Chapter 3
Anti-solvent Crystallization Method
for Production of Desired Crystalline
Particles
Hiroshi Takiyama
Abstract Anti-solvent crystallization is widely used in the pharmaceutical industry
from the viewpoint of the ambient temperature operating condition and high yield
production. In the anti-solvent crystallization, the quality control of crystalline
particles is necessary. Since polymorphism phenomena affect dissolution property,
productivity, and bioavailability, it is important to control polymorph formation.
The consideration of the solution addition methods to control polymorph in antisolvent crystallization is engineering challenge. In this chapter, the operation design
and/or operating strategies to obtain crystalline particles with the desired polymorph
are described. The ternary phase diagram is proposed to control polymorphs. In
order to determine both the anti-solvent addition rate and a temperature profile, the
temperature-dependent solid–liquid equilibrium (ternary phase diagram) is necessary. By using this operation design and the simulation, the required polymorph
is successfully obtained in the anti-solvent crystallization. The proposed operation
design method by using the operation point trajectory is effective for controlling
crystal quality in the anti-solvent crystallization.
Keywords Anti-solvent crystallization · Ternary phase diagram · Polymorphism ·
Pharmaceuticals
3.1 Introduction
Crystal products are widely found in pharmaceutical, food, fine chemicals, agrichemicals, cosmetic, and many other industries. Crystallization is the process of formation
of ordered three-dimensional molecular array (crystal) from solution, melt, or gas.
This process has been used as a method to produce crystalline particles and as a way
to separate and purify the desired component. There are many types of crystallization. In each type, the solubility of solute is reduced by lowering the temperature
H. Takiyama (B)
Department of Chemical Engineering, Tokyo University of Agriculture and Technology (TUAT),
Tokyo, Japan
e-mail: htakiyam@cc.tuat.ac.jp
© Springer Nature Singapore Pte Ltd. 2020
M. Sakamoto and H. Uekusa (eds.), Advances in Organic Crystal Chemistry,
https://doi.org/10.1007/978-981-15-5085-0_3
53
Anti-solvent Crystallization Method
for Production of Desired Crystalline
Particles
Hiroshi Takiyama
Abstract Anti-solvent crystallization is widely used in the pharmaceutical industry
from the viewpoint of the ambient temperature operating condition and high yield
production. In the anti-solvent crystallization, the quality control of crystalline
particles is necessary. Since polymorphism phenomena affect dissolution property,
productivity, and bioavailability, it is important to control polymorph formation.
The consideration of the solution addition methods to control polymorph in antisolvent crystallization is engineering challenge. In this chapter, the operation design
and/or operating strategies to obtain crystalline particles with the desired polymorph
are described. The ternary phase diagram is proposed to control polymorphs. In
order to determine both the anti-solvent addition rate and a temperature profile, the
temperature-dependent solid–liquid equilibrium (ternary phase diagram) is necessary. By using this operation design and the simulation, the required polymorph
is successfully obtained in the anti-solvent crystallization. The proposed operation
design method by using the operation point trajectory is effective for controlling
crystal quality in the anti-solvent crystallization.
Keywords Anti-solvent crystallization · Ternary phase diagram · Polymorphism ·
Pharmaceuticals
3.1 Introduction
Crystal products are widely found in pharmaceutical, food, fine chemicals, agrichemicals, cosmetic, and many other industries. Crystallization is the process of formation
of ordered three-dimensional molecular array (crystal) from solution, melt, or gas.
This process has been used as a method to produce crystalline particles and as a way
to separate and purify the desired component. There are many types of crystallization. In each type, the solubility of solute is reduced by lowering the temperature
H. Takiyama (B)
Department of Chemical Engineering, Tokyo University of Agriculture and Technology (TUAT),
Tokyo, Japan
e-mail: htakiyam@cc.tuat.ac.jp
© Springer Nature Singapore Pte Ltd. 2020
M. Sakamoto and H. Uekusa (eds.), Advances in Organic Crystal Chemistry,
https://doi.org/10.1007/978-981-15-5085-0_3
53