5 Control of Crystal Size Distribution and Polymorphs …
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Some compounds incorporate solvent molecules in the crystals, and such crystals are called solvates or pseudo polymorphs. Nowadays, solvates have also been
considered as one of the polymorphs [3]. In the solvate crystal, not only the interaction between the solute molecules but also the interaction via the solvent molecule
exists. So the solvent molecule should play an important role in crystal formation.
Many hydrates are also found in the pharmaceutical products, and one-third of drugs
registered in the European Pharmacopoeia is hydrate form.
Control of crystal polymorphism is crucial because different crystal structures
have different solubility and stability in the same substance [4]. Particularly in drug
substance, the dissolution properties of crystals may affect the pharmacokinetics
of drugs, and a technique for reliably producing a particular crystal polymorph is
required.
5.1.3 Crystallization Technics
Some oils are crystallized by melt crystallization, but many organic compounds are
generally crystallized from the solution. There are various methods for crystallization from a solution. Cooling crystallization is the most common method. When the
solution containing a given amount of solute is cooled via the outer jacket of the
crystallization vessel or the cooling coil inserted inside, the solution becomes supersaturated. Thereafter, the crystal appears via nucleation and growth. The amount of
crystals obtained can be estimated by the feed concentration and the solubility at
the final cooling temperature. Therefore, the cooling crystallization is advantageous
when crystallizing a substance having a high-temperature dependence of solubility.
When the solubility does not change much with temperature, or when the solubility
at low temperatures is high, the amount of solute recovered by cooling crystallization
may be small. In such a case, a method other than cooling should be selected. For
example, in order to generate supersaturation, the solvent composition is changed.
The additional solvent is added to the solution to reduce solubility. We need to select
such an appropriate solvent so that the solvent and the solution should be miscible.
Usually, in the crystallization of hydrophilic compounds, water is used as a good
solvent, and an organic solvent is used as an antisolvent. Conversely, water is used
as an antisolvent for the crystallization of poorly water-soluble compounds.
What should be taken care of in the drowning out crystallization is that when the
crystallization is performed from a condition where the concentration of the initial
solution is excessively high, liquid–liquid phase separation often occurs without
precipitation of crystals. Liquid–liquid phase separation is a phenomenon in which
solute molecules exist in a liquid state with a super-high concentration, and in many
cases, precipitation of crystals does not occur. It is because even if the concentration
is very high, the solution contains a solvent with high affinity and is stable in the
solution state. Moreover, since the viscosity is high due to the high concentration,
nucleation is suppressed kinetically. On the other hand, there are some examples in
which particle size control is attempted using liquid–liquid separation phenomena.
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Some compounds incorporate solvent molecules in the crystals, and such crystals are called solvates or pseudo polymorphs. Nowadays, solvates have also been
considered as one of the polymorphs [3]. In the solvate crystal, not only the interaction between the solute molecules but also the interaction via the solvent molecule
exists. So the solvent molecule should play an important role in crystal formation.
Many hydrates are also found in the pharmaceutical products, and one-third of drugs
registered in the European Pharmacopoeia is hydrate form.
Control of crystal polymorphism is crucial because different crystal structures
have different solubility and stability in the same substance [4]. Particularly in drug
substance, the dissolution properties of crystals may affect the pharmacokinetics
of drugs, and a technique for reliably producing a particular crystal polymorph is
required.
5.1.3 Crystallization Technics
Some oils are crystallized by melt crystallization, but many organic compounds are
generally crystallized from the solution. There are various methods for crystallization from a solution. Cooling crystallization is the most common method. When the
solution containing a given amount of solute is cooled via the outer jacket of the
crystallization vessel or the cooling coil inserted inside, the solution becomes supersaturated. Thereafter, the crystal appears via nucleation and growth. The amount of
crystals obtained can be estimated by the feed concentration and the solubility at
the final cooling temperature. Therefore, the cooling crystallization is advantageous
when crystallizing a substance having a high-temperature dependence of solubility.
When the solubility does not change much with temperature, or when the solubility
at low temperatures is high, the amount of solute recovered by cooling crystallization
may be small. In such a case, a method other than cooling should be selected. For
example, in order to generate supersaturation, the solvent composition is changed.
The additional solvent is added to the solution to reduce solubility. We need to select
such an appropriate solvent so that the solvent and the solution should be miscible.
Usually, in the crystallization of hydrophilic compounds, water is used as a good
solvent, and an organic solvent is used as an antisolvent. Conversely, water is used
as an antisolvent for the crystallization of poorly water-soluble compounds.
What should be taken care of in the drowning out crystallization is that when the
crystallization is performed from a condition where the concentration of the initial
solution is excessively high, liquid–liquid phase separation often occurs without
precipitation of crystals. Liquid–liquid phase separation is a phenomenon in which
solute molecules exist in a liquid state with a super-high concentration, and in many
cases, precipitation of crystals does not occur. It is because even if the concentration
is very high, the solution contains a solvent with high affinity and is stable in the
solution state. Moreover, since the viscosity is high due to the high concentration,
nucleation is suppressed kinetically. On the other hand, there are some examples in
which particle size control is attempted using liquid–liquid separation phenomena.