Primary manufacture

Solids isolation
Typical process flow diagram:

(V)

(G)
(L)
(S)

reaction

(L)

crystallization

(L-S)

filtration

(S-L)

drying

(L)

(S)

product
Key objectives:
- separate API from solvent and impurities
- achieve reproducible API properties:
- size distribution
- particle shape
- crystal structure (polymorphic phase, hydrate, etc.)

Crystals: structural periodictiy and long-range order

(x-ray diffraction patterns) vs. amorphous materials
Polymorphism = ability to crystallize in more than
one crystallographic form
Example: graphite vs. diamond for carbon
or calcite (rhombohedral) vs. aragonite
(orthorhombic) for calcium carbonate
Number of polymorphs for some compounds:
Aspirin - 4; TiO2 - 3; CaCO3 - 3; NH4NO3 - 5
Polymorphs:
Enantiotropic

interconvertible (e.g. by T)

Monotropic

incapable of transformation

Solubility curves for polymorphs

solubility

solubility

-polymorph
Ttransition

-polymorph

-polymorph
-polymorph
temperature

monotropic

temperature

enantiotropic

Crystal habit modification

-

Growth rates are not constant along facets

Specific adsorption of species on particular

facets can modify crystal growth

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Crystal growth
Surface nucleation

Spiral growth

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Regimes:
Continuous growth (lot of kink sites on surface)
Surface nucleation (several nuclei on surface)
Spiral growth (single nucleus on surface)

Crystal growth rate

expressed as:
1. mass deposition rate, R [kg m-2 s-1]
2. linear growth rate G = dx/dt [m s-1]

R=

1 dm 3"V #G
=
= K g $c g
A dt
"A

m = "V #x 3
!

c supersaturation

A = "A x 2

V, A volume and surface shape factors

Solid-liquid phase equilibria

- Solubility: saturation concentration vs. T
- often tabulated in the form:
logc eq = a1 +

a2
+ a3 logT
T

or

KNO3
2

c eq = A + B" + C" + ...

NaCl

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Solid-liquid phase equilibria

- multiple solvents: drowning out effect
Compound A soluble in two solvents, e.g H2O
and acetone; the two solvents are miscible
0.40
0.35

solubility [g/g]

0.30
0.25
0.20
0.15
0.10
0.05
0.00
0

20

40

60

80

weight % water in acetone

- phase diagrams
- Gibbs phase rule:
P+F=C+2
P number of phases
F number of degrees of freedom
C number of components

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phase diagrams for binary systems forming

solid solutions (mixed crystals)

- liquidus line
- solidus line
-components are
mixed at molecular
level
NOT possible to get
pure components in
a single crystallization
step!
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phase diagrams for eutectic systems

(eu tektos = easily melted)

AEB - liquidus
FG - solidus
Below E - physical
mixture of A and B
domains
It IS possible to
crystallize pure
components in a
single step.

B+Liquid

A+Liquid
F

Yield is limited by
the eutectic point E.
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- driving force for crystallization: supersaturation

In 1724 Fahrenheit
supercooled water
to -9.4C before
freezing
Below solubility
curve:
undersaturated
Above:
supersaturated
Above metastable
limit: liable
(spontaneous
nucleation)
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Creating supersaturation:
- by evaporation of solvent
- by addition of anti-solvent
- by temperature change (cooling for most systems)
Measures of supersaturation:

" # (ss $ eq ) /kT = ln(ass /aeq )

in ideal solutions (activity coefficients = 1):

" = ln(x ss / x eq ) # (x ss $ x eq ) / x eq
!

Supersaturation also often expressed as:

"c = c ss # c eq
!
!
Nucleation
- primary nucleation = in the absence of crystals
- secondary nucleation = in the presence of crystals (seeding
= provision of nuclei)
Primary Nucleation
- homogeneous nucleation = clusters of atoms spontaneously
form in the solution
- heterogeneous nucleation = impurities (e.g. dust particles) act
as nucleation centres
% crystallized

emulsion
bulk solution

emulsion

bulk

temperature

Crystallizer types and operation

Precursor phase:
- from vapour, solution, or melt
Mode of operation:
- continuous vs. batch
Means of crystal removal:
- mixed product removal vs. classifying crystallizers
Means of achieving supersaturation:
- cooled, evaporative, vacuum crystallizers

Melt crystallization - rotary drum crystallizer

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Crystal growth from solution

batch cooling crystallizers (internal/external cooling)

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batch reduced pressure evaporating crystallizer

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- draft-tube evaporating crystallizer

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Mass & energy balances

Fv,out

FL,in
Q

mA = (1-wB) mL
mB = mS + wB mL

FL,out
Fs,out

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Population balances
mass & energy balance amount of product
population balance quality of product! (e.g. CSD)
number (population) density [no m-1 m-3]

n=

dN
dx

Number balance in MSMPR crystallizer - assumptions:

!
-ideally mixed
-steady-state, continuous operation
-no crystals in feed
-no agglomeration or breakage
-size independent growth rate

Number balance
Accumulation = flow in - flow out + birth - death

0 = 0 " Fout n i#x#t + Vn iGi#t " Vn i+1Gi+1#t

In differential form (x dx)

d(nG)
dn
F n
n
=G
= " out = "
dx
dx
V
#

Boundary condition - nucleation rate

n0

Gi
ni

Gi+1
ni+1

B=

dN
dt

= n 0G
x= 0

growth rate, G [m s-1]

number density, n [no m-1 m-3]

xi

xi+1

size, x [m]

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Number balance in MSMPR crystallizer - solution

ln n = ln n 0 "

% x (
x
$ n = n 0 exp'"
*
& G# )
G#

ln n

ln n0 = ln B/G

slope = - 1/G

size, x [m]

Cake filtration

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Filtration - by driving force

Filter types - batch

Nutsche filter

Frame & plate filter

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Filter types - continuous

Drum filter

Belt filter

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Cake filtration
Ptotal = Pfilter + Pcake

slurry

Applying Darcys law:

P=(Rf+Rc)(/A)dV/dt
where
Rf filter resistance
and Rc=hc/c cake resistance
(c cake permeability)

cake, ms

A
fitrate V

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 = ARc /ms specific cake resistance

x = ms /V

dry cake mass per filtrate volume

General filtration equation:

dt/dV = xV/A2P + Rf/AP
Solution for:
- constant pressure P
- constant flowrate dV/dt

Constant pressure (P = const.)

by integrating the filtration equation:
[x / (2A2P)] V2 + [Rf/(AP)] V - t = 0
t/V vs. V is a straight line useful for data analysis
mass balance cake depth as function of filtrate V:
hc = xV/[As(1-)]
moisture ratio: = mass of wet cake / mass of dry cake

= 1 + (L/S) /(1-)

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Constant rate (dV/dt = const.)

from the general filtration equation:
P = (x/A2)(dV/dt) V + (Rf/A) dV/dt
P

Pmax

t
constant pressure

constant rate

Compressible cake:
Rc = hc/c= ms/A

=[c (1-) s]-1

Cake porosity is not constant in this case.

Correlations for average cake porosity:

= 0 (1-n) (P)n

ncompressibility coefficient
calcite:

n=0.2

kaolin:

n=0.6

Dry cake mass per filtrate volume also isnt constant.

from mass balance: x = [(1-wF)/wFL - /(1-)s]-1

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Filtration cycle
-

filtration
cake washing
cake deliquering (drainage)
cake removal
filter cleaning

F
W
D
R
C

Objective:maximize total throughput

single cycle (F + W + D + R + C)
batch scheduling

Cake washing
-wash volume
-Vw=hA=(ms/s) /(1-)
Drainage
-Capillary pressure
Pcap=2 cos/rpore
-Bond number
Bo = gdpore2/
(gravity/surface tension)
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Filtration process applicability

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Centrifugation
Similar analysis as filtration, but
Force on volume element of mass m: F=ma
aacceleration

a=r2

angular velocity [rad s-1]

Modern ultracentrifuges:

up to 600,000 g
up to 70,000 rpm

pressure drop:
P = L2(r02-rL2)/2

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Drying
Filtration/Centrifugation - mechanical
separation of liquid from solids
Drying - separation by L-V phase transition
vapour out
L

heat in

Composition - solid material:

A liquid; B solid
dry basis:

wet basis:

xA = mA / mB

wA = mA / (mA+mB)

Composition - gas phase:

partial pressure

pA = yA P

relative saturation

= pA / p A *

saturated vapour pressure

pA* = pA*(T)

(e.g. from Antoine equation)

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Moisture equilibrium:
free moisture content xA = xA,tot - xA*

equilibrium moisture
content, xA*

relative
humidity,

Classification of drying processes

Means of heat supply:
- direct heat transfer (hot gas)
- indirect heat transfer (heat exchange surface,
microwave, or radiative)
Means of vapour removal:
- cross-flow of carrier gas
- through-flow of carrier gas
- suction
Means of solids motion:
- static vs. agitated (mechanically, fluidisation)

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Vapour removal

cross-flow

through-flow

suction

Solid phase motion

fluidized bed

tumble drum or
agitated vessel

Drying equipment: tray dryer

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Drying equipment: fluid-bed dryer

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Drying equipment: rotary drum dryer

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Drying equipment: contact dryers

Horizontal agitated vessel

Cone mixer

Heat-transfer rate:
Q = hq A T

or

Q = hq aV T

T mean temperature difference, T ~ (Th-Tv)

(not necessarily TLM)
Heat-transfer coefficients:
-from gas to a single particle (or droplet)
Nu = 2.0 + 0.60 Rep1/2 Pr1/3
-from fluid to a flat surface (laminar flow and Pr>0.7)
Nu = 0.664 Re1/2 Pr1/3
(Nu = hqL/

Re=uL/

Pr=cp/)

-otherwise correlations for each geometric arrangement

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Drying curves and drying rates:

moisture content, xA

drying rate, -dxA/dt

(1)

(2)
(2)

(1)

(3)
(3)

(4)

(4)

moisture content, xA

time, t
1) warming-up period

3) 1st falling-rate period

2) constant-rate period

4) 2nd falling-rate period

Calculation of drying time:

-Constant drying conditions
Drying rate R = - (1/A) dmA/dt = - (mB/A) dxA/dt
Drying time tT = (mB/A)

x1

x2 dxA/R

Constant period: R = Rc tc = mB (x1 - x2) / (ARc)

Falling rate period: R = a xA + b

a=(Rc-R)/(xc-x)

tf = mB /(aA) ln(R1/R2)
If single falling-rate period and x=0, then total time:
tT = mB/(ARc)[(xinitial-xc)+xc ln(xc/xfinal)]

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