Many crystallization methods have been used in pharmaceutical
sciences, e.g., melt crystallization, cooling crystallization,
anti-solvent crystallization, gas anti-solvent
crystallization and evaporative crystallization. Cooling and
anti-solvent crystallization were the most common crystallization
method used in pharmaceutical application. In cooling
crystallization, the supersaturation is generated by a decrease
in temperature. Cooling crystallization occurs when a solution
containing solute is cooled at a constant concentration of
dissolved crystals [8]. A similar process occurs for anti-solvent
crystallization, instead of cooling the system, a secondary
solvent known as anti-solvent is added to the original solvent,
resulting in the reduction of the solubility of the solute in the
original solvent and consequently generating a supersaturation
driving force [9]. Many studies reported the effect of
various operating conditions. The different concentrations of
aqueous and anti-solvent solutions affect crystal shape and
distribution [10]. The rate of supersaturation generation in
anti-solvent crystallization is highly dependent on the antisolvent
addition rate. Both supersaturation and solvent
composition are also important factors affecting crystal size
and habit.