Recent Advances In Precipitations

Of
Pharmaceuticals

Balaji Ethiraj
Kinetic data for seventeen aqueous
systems crystallized by cooling
,evaporation ,salting out and reaction
 Sr. no. Aqueous M Temp. C* (mol/lit) C C/C* GX108 Xmax
system (kg/kmol) (oC) (m/s) (μm)

A KCl 74.6 24 4.2 0.0042 0.001 5.0 1000

Kinetic data of seventeen aqueous system crystallized by cooling,
B NaCl 58.5
evaporation, salting out50and reaction
4.6 0.0138 0.003 3.7 500

C (NH2)2CS 76.1 25 2.0 0.0140 0.007 4.8 1000

D (NH4)2SO4 132.1 21 4.1 0.0286 0.007 7.5 800

E KNO3 101.1 20 2.8 0.0420 0.015 4.8 700

F Na2SO4 142.0 40 1.2 0.0720 0.06 7.5 500

G K2SO4 174.2 30 0.72 0.0430 0.06 4.6 170

H NH4Al(SO4)2 237.3 22 0.23 0.0167 0.07 3.3 270

I K2Cr2O7 294.2 - 0.42 0.0420 0.1 8.0 200

J KAl(SO4)2 258.1 25 0.35 0.0157 0.45 3.0 350

K KClO4 138.6 - 0.16 0.0096 0.6 - 46

L NiSO4(NH4)2S 286.7 25 0.27 0.162 0.6 - 330

O4
M BaF2 175.4 20-50 9.2X10-3 0.0660 7.2 - 4.2

N BaCO3 100.1 25 2.5X10-4 0.0024 9.6 0.6 41

O TiO2 80.0 25 3.0X10-3 0.0960 32 0.25 2.8

P CaF2 78.1 18 2.0X10-4 0.0120 60 - 2.0

Q BaSO4 233.4 22 1.0X10-5 0.0010 100 0.1 3.5

 The systems range from highly soluble substances (c* =4.6 mol/l) to
sparingly soluble systems (c* =10-5 mol/l).

 The relative supersaturation at which they were crystallized ranged

from 10-3 to102.

 A general result was the higher the relative supersaturation at which

the system was crystallized the smaller is the obtained maximum
mean crystal size.

 The mean crystal size can be given by

 1/ 4 
 G 
x  3.67
 6k  B /   

 v 0 
Fig maximum obtainable mean crystal size versus
relative supersaturation for 17 systems according to
table1
Processes Occurring During
Precipitation
Chemical Reaction and salting out effect
Chemicalreactionswhichinitiateprecipitationprocess
A  B 
kr
C
withthereactionrate
dc  E 
 A  k0 exp cAa cBb cCc
dt  RT 
kineticsdependonlyontheconcentrationsofreac tan tAthelastequationscanbewrittenforafirstorderreaction :
dcA dcC
  kr cA 
dt dt
Therateofgenerationsof sup ersaturationcanbederivedfromthisequation

 
 
d dS d cc / cc* cA
 kr *
dt dt dt cC
ItisobviousthatlowconcentrationsofcomponentAandmixingareveryimpor tan tforthe lim itationandlevellingoutoftheundesired sup ersaturationpeaks
Mixing Of fluids

• Precipitations system in to which the reactant stream or salting out solvents

are fed can behave very differently according to their state of mixing.
• Mixing is described in terms of macro and micro mixing.
• The Definitions of intensity of segregation is given by

C '2
Is 
C' 2
• The mixing process of liquid within a stirred vessel is composed of macro
mixing time Ɵmacro and Ɵ micro .
• The selectivity of the homogenous chemical reaction and the quality of the
crystalline product depend on the ratios of  micro 
and micro
 macro  reac

. Whereas for heterogeneous reaction the ratios

timeofdiffusion diff

 D
AB / k 2
d 
timeofreaction reac  reac
 In turbulent flow regime (Re=sd2ρ/η>104 ) the mixing time in the baffled
tanks with tank height H equal to tank diameter Td is given by:
Td2
 macro ,turb  7.33 


 For mixing in the laminar flow regime (Re=sd2ρ/η<10 )


 macro ,lam  860 

 The intensity of segregation Is:
1
Is 

2  micro
1 
0.88  ln sc

 Or for Is < 0.01 and Sc > 102 with sufficient accuracy

 
 micro  50  ln Sc 

 ε is the local specific power input which depends upon the turbulent local
fluctuation velocity u’ and the stirrer diameter

  6.25
 u '
3

d
Crystallization
The Crystallization process which leads to the solidifications of the product
consists of nucleation and subsequent growth.
• Nucleation
• Nucleation mechanisms are considered to be either homogeneous, or heterogeneous, where solid
surfaces catalyze the generation of nuclei.
• Primary nucleation was first considered and, in comparison to the other nucleation mechanism, it
had been shown that it was dominant in precipitation processes.
• The dimensionless rate of primary nucleation ɸ was given by with


  exp(  ),
 ln S  2
with
B prism
•  
 

3 SL  M 
3 D AB  cN A 
 7 / 3
8kT   s N A 

 
2
 

   SL 
3
16  M
  f    
3  s N A   kT 
 

 
 In Fig. 7, ɸ is plotted against the relative supersaturation σ =S - 1 =Δ c/c*.
For all the systems from Table 1, the parameter , which represents the
system properties, lies in the hatched area (10-30< ɸ <10-20;5<Г<200)can
be seen that primary nucleation only occurs in the supersaturation range
σ > 1 or S = σ + 1 > 2.
 It can be seen from Fig.7 that a critical supersaturation, at which
nucleation is initiated, can be easily determined for any system with a
given Г -parameter. Contact angles < 180˚ (heterogeneous nucleation)
reduce the critical supersaturation in comparison to homogeneous
nucleation.
 A special case arises when no dust particles and only crystals of the
solute are present in the solution. This represents secondary
nucleation. According to the maximum affinity between cluster and
crystal, the contact angle and the correcting factor f approach zero.
 Consequently ,the critical supersaturation is strongly reduced in
comparison to primary nucleation. In systems containing some
crystals, the critical supersaturation should be reduced to zero.
However, for very small supersaturation and low growth rates of the
nuclei, the induction times may be very long.
 In the case of precipitation of sparingly soluble substances, the
question arises whether nuclei are generated by primary or secondary
nucleation.
to answer this questions the critical supersaturation ccrit, hom is plotted
against the solubility c* as seen from fig.
 The diagram shows that primary nucleation begins at relative supersaturation
Δ c/c* > 0.5, depending on the physical properties of the system .
Growth , Ageing and Agglomeration:
 The growth of the crystals depends upon supersaturation .
 The growth of the small and slowly growing crystals is often surface
integration controlled and can be described by a second order semi-empirical
relations G  k  c 
g *
2

 c 

 The growth rate coefficient kg, was found experimentally to be in the range 10-
12m/s < kg< 10-4m/s . The more complex the shape of the molecules, their
dipole moment and functional groups, the smaller are their growth coefficients
kg. However, the faster the crystal grows, the stronger is the tendency to
incorporate impurities.
 The driving force for ageing is the difference in solubility between the crystals
of different sizes. Small crystals are dissolved and the large ones increase in
size. The speed, at which ageing occurs in saturated solutions, depends largely
on particle size x and solubility c* and may be expressed
Approximately as dissolution time t.
RTx 3
t 
 
 2 
 6 SL *
 v DAB c 
 

ξ is a proportionality factor and v- the molar volume.

 Agglomeration is present in almost all precipitation processes and in some

crystallization systems as well particularly during start-up, where higher
supersaturation prevails.
 When solid-liquid separation is critical, agglomeration is desired since it
leads to larger, easy-to-filter particles. When products of high purity are
needed, however, agglomeration should be avoided since agglomerates trap
impure mother liquor in their interstices. For low solids contents (below 1
vol%) in the precipitator, agglomeration of these solids on large seeds in a
fixed or fluid bed can be advantageously applied.
 The process of agglomeration starts with the transport of particles towards
one another. When the particles have enough kinetic energy to overcome
the repulsion due to their surface potential, they collide. If they remain in
contact long enough for growth to take place and thereby bind the particles
together, an agglomerate is formed. Having this picture of agglomeration in
mind, one understands the variables affecting agglomeration during
industrial precipitation.
 Mixing intensity improves the particle collision frequency and thus
agglomeration. However, a mixing intensity that is too high promotes
particle disruption. Solids concentration also increases the collision
frequency to the second power (since two particles are involved in each
collision).
 pH has a very strong effect on the surface potential, for every compound
there is a pH where the particle surface is electrically neutral . At this pH,
particle-particle repulsion vanishes and agglomeration is highest. A high
ionic strength depresses the double layer, thus stimulating agglomeration. A
high supersaturation decreases the time needed for binding particles
together, thereby facilitating agglomeration.
 Hounslow and coworkers have been studying agglomeration of
calcium oxalate and calcium carbonate for several years. In this model,
it is assumed that solid bridge is formed before its rupture by
fluctuations in flow field. They propose the non-dimensional number
M:
bridgeresi s tan ce  *G 2
M 
force / areaofbrid ge d 2 3

 The parameter δ* derives from parameters of limited usefulness: the

material mechanical resistance, a factor that relates bridge growth rate
and crystal growth rate and a bridge shape factor.
 The agglomeration efficiency y is defined as the ratio between
experimental agglomeration rate and average collision rate. It was
found that the reactant concentration does not affect agglomeration
and that a slight positive effect of particle size is present.
 The mixing intensity was inversely proportional to the agglomeration
rate for both systems studied. The authors postulate that
agglomeration mechanism for both compounds is identical.
Mixing
 Precipitation is often conducted either by chemical reaction or anti-solvent
processes.

 In both cases, mixing has to take place on the molecular level before
precipitation proceeds. Since many precipitation processes are conducted at
very high supersaturation, the characteristic reaction time is of the same
order of magnitude or even smaller than the mixing time. When this
situation prevails, the course of the mixing process helps to determine the
course of supersaturation. This explains why mixing conditions affect
crystal shape, purity, crystallinity, and in some cases, even the phase
modification (e.g., polymorph) that is formed.

 When one wishes to produce large crystals of high crystallinity and purity,
precipitation should be conducted at low supersaturation. Therefore,
reactants should be added near areas of high mixing intensity, and as far as
possible from each other, i.e., a good dispersion of the concentrated reactant
with the reactor contents should be stimulated.
 If fine particles with a narrow size distribution are desired, intense mixing
should provide rapid contact between concentrated reactants.
Recommendations for operating conditions:
 The value of supersaturation Δc has to be selected between 0.01and 0.1mol/l
in order to obtain growth rates between 0.5X10-8 and 5X10-8 m/s.
 The crystallizations process is very sensitive to supersaturation so it
important to avoid excessive supersaturation which is likely to be generated
at the feed inlet.
 Secondary nucleations is the main source of nuclei for systems with
solubilities c* in excess of 0.5mol/l or relative supersaturations σ smaller
than 0.5.secondary nucleation largely depend upon mechanisms and fluid
dynamics in the crystallizer, as seen from

Bo , Pr im  f  d m ,  SL , DAB , candc b 0 withb0  1

B0,sec  f   , x,  s , andc b1with1  b1  3
 A general decrease Of the maximum mean crystal size can be expected with
increasing relative supersaturation. According to an extrapolation of Fig. 1,
the mean crystal size drops below 1μm for σ-values above 1000.
Batch or continuous operation
 The capacity , operational conditions and demand for a large crystal size
often decide whether a process is carried out batch wise or continuously.
 The residence time τ in a continuous crystallizer is given by
t t g
 c 
x  x   Gdt  x  k g    dt  batch
0 0  c * 
or
g
 c 
x  x  G  x  k g    (continuous)
 c*
withgoften1  g  2.
 The relative supersaturation Δc/c* decreases with the batch time
t(batch) or the mean residence time τ (continuous) from the initial
value
to final value.this decrease is given by
  c 
d  b
c *
   k   c 
b  (batch)
dt c
  *
 c 
d  c
 c *    k  c   continuous 
c 
d c
  *
Fig……………………
Seeded and unseeded crystallization:

 It may be advantageous to seed the solution by adding at a suitable

locations a certain quantity of seed crystals with a favourable size
distributions.

 Quantity and size distribution should be chosen in such a way that

the surface area and growth rate of the seed crystals are large. In this
way, a rapid decrease of supersaturation can be achieved within the
induction time of primary nucleation and large numbers of primary
nuclei, which would lead to a fine product, can be avoided.

 It is important to mention that small crystals have large surface areas

but their growth rates may be one or two orders of magnitude less
than those of 1 mm crystals. Consequently, the mean crystal size of
seed crystals represents a compromise between large specific areas
and growth rates.
 The installations of a heated premixing chamber with or without baffles can be
advantageous since this makes it possible to dissipate very high mean
specific power inputs according to 


ch

  w3
 ch 
2D
 It is very important to avoid nucleation and crystallization in the hollow
shaft which would result in incrustation. Since the time required for
mixing strongly depends on the local specific power input ε the chemical
engineer is interested in the ε field of the crystallizer under discussion.

 Fig 15…………………………………………………………………………………..
 Fig shows a stirred vessel equipped with a 3-blade Marine type

propeller  /
(d/Td =0.33), and a 2-stage-2-blade Intermig (d/Td = 0.7) .

 Isoenergetic curves, i.e. curves with constant are plotted for a

stirrer Reynolds number Re=nd2ρ/η>104 and for the mean specific
power inputs of ε = 0.52, 0.1 and 0.15 W/kg.

 These isoenergetic curves do not change for Re >104, for instance, in

larger vessels operating at the same or larger mean specific power
inputs . In the discharge flow region of the 6-blade turbine, the local
specific power input amounts to ε= 5 x 0.52 = 2.6 W/kg which may be
compared with ε = 1 x 0.15 = 0.15 W/kg, valid for the region of the
stirrer tip of the 2-blade Intermig. Thus, the micro mixing time in the
discharge flow of the vessel on the left is 4.15 times shorter than that
for the vessel on the right of Fig.