3 Anti-solvent Crystallization Method for Production …
65
Fig. 3.9 Solubility curves
for α-form and γ -form, and
solution composition
trajectories of Method A
(Run 1), Method B (Run 4)
and Method C (Run 6)
0
0.2
0.4
0.6
0.8
1
0
0.1
0.2
0.3
Heptane w H [mass fraction]
IMC w
I [mass fraction]
solubility of α-Form
solubility of γ-Form
Operation point trajectory
Run 1 end point
(Method A)
Run 4 end point
(Method B)
Run6 end point
(Method C)
3.4.5.3 Method C (Intermittent Anti-solvent Addition)
In order to shorten batch operation time, it is necessary to supply an anti-solvent
at a high addition rate. However, the existence of local supersaturation near the
anti-solvent addition position is a problem under this operating condition. If the
crystallization is carried out by using the lower addition rate than the critical rate
at which the accumulation of α-form occurs by local supersaturation, and in the
operation region in which solution composition does not exceed the solubility of
α-form, it is considered that γ -form can be obtained selectively. In the early stage
of Run 5, the plate-like crystal (γ -form) deposited. However, in the middle stage
of Run 5, the cotton-like crystal deposited in large quantities. In Run 6, although
the cotton-like crystal deposited in the middle of the experiment, the crystals which
suspended at the end of batch operation time became only γ -form (Fig. 3.9).
3.4.5.4 Analysis of Precipitated Crystal and Existence of A
-Form
The cotton-like crystal deposited in the middle stage of the experiment not only under
the condition of Method C but also under the condition with which does not exceed the
solubility of α-form. There is a report that solvate deposits in crystallization of IMC
from an acetone solution. When the precipitated crystal was analyzed in detail, the
cotton-like crystal was the solvate of acetone. Therefore, if the solubility of solvate
(α
-form) is not taken into consideration, γ -form cannot be obtained selectively. The
solubilities of each polymorph are shown in Fig. 3.10.
65
Fig. 3.9 Solubility curves
for α-form and γ -form, and
solution composition
trajectories of Method A
(Run 1), Method B (Run 4)
and Method C (Run 6)
0
0.2
0.4
0.6
0.8
1
0
0.1
0.2
0.3
Heptane w H [mass fraction]
IMC w
I [mass fraction]
solubility of α-Form
solubility of γ-Form
Operation point trajectory
Run 1 end point
(Method A)
Run 4 end point
(Method B)
Run6 end point
(Method C)
3.4.5.3 Method C (Intermittent Anti-solvent Addition)
In order to shorten batch operation time, it is necessary to supply an anti-solvent
at a high addition rate. However, the existence of local supersaturation near the
anti-solvent addition position is a problem under this operating condition. If the
crystallization is carried out by using the lower addition rate than the critical rate
at which the accumulation of α-form occurs by local supersaturation, and in the
operation region in which solution composition does not exceed the solubility of
α-form, it is considered that γ -form can be obtained selectively. In the early stage
of Run 5, the plate-like crystal (γ -form) deposited. However, in the middle stage
of Run 5, the cotton-like crystal deposited in large quantities. In Run 6, although
the cotton-like crystal deposited in the middle of the experiment, the crystals which
suspended at the end of batch operation time became only γ -form (Fig. 3.9).
3.4.5.4 Analysis of Precipitated Crystal and Existence of A
-Form
The cotton-like crystal deposited in the middle stage of the experiment not only under
the condition of Method C but also under the condition with which does not exceed the
solubility of α-form. There is a report that solvate deposits in crystallization of IMC
from an acetone solution. When the precipitated crystal was analyzed in detail, the
cotton-like crystal was the solvate of acetone. Therefore, if the solubility of solvate
(α
-form) is not taken into consideration, γ -form cannot be obtained selectively. The
solubilities of each polymorph are shown in Fig. 3.10.