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Aultons Pharmaceuticals Reduction Mixing PDF
Aultons Pharmaceuticals Reduction Mixing PDF
s e paratio n
C H AP TE R C O N TE N TS KE Y P O IN TS
Introd uc tion to s ize re d uc tion 157
• The particle s ize of s olid drugs and excipients
In ue nc e of ma te ria l p rop e rtie s on has a s igni cant effect on many of their
s ize re d uc tion 157 properties , including rate of dis s olution and
powder ow characteris tics
Crack propagation and toughnes s 157
• During raw material manufacture, the s olid
Surface hardnes s 158 produced is often of a larger s ize than that
Energy requirements of s ize required pharmaceutically and thus s ize
reduction proces s 158 reduction is a key proces s prior to incorporation
into a nis hed product
In ue nc e of s ize re d uc tion on
• Solid particles pos s es s a range of mechanical
s ize d is trib ution 159
properties and cons equently a number of
Size re d uc tion me thod s 160 different mechanis ms of s ize reduction exis t,
dependent upon thes e properties for the
Cutting methods 160 material in ques tion In turn, this in uences
Compres s ion methods 160 the des ign of the commercial equipment for
ef cient s ize reduction
Impact methods 161
• The method of s ize reduction not only
Attrition methods 162 affects mean particle s ize but als o the
Combined impact and attrition methods 162 dis tribution of the s izes of the powdered
material Methods of determining and
Se le c tion of p a rtic le s ize re d uc tion me thod 163
repres enting mean s ize and s ize dis tribution
Introd uc tion to s ize s e p a ra tion 164 are dis cus s ed
• The correct choice of the mos t ef cient
Objectives of s ize s eparation 164 commercial s ize reduction machinery will
Size s eparation ef ciency 164 depend upon knowledge of thes e properties
Size s e p a ra tion me thod s 166 and mechanis ms
• It is often neces s ary to s eparate out from a
Size s eparation by s ieving 166 widely dis tributed range of s izes , the s ingle
Size s eparation by s edimentation 167 s ize, or narrow range of s izes , that is bes t s uited
for the application in hand This required s ize
Size s eparation by elutriation 167 will depend on the s ubs equent us age of the
Size s eparation by cyclone 168 material For example, a drug us ed in a dry
Se le c tion of a s ize s e p a ra tion p roc e s s 169 powder inhalation formulation will need to be
of a very different s ize than that required in an
Bib liogra p hy 169 oral s olid dos age form
30 30
Intro duc tio n to s ize re duc tio n L
15 7
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
where Ep is the energy required to form unit area of of material, which resists comminution at ambient
double surface. or elevated temperatures, can be more easily size
It can therefore be seen that the ease of com- reduced when temperatures are lowered below the
minution depends on the brittleness or plasticity of glass transition point of the material. At these lower
the material because of their relationship with crack temperatures the material undergoes a transition
initiation and crack propagation. from plastic to brittle behaviour and crack propaga-
tion is facilitated.
O ther factors that in uence the process of size
Surface hardnes s reduction include the moisture content of the mate-
rial. In general, a material with a moisture content
In addition to the toughness of the material described below 5% is suitable for dry grinding and one with
above, size reduction may also be in uenced by the greater than 50% will generally require wet grinding
hardness of the material. H ardness can be described to be carried out.
empirically by its position in a scale devised by a
G erman mineralogist called Mohs. Mohs’ scale is a
table of minerals; at the top of the table is diamond, Energy requirements of s ize
with Mohs hardness >7, and this has a surface that
is so hard that it can scratch anything below it. At
reduction proces s
the bottom of the table is talc, with Mohs hardness
O nly a very small amount of the energy put into a
<3, and this is soft enough to be scratched by any-
comminution operation actually effects size reduc-
thing above it.
tion. This has been estimated to be as little as 2%
A quantitative measurement of surface hardness
of the total energy consumption, the remainder
was devised by Brinell. This involves placing a hard
being lost in many ways, including:
spherical indenter (e.g. hardened steel or sapphire)
in contact with the test surface and applying a • elastic deformation of particles
known constant load to the sphere. The indenter • plastic deformation of particles without
will penetrate into the surface until and when the fracture
sphere is removed, the permanent deformation of • deformation to initiate cracks that cause
the sample is measured. From this, the hardness of fracture
the material can be calculated. H ardness has the • deformation of metal machine parts
dimensions of stress (force applied to the indenter • interparticulate friction
divided by the area of test material that will support • particle–machine wall friction
the load, example units are MPa). A similar Vickers
• heat
hardness test employs a square-pyramidal diamond
as the indenter tip. • sound
Such determinations of hardness are useful as a • vibration.
guide to the ease with which size reduction can be A number of hypotheses and theories have been
carried out because, while it appears to be a surface proposed in an attempt to relate energy input to the
assessment, the test actually quanti es the deforma- degree of size reduction produced.
tion characteristics of the bulk solid. In general, Rittinger’s hypothesis relates the energy, E, used
harder materials are more dif cult to comminute in a size reduction process to the new surface area
and can lead to abrasive wear of metal mill parts, produced, Sn, or:
which can then result in product contamination.
Conversely, materials with a large elastic compo- E = κ R ( Sn − Si )
nent, such as rubber, are extremely soft yet dif cult (10.3)
to size reduce.
Materials such as rubber that are soft under where Si is the initial surface area and κ R is Rit-
ambient conditions, waxy substances such as stearic tinger’s constant, expressing energy per unit area.
acid that soften when heated, and ‘sticky’ materials Kick’s theory states that the energy used in
such as gums are capable of absorbing large amounts deforming or fracturing a set of particles of equiva-
of energy through elastic and plastic deformation lent shape is proportional to the ratio of the change
without crack initiation and propagation. This type in size, or:
15 8
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
E = κ K log
di In ue nc e o f s ize re duc tio n o n
dn
(10.4)
s ize dis tributio n
where κ K is Kick’s constant of energy per unit mass, In Chapter 9, several different size distributions
d i is the initial particle diameter and d n the new were discussed and some were based on either a
particle diameter. normal or a log-normal distribution of particle sizes.
Bond’s theory states that the energy used in crack During a size reduction process the particles of feed
propagation is proportional to the new crack length material will be broken down and particles in differ-
produced, which is often related to the change in ent size ranges undergo different amounts of break-
particle dimensions according to the following age. This uneven milling leads to a change in the size
equation: distribution, which is superimposed on the general
movement of the normal or log-normal curve
towards smaller particle diameters. Changes in size
1 1
E = 2κ B − distributions that occur as milling proceeds have
dn di been demonstrated experimentally and this showed
(10.5) that an initial normal particle size distribution was
transformed through a size-reduced bimodal popu-
H ere κ B is known as Bond’s work index and repre- lation into a much ner powder with a positively
sents the variation in material properties and size skewed, leptokurtic particle population (Fig. 10.2)
reduction methods, with dimensions of energy per as milling continued. The initial, approximately
unit mass. normal, size distribution was transformed into a
Walker proposed a generalized differential form size-reduced bimodal population through differ-
of the energy–size relationship that can be shown to ences in the fracture behaviour of coarse and ne
link the theories of Rittinger and Kick, and in some particles (Fig. 10.3). If milling is continued a
cases that of Bond:
∂d
∂E = −κ W
dn
(10.6)
y
where κ W is Walker’s constant and d is a size func-
c
n
e
tion that can be characterized by an integrated
u
q
mean size or by a weight function, n is an exponent.
e
r
f
When n = 1 for particles de ned by a weight func-
t
e
n
m
e
ti
tion, integration of Walker’s equation corresponds
c
g
r
in
e
ill
to a Kick-type theory, when n = 2 a Rittinger-type
P
M
15 9
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Cutting me thods
y
c
n
1 10 100 1000 10 000 100 000
e
u
q
P a rticle dia me te r (µm)
e
r
f
t
Fig . 10.5 • Size reduction range for cutting methods.
n
e
c
r
e
P
Fe e d
P a rticle dia me te r
Fig . 10.4 • Transformation of a ne bimodal particle
population into a ner unimodal distribution following
prolonged milling. S ta tiona ry knive s
16 0
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
End-runne r mills around the mill by the hammers and approach the
mesh tangentially. For this reason, square, rectangu-
Rolle r mills lar or herringbone slots are often used. Depending
on the purpose of the operation, the hammers may
1 10 100 1000 10 000 100 000 be square-faced, tapered to a cutting edge or have a
P a rticle dia me te r (µm) stepped form.
Fig . 10.7 • Size reduction range for compression
methods. Vib ra tion mill
An alternative to hammer milling which produces
size reduction is vibration milling (Fig. 10.10).
Vibra tion mills
Vibration mills are lled to approximately 80% total
Ha mme r mills volume with porcelain or stainless steel balls. During
milling the whole body of the mill is vibrated and
1 10 100 1000 10 000 100 000
size reduction occurs by repeated impact. Commi-
nuted particles fall through a screen at the base of
P a rticle dia me te r (µm) the mill. The ef ciency of vibratory milling is greater
Fig . 10.8 • Size reduction range for impact methods. than that for conventional ball milling described
below.
Rolle r mill
A form of compression mill uses two cylindrical Ha mme rs
rollers mounted horizontally and rotated about their
long axes. In roller mills, one of the rollers is driven
directly while the second is rotated by friction as
material is drawn through the gap between the rollers.
Fe e d
Impact methods
Size re d uc tion ra nge
This is shown in Figure 10.8.
S cre e n
16 1
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Ba ll mills
Attrition me thods
a b c
16 2
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
Ce ntrifuging a ction Fe e d in
throws coa rs e r P ins Uppe r fixe d pla te
pa rticle s outwa rds
S olids inle t
substantial size reduction by impact and some
attrition.
A particle size classi er is incorporated in the
design so that particles are retained in the toroid
until suf ciently ne and are then entrained in the
air stream that exhausts from the mill
P in mill
Zone of
turbule nce Fluid inle t je ts In addition to ball mills and uid energy mills, there
are other methods of comminution that act by pro-
Fig . 10.14 • Fluid energy mill.
ducing particle impact and attrition. These include
pin mills in which two discs with closely spaced pins
rotate against one another at high speeds (Fig.
dynamic angle of repose is exceeded. At this point,
10.15). Particle size reduction occurs by impaction
they fall or roll back to the base of the drum in a
with the pins and by attrition between pins as the
cascade across the diameter of the mill. By this
particles travel outwards under the in uence of cen-
means, the most ef cient size reduction occurs by
trifugal force.
impact of the particles with the balls and by attri-
tion. The optimum rate of rotation is dependent on
mill diameter but is usually of the order of 0.5 revo- Se le c tio n o f partic le s ize
lutions per second.
re duc tio n me tho d
Fluid e ne rgy mill Different mills can produce differing end product
Fluid energy milling is another form of size reduc- from the same starting material. For example, par-
tion method that acts by particle impaction and ticle shape may vary according to whether size
attrition. A form of uid energy or jet mill or micro- reduction occurs as a result of impact or attrition.
nizer is shown in Figure 10.14. Both circular designs In addition, the proportion of ne particles in the
and oval-path designs (as shown in Fig. 10.14) are product may vary, so that other properties of the
available. This circular design is now the most powder will be altered.
common. This consists of a hollow toroid which has The subsequent usage of a powder usually con-
a diameter of 20–200 mm. A uid, usually air, is trols the degree of size reduction needed but in
injected as a high-pressure jet through nozzles at the some cases the precise particle size required is not
bottom of the loop. The high velocity of the air gives critical. In these circumstances, since the cost of size
rise to zones of turbulence into which solid particles reduction increases as particle size decreases, it is
are fed. The high kinetic energy of the air causes the economically undesirable to mill particles to a ner
particles to impact with other particles and with the degree than is necessary. O nce the particle size
sides of the mill with suf cient momentum for frac- required has been established, the selection of mills
ture to occur. Turbulence ensures that the level of capable of producing that size may be modi ed
particle–particle collisions is high enough to produce from knowledge of the particle properties, such as
16 3
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Table 10.1 Selection of size reduction mills according to particle properties and product size required
hardness, toughness, etc. The in uences of various the size characteristics of a powder, whereas the
process and material variables on selection of a size latter is an integral part of a production process and
reduction method are summarized in Table 10.1. results in a product powder of a given particle size
range that is available for separate handling or sub-
sequent processing. Thus, a particle size analysis
Intro duc tio n to s ize s e paratio n method such as microscopy would be of no use as a
size separation method. H owever sieving can be
Objectives of s ize s eparation used for both purposes.
16 4
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
fδ dA
Eo = o o
fFδ F S ie ve dia me te r
b
(10.8)
Fig . 10.16 • Size separation ef ciency determination.
(a) Separation operation. (b) Size distributions of feed,
and the separation ef ciency for undersize material oversize and undersize material to obtain values for d o ,
in the undersize stream is given by: d f and d u.
fu (1 − δ o )
Eu =
fF (1 − δ F )
(10.9)
different ways, for example by taking the percent-
The total ef ciency, Et , for the whole size separation age values from a grade ef ciency curve at the 25%
process is given by: and 75% levels (L25 and L75 , respectively):
Et = Eu Eo L25
(10.10) S25 / 75 =
L75
(10.11)
Separation ef ciency determination can be
applied to each stage of a complete size classi cation or at other percentile points, for example at the 10%
and is often referred to as grade e f ciency. In some and 90% levels:
cases, knowledge of grade ef ciency is insuf cient,
for example where a precise particle size cut is
required. A sharpness index can be used to quantify L10
S10 / 90 =
the sharpness of cut-off in a given size range. A L90
sharpness index, S, can be determined in several (10.12)
16 5
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Size s e paratio n me tho ds high intensity to the sieve and causes the particles
to spin, thereby continuously changing their orienta-
tion and increasing their potential to pass through a
Some of the types of size separation equipment are
given sieve aperture. The output ef ciency of gyra-
discussed brie y below. These have been chosen to
tory sieves is usually greater than that of oscillation
illustrate the basic principles of size separation. The
or vibration methods.
actual equipment in use in pharmaceutical process-
Agitation methods can be made continuous by
ing continues to develop, yet remains based on the
inclination of the sieve and the use of separate
principles illustrated.
outlets for the undersize and oversize powder
streams.
Size s eparation by s ieving Br ushing methods. A brush is used to reorientate
particles on the surface of a sieve and prevent aper-
tures becoming blocked. A single brush can be
Se p a ra tion ra nge s rotated about the midpoint of a circular sieve or, for
These are shown in Figure 10.17. large-scale processing, a horizontal cylindrical sieve
is employed with a spiral brush rotating about its
longitudinal axis. It is important, however, that
P rinc ip le s of op e ra tion the brush does not force the particles through the
The principles of sieving in order to achieve particle sieve by distorting either the particles or the sieve
size analysis are described in Chapter 9. There are mesh.
some differences in the methods used to achieve Centr ifuga l methods. In this type of equipment,
size separation rather than size analysis. The use of particles are thrown outwards on to a vertical cylin-
sieving in size separation usually requires processing drical sieve under the action of a high-speed rotor
of larger volumes of powder than are commonly inside the cylinder. The current of air created by the
found in size analysis operations. For this reason, the rotor movement also assists the sieving process,
sieves used for size separation are often larger in area especially where very ne powders are being
and of more robust construction than those used for processed.
size analysis. Wet sieving can also be used to effect size separa-
There are several techniques for encouraging par- tion and is generally more ef cient than dry sieving
ticles to separate into their appropriate size fractions methods.
ef ciently. In dry sieving processes these are based
on mechanical disturbances of the powder bed and
include the following. Sta nd a rd s for p owd e rs b a s e d
Agita tion methods. Size separation is achieved on s ie ving
by electrically induced oscillation, mechanically
Standards for the size of powders used pharmaceuti-
induced vibration of the sieve meshes or by gyration
cally are sometimes provided in pharmacopoeias.
in which sieves are tted to a exible mounting
These may indicate how the degree of coarseness or
which is connected to an out-of-balance ywheel. In
neness of a powder is differentiated and expressed
the latter case, the eccentric rotation of the ywheel
by reference to the nominal mesh aperture size of
imparts a rotary movement of small amplitude and
the sieves used. G rades of powder are speci ed and
de ned in general terms by most pharmacopoeias.
An example is shown in Table 10.2.
It should be noted that the term ‘sieve number’
has been used as a method of quantifying particle
Ma ximum a va ila ble ra nge size in pharmacopoeias and is still favoured in some
parts of the world. H owever, various monographs
P ha rma copoe ia l ra nge
use the term differently and in order to avoid confu-
sion it is strongly recommended to always refer to
0.1 1 10 100 1000 10 000 particle sizes according to the appropriate equivalent
P a rticle dia me te r (µm) diameters expressed in millimetres, micrometres or
Fig . 10.17 • Separation range for sieving. nanometres, as appropriate.
16 6
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
Wa te r a nd a ir
Table 10.2 Example of powder grades as speci ed gra vita tiona l
in pharmacopoeias e lutria tors
16 7
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Air
outle t
Fine r pa rticle s
de pos ite d
Coa rs e r pa rticle s
Elutria tion de pos ite d
zone P a rticle s in a ir
s us pe ns ion
Fig . 10.21 • Upward air ow elutriator.
a b
Fig . 10.20 • Comparison of (a) sedimentation and soluble particles into different size ranges. There are
(b) elutriation. several types of air elutriator, which differ according
to the air ow patterns used. An example of an
upward air ow elutriator is shown in Figure 10.21.
different size fractions depending on the velocity of Particles are held on a supporting mesh through
the uid. which air is drawn. Classi cation occurs within a
Elutriation and sedimentation methods are com- very short distance of the mesh and any particles
pared diagrammatically in Figure 10.20, where the remaining entrained in the air stream are accelerated
arrows are vectors; that is, they show the direction to a collecting chamber by passage through a conical
and magnitude of particle movement. This gure section of tube. Further separation of any ne par-
may indicate that if particles are suspended in a uid ticles still entrained in the air ow may be carried
moving up a column, there will be a clear cut into out subsequently using different air velocities.
two fractions of particle size. In practice this does
not occur, as there is a distribution of velocities
across the tube in which a uid is owing – the
Size s eparation by cyclone
highest velocity is found in the centre of the tube
and the lowest velocity at the tube walls. Therefore, Se p a ra tion ra nge
the size of particles that will be separated depends This is shown in Figure 10.22.
on their position in the tube: the largest particles in
the centre, the smallest towards the outside. In
P rinc ip le s of op e ra tion
practice, particles may rise with the uid in the
centre of the apparatus and then move outwards to Probably the most common type of cyclone used to
the tube wall, where the velocity is lower and they separate particles from uid streams is the reverse-
then fall. A separation into two size fraction occurs, ow cyclone (Fig. 10.23). In this system, particles
but the size cut is not clearly de ned. Assessing the in air or liquid suspension are often introduced tan-
sharpness of size cuts is discussed above. gentially into the cylindrical upper section of the
Separation of powders into several size fractions cyclone, where the relatively high uid velocity pro-
can be achieved by using a number of elutriators duces a vortex that throws solid particles out on to
connected in series. The suspension is fed into the the walls of the cyclone. The particles are forced
bottom of the narrowest column, over owing from down the conical section of the cyclone under the
the top into the bottom of the next widest column
and so on. Because the mass ow remains the same,
Cyclone me thods
as the column diameter increases the uid velocity
decreases and therefore particles of decreasing size
will be separated.
Adaptations of this technique in which the liquid 0.1 1 10 100 1000 10 000
is replaced by air are available. Air is used as the P a rticle dia me te r (µm)
counter ow uid in place of water for elutriation of Fig . 10.22 • Separation ranges for cyclone methods.
16 8
P a rtic le s iz e re d u c tio n a n d s iz e s e p a ra tio n C H AP TE R 1 0
Inne r vorte x
of fluid Bibliography
Allen, T. (1997) Particle Size M easurement, vols 1 and 2,
5th edn. Chapman and H all, London.
Banker, G .S., Rhodes, C.T. (2002) M odern Pharmaceutics,
4th edn. Marcel Dekker, New York.
G otoh, K., Masuda, H ., H igashitan, K. (1997) Powder
P a rticle outle t Technology H andbook, 2nd edn. Marcel Dekker,
New York.
Fig . 10.23 • Reverse- ow cyclone separation. Lachman, L., Lieberman, H .A., Kanig, J.L. (1986) Theory
and Practice o Industrial Pharmacy. Lea and Febiger,
Philadelphia.
Lieberman, H ., Lachman, L., Schwartz, J.B. (1990)
in uence of the uid ow – gravity interactions are Pharmaceutical Dosage Forms: Tablets, vol. 2, 2nd edn.
a relatively insigni cant mechanism in this process. Marcel Dekker, New York.
At the tip of the conical section, the vortex of uid M anual on Test Sieving M ethods (1972) ASTM
is above the critical velocity at which it can escape Special Technical Publication. American
Society for Testing and Materials Standards,
through the narrow outlet and forms an inner vortex Pennsylvania.
which travels back up the cyclone and out through Niazi, S.K. (ed.) (2004) H andbook o Pharmaceutical
a central outlet or vortex nder. Coarser particles M anu acturing Formulations: vol 2 Uncompressed Solid
separate from the uid stream and fall out of the Products, Part V. Powder Flow Properties. CRC Press,
Boca Raton, Florida.
cyclone through the dust outlet, whereas ner par-
Rhodes, M. (ed.) (1990) Principles o Powder Technology.
ticles remain entrained in the uid stream and leave John Wiley, New York.
the cyclone through the vortex nder. In some cases, Salmon, A.D., H ounslow, M.J., Seville, J.P.K. (eds) (2007)
the outer vortex is allowed to enter a collector con- H andbook o Powder Technology, vol. 11, 1st edn.
nected to the base of the cyclone, but the coarser Elsevier, Amsterdam.
particles still appear to separate from the uid Schweitzer, P.A. (ed.) (1997) H andbook o Separation
Techniques or C hemical Engineers. McG raw-H ill
stream and remain in the collector. A series of Professional, New York.
cyclones having different ow rates or different Seibert, K.D., Collins, P.C., Fisher, E. (2010) Milling
dimensions could be used to separate a powder into operations in the pharmaceutical industry. In: am Ende,
different particle size ranges. D.J. (ed.) C hemical Engineering in the Pharmaceutical
Industry: R&D to manu acture. John Wiley & Sons (in
conjunction with AIChE), New Jersey, USA.
Se le c tio n o f a s ize Svarovsky, L. (1981) Solid gas separation. In: Williams, J.C.,
Allen, T. (eds) H andbook o Powder Technology, vol. 3.
s e paratio n pro c e s s Elsevier, Amsterdam.
Swarbrick, J., Boylan, J.C. (2002) Encyclopedia o
Pharmaceutical Technology. Marcel Dekker, New York.
Selection of a speci c size separation method may Wheeler, D.A. (1982) Size reduction. Processing, Dec,
be limited by pharmacopoeial requirements, but for 55–58.
16 9
11 Mixing
Andrew M. Twitchell
produce a tablet dosage form containing a drug potent drug in a powder mix, the degree of mixing
which is active at a dose of 1 mg, other components must be of a high order to ensure a consistent dose.
(e.g. a diluent, binder, disintegrant and lubricant) Similarly, when dispersing two immiscible liquids or
will be needed both to enable the product to be dispersing a solid in a liquid, a well-mixed product
manufactured and for it to be handled by the patient. is required to ensure product quality/ stability. In the
Whenever a product contains more than one case of mixing lubricants with granules during tablet
component, a mixing or blending stage will be production, however, there is a danger of ‘overmix-
required in the manufacturing process. This may be ing’ and the subsequent production of a weak tablet
to ensure an even distribution of the active with an increased disintegration time (discussed in
component(s), an even appearance or that the Chapter 30).
dosage form releases the drug at the correct site and
at the desired rate. The unit operation of mixing is Types o mixtures
therefore involved at some stage in the production
of practically every pharmaceutical preparation and Mixtures may be categorized into three types that
control of mixing processes is of critical importance differ fundamentally in their behaviour.
in assuring the quality of pharmaceutical products.
The importance of mixing is illustrated below by the
list of products which invariably utilize mixing pro-
P os itive mixture s
cesses of some kind: Positive mixtures are formed from materials such as
• tablets, capsules, sachets and dry powder gases or miscible liquids which mix spontaneously
inhalers – mixtures of solid particles and irreversibly by diffusion and tend to approach a
perfect mix. There is no input of energy required
• linctuses – mixtures of miscible liquids
with positive mixtures if the time available for
• emulsions and creams – mixtures of immiscible mixing is unlimited, although input of energy will
liquids
shorten the time required to obtain the desired
• pastes and suspensions – dispersions of solid degree of mixing. In general, materials which mix
particles. by positive mixing do not present any problems
Mixing and its control are also important in unit during product manufacture.
operations such as granulation, drying and coating.
This chapter considers the objectives of the Ne ga tive mixture s
mixing operation, how mixing occurs, and the ways
in which a satisfactory mix can be produced and With negative mixtures, the components will tend
maintained. to separate out. If this occurs quickly, then energy
must be continuously input to keep the components
adequately dispersed, e.g. with a suspension formu-
lation where there is a dispersion of solids in a liquid
Def nition and objectives o mixing of low viscosity. With other negative mixtures, the
components tend to separate very slowly, e.g. emul-
Mixing may be de ned as a unit operation that aims
sions, creams and viscous suspensions. Negative
to treat two or more components, initially in an
mixtures are generally more dif cult to form and to
unmixed or partially mixed state, so that each unit
maintain and require a higher degree of mixing ef -
(particle, molecule, etc.) of the components lies as
ciency than do positive mixtures.
nearly as possible in contact with a unit of each of
the other components.
If this is achieved, it produces a theoretical ‘ideal’ Ne utra l mixture s
situation, i.e. a perfect mix. As will be shown, Neutral mixtures are said to be static in behaviour,
however, this situation is not normally practicable, i.e. the components have no tendency to mix spon-
is actually unnecessary and, indeed, is sometimes taneously or segregate spontaneously once work has
undesirable. been input to mix them. Examples of this type of
H ow closely it is attempted to approach the mixture include mixed powders, pastes and oint-
‘ideal’ situation depends on the product being manu- ments. Neutral mixes are capable of demixing, but
factured and the objective of the mixing operation. this requires energy input (as discussed in relation
For example, when mixing a small amount of a to powder segregation later in this chapter).
171
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
It should be noted that the type of mixture can three dimensions then behind and in front of each
change during processing. For example, if the viscos- coloured particle would be a white particle and vice
ity increases suf ciently, a mixture may change from versa. Powder mixing, however, is a ‘chance’ process
a negative to a neutral mixture. Similarly, if the and while the situation shown in Figure 11.1b could
particle size, degree of wetting or liquid surface arise, the odds against it are so great that for practi-
tension changes, the mixture type may also change. cal purposes it can be considered impossible. For
example, if there are only 200 particles present, the
chance of a perfect mix occurring is approximately
The mixing proces s 1 in 10 60 and is similar to the chance of the situation
in Figure 11.1a occurring after prolonged mixing. In
To discuss the principles of the mixing process, a practice, the best type of mix likely to be obtained
situation will be considered where there are equal will have the components under consideration dis-
quantities of two powdered components of the same tributed as indicated in Figure 11.1c. This is referred
size, shape and density that are required to be to as a random mix which can be de ned as a mix
mixed, the only difference between them being where the probability of selecting a particular type
their colour. This situation will not, of course, occur of particle is the same at all positions in the mix and
practically but it will serve to simplify the discussion is equal to the proportion of such particles in the
of the mixing process and allow some important total mix.
considerations to be illustrated with the help of If any two adjacent particles are selected from
statistical analysis. the random mix shown:
If the components are represented by coloured
• the chance of picking two coloured particles
cubes, then a two-dimensional representation of the
= 1 in 4 (25%)
initial unmixed or completely segregated state can
be shown as in Figure 11.1a. • the chance of picking two white particles
From the de nition of mixing, the ideal situation = 1 in 4 (25%)
or perfect mix in this case would be produced when • and the chance of picking one of each
each particle lies adjacent to a particle of the other = 2 in 4 (50%).
component (i.e. each particle lies as closely as pos- If any two adjacent particles are selected from the
sible in contact with a particle of the other compo- perfect mix shown in Figure 11.1b, there will always
nent). This is shown in Figure 11.1b where it can be be one coloured and one white particle.
seen that the components are as evenly distributed Thus if the samples taken from a random mix
as possible. If this mix was viewed in contain only two particles, then in 25% of cases the
a b c
Fig . 11.1 • Different states of powder mixing. (a) Complete segregation. (b) An ideal or ‘perfect’ mix.
(c ) A random mix.
172
M ixin g C H AP TE R 1 1
173
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
174
M ixin g C H AP TE R 1 1
indicates the average deviation as a percentage of the Ideally for a pharmaceutical product the active
mean amount of active component in the samples. component should not deviate by more than ± 5%
Thus, % CV = (content standard deviation/ mean of the mean or speci ed content, i.e. the acceptable
content) × 100. The value of % CV will increase as
p decreases, as illustrated in Box 11.1.
Box 11 2
175
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
176
M ixin g C H AP TE R 1 1
mix as a whole must be analysed. A minimum of 10 C onvective mixing arises when there is the trans-
samples is usually analysed, these being removed fer of relatively large groups of particles from one
from different depths into the mixer and from the part of the powder bed to another, e.g. as might
middle and sides. Areas where blending may poten- occur when a mixer blade or paddle moves through
tially be poor should also be included in the sam- the mix. This type of mixing contributes mainly to
pling. Samples are often taken with a ‘sampling the macroscopic mixing of powder mixtures and
thief ’ which is a device that can be inserted into the tends to produce a large degree of mixing fairly
mix and samples withdrawn with minimum disrup- quickly (as evidenced by a rapid drop in SACT).
tion to the powder bed. Venables & Wells (2001) Mixing does not, however, occur within the group
have discussed some of the problems associated of particles moving together as a unit and thus in
with removing representative samples and analysing order to achieve a random mix, an extended mixing
powder blends. Second, a suitable analytical tech- time is required.
nique must be available so that the value of SACT is Shear mixing occurs when a ‘layer’ of material
a true re ection of the variation in content in the ows over another ‘layer’ resulting in the layers
samples and not due to variation arising from the moving at different speeds and therefore mixing at
method of analysis. the layer interface. This might occur when the
When mixing formulations where the proportion removal of a mass by convective mixing creates an
of active component is high, it is possible to achieve unstable shear/ slip plane which causes the powder
an acceptably low variation in content without bed to collapse or in high-shear or tumbling mixers
obtaining a random mix. Thus it may be possible to where the action of the mixer induces velocity gra-
stop the mixing process before a random mix is dients within the powder bed and hence ‘shearing’
achieved and therefore reduce manufacturing costs. of one layer over another.
The quality of a mixture may be assessed by its In order to achieve a true random mix, movement
ability to meet prede ned speci cation limits. These of individual particles is required. This occurs with
could include assay limits for individual samples diffusive mixing. When a powder bed is forced to
taken from the mix (e.g. 90 – 110% of the target move or ow, it will ‘dilate’, i.e. the volume occu-
content) and for the variation in content of these pied by the bed will increase. This arises because the
samples (e.g. % CV ≤ 3%). powder particles become less tightly packed and
An alternative method for monitoring and con- there is an increase in the air spaces or voids between
trolling powder blending is to ultilize near-infrared them. Under these circumstances there is the
(NIR) analysis. As most pharmaceutical active ingre- potential for the powder particles to pass through
dients and excipients absorb NIR radiation, this the void spaces created either under gravitational
technique has the potential advantage of providing forces (e.g in a tumbling mixer) or by forced move-
homogeneity information on all of the mixture com- ment (e.g in a uidized bed). Mixing of individual
ponents. NIR spectroscopic methods may also be particles in this way is referred to as diffusive mixing.
used non-invasively which can eliminate the prob- All three mixing mechanisms are likely to occur
lems associated with the use of a sampling thief. in a mixing operation. Which mechanism predomi-
O ther potential advantages include the speed and nates and the extent to which each occurs will
non-destructive nature of the analysis. The reader is depend on the mixer type, mixing process condi-
referred to texts by Ciurczak and Drennen (2002) tions (mixer load, speed, etc.), particle characteris-
and Bakeev (2010) for further information. tics and owability of the components of the powder.
177
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
quickly, but leaves the liquid within the moving tend to behave differently when forced to move and
material unmixed. hence tend to separate. Particles exhibiting similar
Turbulent mixing arises from the haphazard properties tend to congregate together, giving regions
movement of molecules when forced to move in a in the powder bed which have a higher concentra-
turbulent manner. The constant changes in speed tion of a particular component. Segregation is more
and direction of movement mean that induced tur- likely to occur, or may occur to a greater extent, if
bulence is a highly effective mechanism for mixing. the powder bed is subjected to vibration and when
Within a turbulent uid there are, however, small the particles have greater owability.
groups of molecules moving together as a unit,
referred to as eddies. These eddies tend to reduce P a rtic le s ize e ffe c ts
in size and eventually break up, being replaced by
Differences in the particle sizes of components of a
new eddies. Turbulent mixing alone may therefore
formulation are the main cause of segregation in
leave small unmixed areas within the eddies and in
powder mixes in practice. Smaller particles tend to
areas near the container surface which will exhibit
fall through the voids between larger particles and
streamlined ow (see Chapter 6). Mixing of indi-
thus move to the bottom of the mass. This is known
vidual molecules in these regions will occur by the
as percolation segregation. It may occur in static
third mechanism, which is molecular diffusion (anal-
powder beds if the percolating particles are small
ogous to diffusive mixing in powders). This will
enough to fall into the void spaces between larger
occur with miscible uids wherever a concentration
particles, but occurs to a greater extent as the bed
gradient exists and will eventually produce a well-
‘dilates’ on being disturbed. Domestically, percola-
mixed product, although considerable time may
tion segregation is often observed in cereal packets
be required if this is the only mixing mechanism.
or jars of coffee where the smaller ‘particles’ con-
In most mixers all three mechanisms will occur,
gregate towards the bottom of the container.
bulk transport and turbulence arising from the
Percolation can occur whenever a powder bed
movement of a stirrer or mixer paddle set at a suit-
containing particles of different size is disturbed in
able speed.
such a way that particle rearrangement occurs, e.g.
during vibration, stirring or pouring.
During mixing, larger particles will tend to have
Powder s egregation (demixing) greater kinetic energy imparted to them (owing to
their larger mass) and therefore move greater dis-
Segregation is the opposite effect to mixing, i.e.
tances than smaller particles before they come to
components tend to separate out. This is very
rest. This may result in separation of particles of
important in the preparation of pharmaceutical
different size; an effect referred to as trajectory
products because if it occurs, an already formed
segregation. This effect, along with percolation seg-
random mix may change to a non-random mix, or a
regation, accounts for the occurrence of the larger
random mix may never be achieved. Care must be
particles at the edge of a powder heap when it is
taken to avoid segregation occurring during handling
poured from a container.
after powders have been satisfactorily mixed, e.g.
During mixing, or when a material is discharged
during transfer to lling machines or in the hopper
from a container, very small particles (‘dust’) in a
of a tablet/ capsule/ sachet lling machine. Segrega-
mix may tend to be ‘blown’ upwards by turbulent
tion will cause an increase in content variation in
air currents as the mass tumbles, and remain sus-
samples taken from the mix, i.e. it will result in a
pended in the air. When the mixer is stopped or
reduction in the quality of the mix and may cause a
material discharge is complete, these particles will
batch to fail a uniformity of content or uniformity
sediment and subsequently form a layer on top of
of dosage units test. If segregation of granules occurs
the coarser particles. This is called eluthation segre-
in the hopper of a lling machine, an unacceptable
gation and is also referred to as dusting out or uidi-
variation in weight may result.
zation segregation.
Segregation arises because powder mixes encoun-
tered in practice are not composed of monosized
spherical particles but contain particles that differ P a rtic le d e ns ity e ffe c ts
in size, shape, density and surface properties. These If components are of different density, the more
variations in particle properties mean that they will dense particles will have a tendency to move
178
M ixin g C H AP TE R 1 1
n
difference in mass. The effect of density on percola-
o
i
Z = optimum mixing time
t
a
tion segregation may be potentiated if the denser
vi
e
particles are also smaller. O ften materials used in
d
S ACT
d
r
pharmaceutical formulations have similar densities
a
d
and density effects are not generally too important.
n
a
t
An exception to this is in uidized beds, where
s
t
n
density differences often have a greater adverse
e
t
n
Z
effect on the quality of the mix than particle size
o
C
SE
differences.
SR
Y
P a rtic le s ha p e e ffe c ts
Mixing time /numbe r of mixe r rota tions
Spherical particles exhibit the greatest owability
and therefore are more easily mixed, but they also Fig . 11.4 • Possible effect of extended mixing time on
segregate more easily than non-spherical particles. the content standard deviation of samples taken from a
Irregular or needle-shaped particles may become mix prone to segregation. S ACT represents the content
interlocked, decreasing the tendency to segregate standard deviation of samples taken from the mix, S E
once mixing has occurred. Non-spherical particles the estimated acceptable standard deviation and S R the
will also have a greater surface area to weight ratio standard deviation expected from a random mix.
(speci c surface area), which will tend to decrease
segregation by increasing any cohesive effects
(greater contact surface area) but will increase the to rectify the situation. These include the
likelihood of ‘dusting out’. following:
It should be remembered that the particle size • selection of particular size fractions (e.g. by
distribution and particle shape may change during sieving to remove nes or lumps) to achieve
processing (due to attrition, aggregation, etc.) and drug and excipients of the same narrow particle
therefore the tendency to segregate may also change. size range
Non-segregating mixes will improve with contin- • milling of components (size reduction) to either
ued increases in mixing time, as shown in Figure reduce the particle size range (this may need to
11.3. This may not, however, occur for segregating be followed by a sieving stage to remove nes)
mixes, where there is often an optimum mixing or to ensure all particles are below
time. This arises since the factors causing segrega- approximately 30 µm at which size segregation
tion generally require a longer time to take effect does not tend to cause serious problems (but
than the time needed to produce a reasonable degree may give rise to aggregation)
of mixing. During the initial stages of the process, • controlled crystallization during production of
the rate of mixing is greater than the rate of demix- the drug/ excipients to give components of a
ing. After a period of time, however, the rate of particular crystal shape or size range
demixing may predominate until eventually an equi- • selection of excipients which have a density
librium situation will be reached where the two similar to the active component(s); there is
effects are balanced. This is illustrated in Figure usually a range of excipients which will produce
11.4 which demonstrates that, if factors exist which a product of the required properties
may cause segregation, then a random mix will not • granulation of the powder mix (size
be achieved and there may be both an optimum enlargement) so that large numbers of different
mixing time and a time range over which an accept- particles are evenly distributed in each
able mix can be produced. segregating ‘unit’/ granule (see Fig. 28.1)
• reducing the extent to which the powder mass
Ap p roa c he s to minimize s e gre ga tion is subjected to vibration or movement after
If segregation is a problem with a formulation there mixing (e.g. avoid the use of pneumatic transfer
are a number of approaches that may be attempted systems)
179
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
• using lling machine hoppers designed so that O rdered mixing has been shown to be important
powder residence time is minimized in direct-compression tablet formulations (Chapter
• using equipment where several operations can 30) in preventing segregation of drug from direct
be carried out without transferring the mix, e.g. compression bases.
a uidized-bed drier or high-speed mixer/ Dry powder inhaler formulations also utilize
granulator for mixing and granulating ordered mixing to deliver drugs to the lungs (Chapter
• production of an ‘ordered’ mix. This technique 37). In this case, the drug needs to be in a micro-
is also referred to as adhesive or interactive nized form in order to reach its site of action. By
mixing and is described in more detail below. adsorbing the drug onto larger carrier particles
(usually lactose), it is possible to manufacture a
product which will provide an even dosage on each
Ordered mixing inhalation.
18 0
M ixin g C H AP TE R 1 1
being more likely to be dislodged than those lying whether problems could occur if the mixing time is
parallel to the surface. extended.
When particles rub past each other as they move
within the mixer, static charges will be produced.
Mixing o f po wde rs These tend to result in ‘clumping’ and a reduction
in diffusive mixing and cause material to adhere to
Practical cons iderations machine or container surfaces. To avoid this, mixers
should be suitably earthed to dissipate the static
When mixing formulations in which there is a rela- charge and the process should be carried out at a
tively low proportion of active ingredient(s), a more relative humidity greater (although not excessively)
even distribution may be obtained by sequentially than approximately 40%.
building up the amount of material in the mixer.
This may be achieved by initially mixing the active
component(s) with an approximately equal volume
Powder-mixing equipment
of diluent(s). Further amounts of diluents, equal to
the amount of material in the mixer, can then be Tumb ling mixe rs /b le nd e rs
added and mixed, the process being continued until Tumbling mixers are commonly used for mixing/
all material has been added. It may be more appro- blending granules or free- owing powders. There
priate to preblend the active component with a are many different designs of tumbling mixer, e.g.
diluent in a smaller mixer prior to transferring it to double-cone, twin-shell, cube, Y-cone and drum
the main mixer in cases where the amount of active mixers, some of which are shown diagrammatically
ingredient is very low. in Figure 11.5. It is now common to use intermedi-
Care must be taken to ensure that the volume of ate bulk containers (IBCs) as both the mixer bowl
powder in the mixer is appropriate, as both over- and to either feed the hopper of a tablet or a capsule
and under lling may signi cantly reduce mixing ef - machine, or act as the hopper itself. The shape of
ciency. In the case of over lling, for example,
suf cient bed dilation may not take place for dif-
fusive mixing to occur to the required extent or the
material may not be able to ow in a way that
enables shear mixing to occur satisfactorily. Under-
lling may mean the powder bed does not move in
the required manner in the mixer or that an increased
number of mixing operations may be needed for a
batch of material.
The mixer used should produce the mixing Y-cone mixe r Rota ting cube
mechanisms appropriate for the formulation. For
example, diffusive mixing is generally preferable
if potent drugs are to be mixed, and high shear is
needed to break up aggregates of cohered material
and ensure mixing at a particulate level. The impact
or attrition forces generated if too-high shear forces
are used may, however, damage fragile material and
thus produce nes. The mixer design should be such Double cone Oblique cone
that it is dust tight, can be easily cleaned and the
product can be fully discharged. These features
reduce the risk of cross-contamination between
batches and protect the operator from the product.
In order to determine the appropriate mixing
time, the process should be checked by removing
Twin s he ll (V) mixe r
and analysing representative samples after differ- with a gita tor ba r
ent mixing intervals. This may also indicate if
segregation is occurring within the mixer and Fig . 11.5 • Different designs of tumbling mixers.
18 1
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
18 2
M ixin g C H AP TE R 1 1
18 3
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Ve rtica l
ba ffle
Vorte x
Rota tiona l pa th
of bla de s ha ft
lubricants care is needed to avoid overlubrication likely to settle rapidly when mixing is discontinued.
which may, for example, lead to soft tablets and Viscous liquids are more dif cult to stir and mix but
delayed disintegration and dissolution. they reduce the sedimentation rate of suspended
Problems associated with a de ciency of some of particles (discussed further in Chapter 26).
the components of a formulation, which have been
encountered at a production scale but not in devel- Mixers or mis cible liquids
opment work, have been traced to adsorption of a
minor constituent (e.g. a drug or colourant) onto the and s us pens ions
mixer wall or mixing blade.
Drug particle characteristics may also change P rop e lle r mixe rs
when the drug is manufactured on a large scale. This A common arrangement for medium-scale uid
in turn may affect the movement of the particles mixing is a propeller-type stirrer which is often used
in the mixer and the interaction with other com- clamped to the edge of a vessel. A propeller has
ponents and hence the tendency to mix and angled blades, which cause the circulation of the
segregate. uid in both an axial and radial direction. An off-
The optimum mixing time and conditions should centre mounting discourages the formation of a
therefore be established and validated at a produc- vortex, which may form when the stirrer is mounted
tion scale so that the appropriate degree of mixing centrally. A vortex forms when the centrifugal force
is obtained without segregation, overlubrication or imparted to the liquid by the propeller blades causes
damage to component particles. Minimum and it to back up round the sides of the vessel and form
maximum mixing times which give a satisfactory a depression around the shaft. As the speed of rota-
product should be determined, if appropriate, so tion is increased, air may be sucked into the uid
that the ‘robustness’ of the mixing process is due to the formation of a vortex; this can cause
established. frothing and possible oxidation (Fig. 11.12a).
Another method of suppressing a vortex is to t
vertical baf es into the vessel. These divert the
Mixing o f mis c ible liquids rotating uid from its circular path into the centre
and s us pe ns io ns of the vessel where the vortex would otherwise
form (Fig. 11.12b).
Mobile liquids with a low viscosity are easily mixed The ratio of the diameter of a propeller stirrer to
with each other. Similarly, solid particles are readily the diameter of the vessel is commonly 1 : 10 to
suspended in mobile liquids though the particles are 1 : 20 and it typically operates at speeds of 1–20
18 4
M ixin g C H AP TE R 1 1
revolutions/ second. The propeller stirrer depends generation of droplets of the dispersed phase which
for its action on a satisfactory axial and radial ow are small enough to produce stable dispersions
pattern which will not occur if the uid is too (water-in-oil or oil-in-water). Turbine mixers of this
viscous. There must be a fast ow of uid towards type (homogenizers) are therefore often tted to
the propeller which can only occur if the uid is vessels used for the large-scale production of emul-
mobile. sions and creams.
Turbine-type mixes will not cope with liquids of
Turb ine mixe rs very high viscosity since the material will not be
drawn into the mixer head. These liquids are best
A turbine mixer may be used for more viscous uids treated as semi-solids and handled in the same
and a typical construction is shown in Figure 11.13. equipment as used for such materials (see below).
The impeller has four at blades surrounded by
perforated inner and outer diffuser rings. The rotat-
ing impeller draws the liquid into the mixer ‘head’ In-line mixe rs
and forces the liquid through the perforations with As an alternative to mixing uids in batches in
considerable radial velocity, suf cient to overcome vessels, mobile miscible components may be fed
the viscous drag of the bulk of the uid. O ne draw- through an ‘inline’ mixer designed to create turbu-
back is the absence of an axial component, but a lence in a owing uid stream. In this case, a con-
different head with the perforations pointing tinuous mixing process is possible.
upwards can be tted if this is desired. As the liquid
is forced through the small ori ces of the diffuser
rings at high velocity, large shear forces are pro- Mixing o f s e mi-s o lids
duced. When mixing immiscible liquids, if the ori-
ces are suf ciently small and velocity suf ciently The problems that arise during the mixing of semi-
high, the shear forces produced enable the solids (ointments and pastes) stem from the fact
that, unlike liquids, semi-solids will not ow easily.
Material that nds its way to a ‘dead spot’ will
remain there. For this reason, suitable mixers must
have rotating elements with narrow clearances
between themselves and the mixing vessel wall, and
they must produce a high degree of shear mixing
since diffusion mixing cannot occur.
18 5
P AR T TW O Partic le Sc ie nc e and Po wde r Te c hno lo g y
Re erences
Bakeev, K.A. (2010) Process Analytical Technology. John
Wiley & Sons, Chichester, UK.
Ciurczak, E.W., Drennen, J.K. (2002) Pharmaceutical and
medical applications of near-infrared spectroscopy. Marcel
Dekker, New York.
Nikolakakis, N., Newton, M. (1989) Solid state adsorption
of antibiotics onto sorbitol. Journal of Pharmacy and
Pharmacology, 41, 145–148.
Fig . 11.14 • Sigma blade mixer. Travers, D.N., White, R.C. (1971) The mixing of
micronized sodium bicarbonate with sucrose crystals.
Journal of Pharmacy and Pharmacology, 23, 260S–261S.
semi-solid materials. As the blades continuously Venables, H .J., Wells, J.I. (2001) Powder mixing. Drug
advance along the periphery of the mixer vessel, Development and Industrial Pharmacy, 27, 599–612.
they remove material from the walls and transport
it towards the interior.
Bibliography
Sigma b la d e mixe rs H arnby, N., Edwards, M.F., Nienow, A.W. (1997) M ixing in
the Process Industries, 2nd edn. Butterworth-H einemann,
This robust mixer will deal with stiff pastes and O xford.
ointments and depends for its action on the close Kaye, B.H . (1997) Powder M ixing. Chapman and H all,
intermeshing of the two blades which resemble the London.
G reek letter Σ in shape – hence the name. The Levin, M. (2011) Pharmaceutical Process Scale-up, 3rd edn.
Informa H ealthcare, London.
clearance between the blades and the mixing trough
Miyanami, K. (1996) Mixing. In: Masuda, H ., H igashitani,
is kept small by the design shown in Figure 11.14. K., Yoshida, H . (eds) Powder Technology H andbook, 3rd
edn. Marcel Dekker, New York.
Paul, E.L., Atiemo-O beng, V.A., Kresta, S.M. (2004)
Furthe r tre a tme nt of s e mis olid H andbook of Industrial M ixing – Science and Practice.
d is p e rs ions John Wiley and Sons, New Jersey.
Staniforth, J.N. (1982) Advances in powder mixing and
It is very dif cult, using primary mixers, to com-
segregation in relation to pharmaceutical processing.
pletely disperse powder particles in a semi-solid International Journal of Pharmaceutical Technology and
base so that they are invisible to the eye. The mix Product M anufacture, 3(Suppl), 1–12.
18 6