3 Anti-solvent Crystallization Method for Production …
59
solubility profiles are essential data for crystallization operation design to selectively isolate the target polymorph. By using solubility data, operation strategies
were designed [13], and the anti-solvent was added at controlled rates as reflected by
the changes in the solubility curves. In such a way the operating conditions should
be designed to obtain the target polymorph with consideration of solubility.
3.4.1 Operation Design of Anti-solvent Crystallization
Indomethacin (IMC)–Acetone (original solvent)–Heptane (anti-solvent) is a target
system in this chapter. There are several polymorphs and solvates in IMC [14, 15].
Two polymorphs (α-form and γ -form) were mainly handled this study chapter. The
solubility of each polymorph was measured in detail by using pure α-form and γ -
form crystals. Temperature and composition of mixed solvent (acetone and heptane)
were changed as the experimental conditions. The stable and metastable polymorph
solubilities were determined by measuring solution concentration during solutionmediated transformation. From the experimental results, the ternary phase diagram
of IMC–acetone–heptane system was prepared based on the mass fraction.
In the anti-solvent crystallization for IMC, supersaturation was generated by
adding heptane (anti-solvent) and the crystals were precipitated. Operation strategy
for controlling polymorph formation based on ternary phase diagram is shown in
Fig. 3.5 as a rectangular triangle diagram. Figure 3.5 is the part of ternary phase
diagram. In order to perform anti-solvent crystallization in the operation area where
only a certain polymorphism (γ -form was a target polymorph in this study) deposits,
it is necessary to control the feed rate of heptane according to the deposition rate of
γ -form. If α-form crystals deposit in the solution, it is difficult to agitate the slurry
because agglomerated α-form crystals have cotton-like shape. By the consideration
of a ternary phase diagram [16], an operation point leaves from a solubility curve by
addition of heptane. According to ternary phase diagram, when the anti-solvent is
fed to the solution, an operation point moves to w H = 1.0 by using lever rule along
with the line A. When the crystals are deposited, an operation point closes to solubility curve along the line B by using lever rule. Finally, an operation point moves
toward resultant vector of anti-solvent addition rate and crystal deposition rate. An
operation point becomes higher supersaturation by anti-solvent addition and then an
operation point approaches a solubility curve by precipitation of IMC. Hence, the
operation point can pass through a specific solution concentration range which does
not exceed the solubility of α-form (undesired polymorph) by choosing the optimal
anti-solvent feed rate suitably.
59
solubility profiles are essential data for crystallization operation design to selectively isolate the target polymorph. By using solubility data, operation strategies
were designed [13], and the anti-solvent was added at controlled rates as reflected by
the changes in the solubility curves. In such a way the operating conditions should
be designed to obtain the target polymorph with consideration of solubility.
3.4.1 Operation Design of Anti-solvent Crystallization
Indomethacin (IMC)–Acetone (original solvent)–Heptane (anti-solvent) is a target
system in this chapter. There are several polymorphs and solvates in IMC [14, 15].
Two polymorphs (α-form and γ -form) were mainly handled this study chapter. The
solubility of each polymorph was measured in detail by using pure α-form and γ -
form crystals. Temperature and composition of mixed solvent (acetone and heptane)
were changed as the experimental conditions. The stable and metastable polymorph
solubilities were determined by measuring solution concentration during solutionmediated transformation. From the experimental results, the ternary phase diagram
of IMC–acetone–heptane system was prepared based on the mass fraction.
In the anti-solvent crystallization for IMC, supersaturation was generated by
adding heptane (anti-solvent) and the crystals were precipitated. Operation strategy
for controlling polymorph formation based on ternary phase diagram is shown in
Fig. 3.5 as a rectangular triangle diagram. Figure 3.5 is the part of ternary phase
diagram. In order to perform anti-solvent crystallization in the operation area where
only a certain polymorphism (γ -form was a target polymorph in this study) deposits,
it is necessary to control the feed rate of heptane according to the deposition rate of
γ -form. If α-form crystals deposit in the solution, it is difficult to agitate the slurry
because agglomerated α-form crystals have cotton-like shape. By the consideration
of a ternary phase diagram [16], an operation point leaves from a solubility curve by
addition of heptane. According to ternary phase diagram, when the anti-solvent is
fed to the solution, an operation point moves to w H = 1.0 by using lever rule along
with the line A. When the crystals are deposited, an operation point closes to solubility curve along the line B by using lever rule. Finally, an operation point moves
toward resultant vector of anti-solvent addition rate and crystal deposition rate. An
operation point becomes higher supersaturation by anti-solvent addition and then an
operation point approaches a solubility curve by precipitation of IMC. Hence, the
operation point can pass through a specific solution concentration range which does
not exceed the solubility of α-form (undesired polymorph) by choosing the optimal
anti-solvent feed rate suitably.