Blending
» Definitions
Engineering of Chemical and Pharmaceutical
Processes
Mixing and segregation of particulate solids
» Operation aimed at processing two or more separate
components, so as to achieve a situation, when each
particle of any component is as close as possible to a
particle of the other component
» Objectives
» Achieve the mixture uniformity
» uniformity of final products
» Maximize the contact surface area of components
» promote interfacial physical and chemical processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Mixing is reversible process
Spontaneity of mixing
» Positive
mixing, blending
(mixing, blending)
» proceeds spontaneously without external action
» e.g. diffusive mixing of gases in a vessel
» Negative
» segregation proceeds spontaneously, without
external action the components will separate
» e.g. suspension settling
demixing, segregation
(demixing, segregation)
» Neutral
» nothing happens without external action
» e.g. powder mixture
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Types of mixtures
Real mixture
» Random
» well flowing particulate solids
» Ordered
perfectly separated
mixture
» cohesive materials
» interaction between components
perfectly mixed
random
(ordered)
mixture
probability of occurence of specific
component
in
any
position
in the mixture is equal to the content of that component in the mixture
mixture
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
1
Practical homogeneity in
pharmaceutical production
Scale of scrutiny
» Homogeneous mixture = samples
taken from the mixture have
equal properties
» Homogeneity depends on the
sample size
» all mixtures seem being uniform at
sufficiently large sample size
» Scale of scrutiny
» Minimum sample size to be used to
achieve the variance of samples
below desired limit
» Character of mixtures
» probability of achieving ordered mixtures is small
» most mixtures are random (especially for powderpowder) - random nature of mixtures
» Multi-component mixtures
» API homogeneity is important
» pseudo-binary approach to mixtures, API + excipients
» Scale of scrutiny
» corresponds to the size of final dosage form
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Statistics tutorial
Statistics tutorial
» Random variable
» Mean value of a random variable
» mean value of API content in sample taken from a bulk
N
mixture
» variable, the value of which is given by the result of
random event
E  X   lim
» throwing dice result
» API content in sample of random mixture
» mean value of a random variable
 2
1
6
3
1
6
 4
1
6
5
1
6
6
1
6
N
» Selective mean value - arithmetic average
» mean value of API content in taken sample, calculated from
N number of carried out experiments
selection of finite
» mean value of dice throw result
1
6
Xi
i 1
» number of random sampling results is almost infinite
» sum of all possible results of random event
multiplied by their probability
E X   1

N
 3,5
X 

Xi
i 1
N
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Statistics tutorial
Statistics tutorial
» Standard error of a random variable
» Selective standard error
» measure of variability of random variable
» random variable result will be within +- standard deviation from average
with approximately 2/3 probability
» andom variable result will be within +- 2 x standard deviation from
average with with very high probability
 X
N
» measure of random events variability
» API content variability in taken samples
sx 
i
 X

i 1
N 1
» Relative (selective) standard error, RSD %
» measure of variability related to mean value
 X
N

X

i
 X
» e.g. comparable for two drug potencies (2 mg and 4 mg of
API content)

2
i 1
N
 X
N
RSD 
sX
X
 100 % 
1
X
i
 X
i 1
N 1
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending

 100 %
2
Evaluating homogeneity
Random mixture properties
» Relative selective standard error of taken
samples
» Variability of taken samples
» Assumption of (pseudo) binary mixture of similar
components
w 1  w 
» simple
» frequently used
» not in 0 - 100 % range
 
API
n
» wAPI … single component conteny in mixture (API)
» s … standard error of API content
» n … number of particles in the sample
» Mixing index
»
»
»
»
API
multiple definitions
 
M 


0 - 100 % range

w
σMAX … completely segregated state
σMIN … minimum achievable non-homogenity
(analytical error)
Engineering of Chemical and Pharmaceutical Processes
2
2
MAX
2
MIN
2
MIN
2
MAX
Blending
API
1  w API 
» Defines the number of particles needed in dosage
form to achieve desired uniformity
Engineering of Chemical and Pharmaceutical Processes
Blending
Sampling
Mixing particulate solids
» Mechanisms of mixing
» convestion
» movement of particle groups relative to other groups
» macroscopic mixing,
» dispersion
» movement of individual particles among other particles
» micro-mixing
» shear
» movement of powder layers
» disruption of agglomerates
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Mixing particulate solids
Convective and dispersion mixing
» Mechanisms of mixing
» convection
a)
» dispersion
b)
» shear
»
c)
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
3
Mixing particulate solids
Mixing particulate solids
» Tumbling blenders
» Convective blenders
vertical
agitator
horizontal
agitator
orbital
agitator
»
»
»
»
» rotating vessels with elements
» convection and diffusion
» rotating frequency 5 – 30 s-1
static vessel equipped by conveyor
convection, shear
good for agglomerating mixtures
difficult cleaning
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Mixing particulate solids
Blender selection
» Fluid mixers
» Idealized blender
spouting fluidized bed
bubbling
fluidized bed
» 3D movement of particles (not agglomerates)
» eliminating dead zones
» Real blender
» trade-off between mixing quality and process
compatibility
» Very fast mixing
» Multiple operations in single unit
» drying, granulation
» suitable for free flowing and mildly cohesive
materials.
» Blender selection
» eliminate inadequate types
» select optimal blender by mixing efficiency,
throughput, price
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Selected factors influencing the
blender choice
Process parameters of tumbling blenders
» Process requirements
» Key parameters
» Particle comminution during blending
» Cleaning
» Continuous / Batch
» Mixing / Segregation relationship
» Better for convection, worse for dispersion
» rotating frequency … f [s-1]
» filling ratio … φ [%]
» equipment size
» Critical rotating speed
» causes centrifugal movement of particles = no mixing
» Effect of particulate solid flowability
fc 
1
g
2π
R
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
4
Powder movement in blender
Powder movement in blender
» Rolling and cascading motion
a.
b.
c.
d.
e.
f.
a. sliding
b. slumping (0 – 3 % fc)
c. rolling (3 – 30 % fc)
d. cascading (3 – 30 % fc)
e. cataracting (30 – 100 % fc)
f. centrifuging
Stupeň zaplnění, %
» Powder movement regimes
»
»
»
»
»
»
Aktivní
oblast
Aktivní
oblast
d.
Statická
oblast
Statická
oblast
e.
Rolovací pohyb
b.
f.
c.
Kaskádový pohyb
» Depends on the filling ratio
» Mixing proceeds only in the active zone
a.
Frekvence otáčení, ot.min-1
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Filling ratio
Kinetics and eqiuilibrium of blending
» Filling ratio > 50 %
» Kinetics – How long to mix ?
» Equilibrium – How well mixed it can become ?
10
10
7,5
7,5
API, mg
API, mg
» non-mixed core may develop
5
2,5
5
2,5
0
0
0
20
40
60
80
100
0
Time
40
60
80
100
Time
Kinetics
Kinetics
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Processes taking place in powder
homogenization
20
Mixing kinetics
Mixing
Počáteční stupeň
homogenity, a+c
Konvekce
RSD, %
Segregation
Mixing is reversible process
Střih
Difúze
RSD, %
Nejvyšší stupeň
homogenity, c
čas, min
0
Time, min
R SD  a .e
 bt
c
Optimální doba
mísení
dRSD
dt
  k M RSD  k S RSD
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
0
 RSD

5
Causes for segregation
Segregation mechanisms
» Differences in particle size
» Trajectory
» Differences in morphology
» Percolation
» Differences in density
» Components ratio
» Fluidization
» Cohesive interactions
» moisture
» static charge
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Segregation mechanisms
Wall segregation
» Sifting
» Flow of
particulate solid
near wall
» Fluidization
» Adhesive
discrimination
between particles
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Segregation
Segregation examples
» Segregation in different blenders
» Larger particles are
heavier and are
subjected to higher
inertial forces
» Some particles
possess higher
affinity to
equipment wall
» Different angle of
repose
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
6
Segregation examples
Segregation examples
» Larger particles are
heavier and fall into
the "crater"
» Larger particles may
trigger an avalanche
» Sifting - large
particles cannot pass
through the small
ones, but the
opposite is possible
» Trajectory
segregation in
aerodynamic
conditions
Engineering of Chemical and Pharmaceutical Processes
Engineering of Chemical and Pharmaceutical Processes
Blending
Blending
Segregation examples
» Fluidizing at silo
filling
» Discharging
segregated mixture by
funnel flow
Engineering of Chemical and Pharmaceutical Processes
Blending
7