54
H. Takiyama
(cooling crystallization), removing the solvent (evaporative crystallization), the addition of anti-solvent (anti-solvent/drowning-out crystallization), activating a reaction
(reaction crystallization), and sublimation of solute (vapor crystallization). As in
most industrial crystallization processes, polymorph, crystal morphology, and size
are important qualities of crystal products. These qualities can have a huge impact
on downstream processes. Fluidity, granularity, and compressibility of crystals may
differ due to the polymorph, morphology, and size. Hence, solid–liquid separation
characteristics, washing and drying process, tableting operation will be affected.
Eventually, the time of process, purity, and cost of the products will also be affected.
In addition, solubility of crystals also varies with crystal polymorph, morphology,
and size. This causes significant effects on the bioavailability and safety of medicine
in pharmaceutical field. Therefore, it is crucial to control the crystal polymorph,
morphology and size. In anti-solvent crystallization, when anti-solvent or solvent
mixture is added into the crystallizer, the solubility of the solute will be reduced,
and supersaturation which acts as the driving force of crystallization is generated.
Since this method can be carried out in ambient temperature, it is suitable for the
production or separation of heat-sensitive materials.
Polymorphism means that a compound has two or more crystal structures. Differences in crystal structures cause changes in physicochemical properties. In the pharmaceutical industry, it is necessary to control polymorphs because of their differences in bioavailability. There are many papers on the effects of operation factors
such as solvent and solution concentration. In particular, polymorphic crystallization
is affected by solvents, different polymorphs can be obtained from solutions with
different solvents. In the manufacture of pharmaceuticals, anti-solvent crystallization
is widely used from the viewpoint of high yield production. However, it is difficult
to select the suitable operating conditions for controlling polymorph formation in
anti-solvent crystallization because a particular polymorph may precipitate at limited
temperatures and in limited solvent compositions.
Much effort has been devoted to determine the influence of operating conditions
on crystal polymorph in anti-solvent crystallization, such as feeding rate, feed and
bulk concentration, agitation rate, and so on. It was found out that the operating
conditions have strong effects on the qualities of crystalline particles. Therefore, if
the relationship between crystal polymorph and operating conditions can be clarified,
we can easily determine the operating conditions and design the optimum method to
obtain desired crystal polymorph.
3.2 Anti-solvent Crystallization
3.2.1 Theory and Characteristics
In anti-solvent crystallization, supersaturation (driving force) is produced by adding
anti-solvent or solvent mixture into a solution. This will reduce the solubility of the
H. Takiyama
(cooling crystallization), removing the solvent (evaporative crystallization), the addition of anti-solvent (anti-solvent/drowning-out crystallization), activating a reaction
(reaction crystallization), and sublimation of solute (vapor crystallization). As in
most industrial crystallization processes, polymorph, crystal morphology, and size
are important qualities of crystal products. These qualities can have a huge impact
on downstream processes. Fluidity, granularity, and compressibility of crystals may
differ due to the polymorph, morphology, and size. Hence, solid–liquid separation
characteristics, washing and drying process, tableting operation will be affected.
Eventually, the time of process, purity, and cost of the products will also be affected.
In addition, solubility of crystals also varies with crystal polymorph, morphology,
and size. This causes significant effects on the bioavailability and safety of medicine
in pharmaceutical field. Therefore, it is crucial to control the crystal polymorph,
morphology and size. In anti-solvent crystallization, when anti-solvent or solvent
mixture is added into the crystallizer, the solubility of the solute will be reduced,
and supersaturation which acts as the driving force of crystallization is generated.
Since this method can be carried out in ambient temperature, it is suitable for the
production or separation of heat-sensitive materials.
Polymorphism means that a compound has two or more crystal structures. Differences in crystal structures cause changes in physicochemical properties. In the pharmaceutical industry, it is necessary to control polymorphs because of their differences in bioavailability. There are many papers on the effects of operation factors
such as solvent and solution concentration. In particular, polymorphic crystallization
is affected by solvents, different polymorphs can be obtained from solutions with
different solvents. In the manufacture of pharmaceuticals, anti-solvent crystallization
is widely used from the viewpoint of high yield production. However, it is difficult
to select the suitable operating conditions for controlling polymorph formation in
anti-solvent crystallization because a particular polymorph may precipitate at limited
temperatures and in limited solvent compositions.
Much effort has been devoted to determine the influence of operating conditions
on crystal polymorph in anti-solvent crystallization, such as feeding rate, feed and
bulk concentration, agitation rate, and so on. It was found out that the operating
conditions have strong effects on the qualities of crystalline particles. Therefore, if
the relationship between crystal polymorph and operating conditions can be clarified,
we can easily determine the operating conditions and design the optimum method to
obtain desired crystal polymorph.
3.2 Anti-solvent Crystallization
3.2.1 Theory and Characteristics
In anti-solvent crystallization, supersaturation (driving force) is produced by adding
anti-solvent or solvent mixture into a solution. This will reduce the solubility of the