
Essential reading for anyone wishing to have a better qualita- be followed and problems to be predicted and avoided. The
tive understanding of mixture quality is the article written in sample variance value alone gives no absolute assessment of
1953 by Danckwerts2. Danckwerts defines a ‘scale of segre- mixture quality; this value has to be related to the limiting mix-
gation’ and an ‘intensity of segregation’, which describe the ture variance values of complete segregation and of random-
size and amount of dilution of patches or volumes of unmixed ized mixing. The variance of the randomized mixture is the
material within the mixture, respectively. Thus, a poor mixture more helpful datum of comparison because it usually repre-
will have a large scale of segregation and a high intensity of sents the attainable mixture quality in an industrial process and
segregation whereas a good mixture will have a small scale of represents a random positioning of the components within the
segregation and a low intensity of segregation. Mixtures with mixture with no segregation or preferential positioning.
identical scales of segregation will differ in quality if the The limiting random variance can be calculated for most
amount of dilution of the segregated patches is different, as industrial mixtures. The simplest case is that for a two-com-
will mixtures of constant dilution but varying scale of segre- ponent mixture of equi-sized particles4 where in Eqn 1,
gation.The role of a mixer is to reduce the scale of segregation pq
sR 2 =
and to lower the intensity of segregation. B
Although these two definitions are helpful in describing the sR2 is the random variance of the samples, p and q are the
role of the mixer, they give no indication of the ‘end point’ in proportions of the two components and B the number of
the mixing process. To what extent should the scale and inten- particles in the sample.
sity of segregation be reduced within the mixer? What is the Similar but more complex relationships are available for
end point of the mixing operation for a particular process? multisized, two-component systems5, for multisized, multi-
Danckwerts established the concept of a ‘scale of scrutiny’ for a component systems6 and for some cases of agglomerating mix-
process; this enables us to answer these questions. tures7. These random variance values represent an invaluable

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reviews research focus PSTT Vol. 3, No. 9 September 2000

datum of comparison for experimental values. They represent packaging operations would have many advantages. Further,
the possible goal of a mixing process but do not take into ac- easy access for sampling is desirable.
count any of the shortcomings of the mixer or of a segregating
mechanism in a real process. Product containment
The mixing process attempts to minimize the variance value Product containment can be a two-way problem with risks of
between samples. Ideally, this value should be kept as small as either contamination of the product from an external source
possible. Inspection of Eqn 1 shows that the random variance or contamination of the surroundings by the product. How
can be reduced either by having one component in a very small well can the mixer isolate the process materials? Product con-
proportion or by having a very large number of particles in tamination is not only caused by other powders but can also
each sample. Usually, the proportion of the components is be sourced from bearings or from moisture in the atmosphere.
fixed by the process and cannot be adjusted. The number of
particles in the sample can be increased by either having a Product sensitivity
larger sample, or smaller particles, or both. If the weight of the Mixers handle products in different ways depending on
samples is fixed then the only process freedom remaining is to whether the product is fragile, abrasive, explosive, contami-
reduce the size of the particles in the mixture. nated by metallic surfaces, heat sensitive, agglomerative or
The inspection of the expressions for the random variance dusty. All these factors can influence a final mixture choice.
of more complex systems confirms the importance of com-
minution and especially the control of particle size if a consist- Cleaning
ent and high quality is to be maintained. Although a random Does the mixer require frequent cleaning and to what stand-
arrangement of particles is normally the attainable ideal for ard? Cleaning between batches of different products or cleaning
powder mixing, it is possible, in certain circumstances, to have to ensure the flushing out of batch residues can be a time-
an ordered or ideal arrangement of particles and thus approach consuming operation that cuts into profitable product-production
a mixture variance of zero. Such mixtures are of great interest time. Do the mixing surfaces require highly polished surfaces
to those industries requiring very high mixture standards7. or to be constructed with exotic materials? These are all factors
that will contribute to the final mixer selection.
Process requirements
Of the three information inputs needed to logically select a Mixer selection
mixer, the process and product requirements are usually the easi- There are a very large number of mixers and mixer manufac-
est to specify. A logic-based assessment of the mixer require- turers and the temptation to choose ‘the same as last time’ can
ments would flag up questions under the following headings. be strong. The selection problem can be simplified consider-
ably by grouping most mixers under the broad descriptive
Throughput headings of convective, tumbler, impaction and high shear.
If a batch process is envisaged, does the mixer have the flexi- These categories will be reviewed giving generic descriptions
bility to cope with a variable batch size? Is the mixer loaded and their relative merits under the three information input
with all the mixture ingredients or is there a sequential ad- headings.
dition of ingredients at staged mixing times? For a high
material throughput and/or for a strongly segregating system, Convective
serious consideration should be given to specifying a continuous Convective mixers relocate groups of related particles within a
rather than a batch mixer. static shell by means of a rotating impeller. The shell can be a
trough, a double trough, a vertical cone or a cylindrical hopper;
Batch integrity the impeller can be a blade, a ribbon, an Archimedian screw, a
Traceability is rapidly becoming a requirement for all the Z-blade or a paddle. Rotational speeds are typically five to
process industries. For the pharmaceutical industry it is an es- 30 revolutions per minute.They are probably the most frequently
sential requirement and usually precludes the ‘open-ended’ used group of industrial powder mixers (Fig. 2).
continuous mixing route. If batch integrity is to be maintained The greatest advantage of convective mixers is their ability
from the loading of the mixture ingredients through mixing to to handle a wide range of process materials from free-flowing
the final packaging of the product then intermediate storage powders to pastes and doughs. In the powder sector, the mix-
and handling should be minimized and all process equipment ing mechanism of pushing and relocating groups of particles
should be capable of easy flushing and cleaning. A mixing ves- minimizes the opportunity for segregation and optimizes the
sel that can be transported between the loading, mixing and mixture quality. Cohesive powders mix well but risk searching

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PSTT Vol. 3, No. 9 September 2000 research focus reviews

out unswept corners of the mixer to lodge

as dead spots. Because of the static shell, (a) (b)
the mixers are accessible for sequential
ingredient additions, for heat transfer
and for the addition of liquid sprays.The
disadvantages of this generic group of
mixers are that they risk contamination
with their moving parts, are difficult to
access for cleaning and sampling, and
have to be carefully integrated with the
overall process. (c)

Tumbler
Simple mixer shell shapes are rotated
horizontally on bearings and mixing oc- Pharmaceutical Science & Technology Today
curs by the powder within the mixer
tumbling and cascading on the free sur- Figure 2. Convective mixers: (a) Hosokawa Nauta mixer, (b) Ribbon blender and (c) a typical ribbon.
face. A variety of simple shapes such as
cubes, double cones and V-shapes are
used with rotational speeds of typically
five to 30 revolutions per minute (Fig. 3).
Tumbler mixers can handle free-flow-
ing and cohesive powders but not pastes
or doughs, and quality is a problem.
Free-flowing powders can segregate rel-
atively dramatically on the tumbling
surface and the emptying process fre-
quently reinforces this segregation.
Weakly structured powders will be
broken down within the mixer but small
agglomerates or aggregates of an ingre-
dient might remain intact.The degree of
fill of the mixer can also affect mixture
quality leading to an inflexibility in
batch size.
Although quality will always remain
a problem, the tumbler mixer has sig-
nificant process advantages. The simple
shape enables the mixer to be manu-
factured in a wide variety of non-
Pharmaceutical Science & Technology Today
contaminating materials, gives good
access for both cleaning and sampling, Figure 3. Tumbler mixers: V-mixer.
and has no internal bearings contacting
the product. Interaction with the mix-
ing process for heat transfer, liquid addition or the stage-wise within the range of 2000 to 3000 revolutions per minute
addition of ingredients is difficult. within a static vessel, similar to a kitchen food processor.
Frequently, an impaction element is introduced along the axis
Impaction of rotation of a tumbler mixer to present the possibility of an
Impaction mixers (Fig. 4) represent a significant increase in alternative mixing mechanism. The impaction mixer finds an
energy input into a mixture because the blade rotates at speeds important process niche as a combined mixer-granulator when

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reviews research focus PSTT Vol. 3, No. 9 September 2000

Impeller
bar
Scraping
tool
Motor

Discharge

+ +
Pharmaceutical Science & Technology Today

Figure 4. Impaction mixers: Henschel mixer.

the high tip speed of the blades can repeatedly break granules
as they form and reform. The simple cylindrical or spherical
shape of this class of mixer carries the advantages of ease of
cleaning and of manufacture in a variety of materials and + +
material finishes.
For dry mixtures, the hold-up of fine material on the
unswept walls of the vessel creates dead spots, and for a free-
flowing powder the emptying of the mixer is vulnerable to
physical or chemical segregation. There is good evidence that
impactor blades are effective at breaking up aggregates of
powder only down to a limiting size, and below that it is poss-
ible to have a small scale of segregation but with a high inten-
sity of segregation. In some cases, though, this will limit the
application of the impactor mixer.

High shear
High-shear mixers (Fig. 5) are industrial developments of the
alchemist’s mortar and pestle and the miller’s millstone for the
Pharmaceutical Science & Technology Today
grinding of grain. Powder is ‘pinched’ between a moving and a
static surface as in a Comil or between two moving surfaces as Figure 5. High-shear mixers: Chilsonator.
in a pair of pressurized rolls.The speed of rotation is low but the
powder is subjected to a very high shear that will break down
most aggregates. It is commonly preceded by a convective or selection is constrained by the joint requirements of the mixture
tumbler mixer to give a general bulk quality before the con- meeting the quality requirements, and the mixing equipment
ditioning of the mixture on a microscale in the high-shear mixer. meeting the specific process requirements of the product. The
In some cases the pressure exerted on the powder in the pinch pharmaceutical industry is perhaps less flexible than other
zone is sufficient to consolidate it into a flake form. High-shear industries in its approach to process design because of the
mixers tend to have a limited throughput rate and are reserved necessary constraints of quality regulation and process
for those mixtures requiring homogeneity on a microscale. approval that are imposed on it.
Achieving and maintaining a high product quality is never
Conclusions easy; typically, the problem is exacerbated in the pharmaceutical
What lessons does a logical mixer-selection procedure hold for industry by having to ultimately blend a small amount of ac-
the pharmaceutical industry? Similar to other process industries, tive drug with a large amount of excipient in order to produce

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PSTT Vol. 3, No. 9 September 2000 research focus reviews

a product with a scale of scrutiny of a single tablet or less. The problems when their clear roles in the high-speed tabletting
statistics of powder mixing therefore require the active drug to process are forgotten. If the direct compression route to tab-
be finely milled in order to achieve a finely textured product. letting is attempted by omitting the granulation step then the
flow characteristic of the bulk mixture has to be intermediate
High-speed tabletting between cohesion and free flow in order to suppress segre-
The onset of high-speed tabletting posed a difficult problem in gation within the tumbler mixer whilst maintaining flow on
that the cohesive blend was required to flow consistently and the tabletting plate. The risk of segregation within the tumbler
at speed into the die of the tabletting plate. This contradiction mixer is ever present in this delicate flow balance. If the
in flow requirements was satisfied by granulating the cohesive alternative of using the high-speed impactor as a dry mixer
mixture in a high-speed impaction mixer and/or granulator is used, there are the combined risks of hold-up of powder
and then feeding a dried and free-flowing granular mixture to on the unswept walls and segregation occurring on discharg-
the tabletting machine. The pre-mix followed by the granu- ing the mixer. A new quality-assurance danger arises as
lation is optimal because the chemical uniformity of the prod- process segregation is possible. The tacit assumption that if a
uct is achieved at the pre-mix stage, and at the tabletting stage mixture is ‘well mixed’ within the mixer then the mixture
any segregation associated with the free-flowing granules is quality can only be improved by subsequent handling is in-
physical rather than chemical. correct and the equilibrium nature of a mixture of a segregat-
The pre-mix stage is usually carried out in a tumbler mixer ing powder can cause quality degradation downstream of the
possibly with the aid of an impactor or intensifier bar. With a mixer. The possible use of a convective mixer and the careful
cohesive powder charge a tumbler mixer will not segregate the sequencing and design of the downstream process are now
mixture and is capable of breaking up and mixing loosely essential.
structured systems. The use of an impactor along the axis of
rotation will break up stronger structures but experience in the References
ceramic and cosmetic industries suggests that impaction will 1 Harnby, N. et al. (1997) Mixing in the Process Industries,
not be as effective as high shear in breaking down the Butterworth–Heinemann
microstructure of a mixture. Nonetheless, an effective and 2 Danckwerts, P.V. (1953) Theory of mixtures and mixing. Chem. Eng. Res. 6,
high-throughput process can be built about a combination of 355
tumbler and high-impaction mixers. However, the sequencing 3 Harnby, N. (1975) 1st International Powder and Bulk Granular Conference,
of a tumbler mixer with a high-speed mixer granulator has lost Proceedings of Powtech 71, 19
the effective shearing action of the mortar and pestle, and 4 Lacey, P.M.C. (1943) The mixing of solid particles. Trans. Inst. Chem. Eng. 21,
if strongly structured aggregates are to be broken down in 53
order to optimize the microstructure of the powder then a 5 Stange, K. (1954) The mixture quality of a random mixture of a two-
high-shear mixer needs to be introduced into the sequence. component mixture. Chem. Ingr-Tech. 26, 331
6 Stange, K. (1963) The mixture quality of a random mixture of three or
Direct compression more components. Chem. Ingr-Tech. 35, 580
The familiarity and availability of tumbler and high-impaction 7 Coehlo, M.D.C. et al. (1977) Second European Conference on Mixing, 30 March,
mixers within the industry can lead to quality-control BHRA Fluid Engineering

Monitoring blood glucose

FreeStyle™, a blood glucose monitor that enables diabetics to take a blood sample from their arm instead of their fingertips,
has been developed by TheraSense (Alameda, CA, USA). This monitor was developed for diabetics in response to the need
for less-painful testing; frequent sampling of blood from the fingertips causes pain because of the more-sensitive nerve
endings in this area.
It is hoped that FreeStyle™, a method that is almost painless (as shown recently in clinical trials), will improve the control of
diabetes. The pain currently involved in testing for blood glucose discourages regular testing. A reduced volume of blood is
required for glucose analysis compared with other monitors because of the usage of coulometric technology.
‘FreeStyle™ quickly and accurately provides a blood glucose value using a very small blood sample, giving people the
freedom to test on sites other than their fingertips. Our objective is to make it easier for people to take better control of their
diabetes and enjoy a healthier life,’ said Mark Cortz, President and CEO of TheraSense.

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