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K. Igarashi and H. Ooshima
production process of API, the crystallizations are performed to separate the target
substance from raw materials or by-products at each step of the synthesis route,
which involves multiple steps. Care must be taken to improve yield and purity at
each step. It is because desired crystal characteristics may not be obtained due to the
influence of a small amount of raw material and by-products contained in crystals.
When the crystallization is performed in the manufacture of pharmaceuticals, it is
necessary to control various crystal characteristics to produce the desired crystals with
good reproducibility. There are various crystal characteristics to be controlled, such
as particle size, particle size distribution, crystal polymorphism, purity, shape, and
crystallinity. If control of such characteristics insufficient, the subsequent operability
and quality may be significantly affected. Therefore, it is important to clarify the
causal relationship between the crystallization conditions and the characteristics of
the obtained crystals and to control the crystal characteristics based on the theory
[1, 2].
5.1.2 Crystal Properties to Be Controlled
5.1.2.1 Crystal Size and Crystal Size Distribution
Crystal size and size distribution are one of the critical characteristics to be controlled
in the crystallization process. In industrial crystallization, depending on the purpose,
a large crystal may be desired, or a small crystal may be desired.
When importance is attached to solid–liquid separation in the filtration, uniform
and large crystals without small crystals are desired because unwanted fine crystals
can cause clogging of the filtration device. If it is difficult to obtain large crystals and
there is a problem in the filterability due to generation of fine particles, preparation
of agglomerates of the desired size by aggregation the micro crystals are attempted.
On the contrary, small crystals are often desired. When the size of the crystal is
large, the gap between the crystals becomes wide, and the amount of the crystal that
can be put in a specific container is reduced. When paying attention to the transportation of products, smaller crystals are advantageous because of their higher bulk
density. Furthermore, in recent years, the number of poorly water-soluble pharmaceuticals has increased, and in order to improve the solubility, it is necessary to make
fine crystals.
5.1.2.2 Polymorphs
In the crystal, the molecules are regularly arranged and bonded by appropriate intermolecular interactions. In the crystal, molecules at each point in the lattice have the
same conformation. There may be one or more regular arrangements for a substance,
and crystals with different structures are called crystal polymorphs.
K. Igarashi and H. Ooshima
production process of API, the crystallizations are performed to separate the target
substance from raw materials or by-products at each step of the synthesis route,
which involves multiple steps. Care must be taken to improve yield and purity at
each step. It is because desired crystal characteristics may not be obtained due to the
influence of a small amount of raw material and by-products contained in crystals.
When the crystallization is performed in the manufacture of pharmaceuticals, it is
necessary to control various crystal characteristics to produce the desired crystals with
good reproducibility. There are various crystal characteristics to be controlled, such
as particle size, particle size distribution, crystal polymorphism, purity, shape, and
crystallinity. If control of such characteristics insufficient, the subsequent operability
and quality may be significantly affected. Therefore, it is important to clarify the
causal relationship between the crystallization conditions and the characteristics of
the obtained crystals and to control the crystal characteristics based on the theory
[1, 2].
5.1.2 Crystal Properties to Be Controlled
5.1.2.1 Crystal Size and Crystal Size Distribution
Crystal size and size distribution are one of the critical characteristics to be controlled
in the crystallization process. In industrial crystallization, depending on the purpose,
a large crystal may be desired, or a small crystal may be desired.
When importance is attached to solid–liquid separation in the filtration, uniform
and large crystals without small crystals are desired because unwanted fine crystals
can cause clogging of the filtration device. If it is difficult to obtain large crystals and
there is a problem in the filterability due to generation of fine particles, preparation
of agglomerates of the desired size by aggregation the micro crystals are attempted.
On the contrary, small crystals are often desired. When the size of the crystal is
large, the gap between the crystals becomes wide, and the amount of the crystal that
can be put in a specific container is reduced. When paying attention to the transportation of products, smaller crystals are advantageous because of their higher bulk
density. Furthermore, in recent years, the number of poorly water-soluble pharmaceuticals has increased, and in order to improve the solubility, it is necessary to make
fine crystals.
5.1.2.2 Polymorphs
In the crystal, the molecules are regularly arranged and bonded by appropriate intermolecular interactions. In the crystal, molecules at each point in the lattice have the
same conformation. There may be one or more regular arrangements for a substance,
and crystals with different structures are called crystal polymorphs.