The controlling factor and mechanism of the crystallization of polymorphs were investigated in various systems; i.e. amino acids, inorganic compounds (calcium carbonate), pharmaceuticals and inclusion compounds. The controlling factor depends on the systems (compounds and solvents and additives) and the crystallization methods (cooling crystallization, reactive crystallization and anti-solvent crystallization). The controlling factors for each system were found and a schematic diagram was shown. The mechanism of each controlling factor was investigated and some rules were found. It appears that the establishment of “Ostwald's step rule” depends on the systems. In the cooling crystallization of amino acids (L-glutamic acid and L-histidine), the “Ostwald's step rule” cannot be observed; however, in the crystallization of BPT esters, it is clearly established. The difference of the temperature effect between L-glutamic acid and L-histidine polymorphs may be related to the difference of the molecular conformation between the polymorphs. In the reactive crystallization of calcium carbonate polymorphs, the concentration (supersaturation) of reactant solutions, the mixing rate of the solutions, pH, stirring rate and temperature were found to be the controlling factors for the morphology and the crystallization behavior of polymorphs. As for the effect of additives it should be noted that the additive affects not only one polymorph, but on each polymorph. Then, knowing the relative effect of additives on each polymorph is important for the control. The growth kinetics of polymorphs of L-glutamic acid and the mechanism of morphology change of each polymorph were examined in the presence of L-phenylalanine (as an additive) with batch crystallization and the single crystal method. The growth rate model including the additive concentration was proposed for each polymorph and the method of the selective crystallization of the polymorphs by controlling the supersaturation and the additive concentration was also indicated. In anti-solvent crystallization of pharmaceuticals (BPT) it was shown that the addition rate of anti-solvent, initial concentration of solute and temperature are the controlling factors. With the increase of the addition rate the water composition in the nucleation zone increases, resulting in the preferential crystallization of the hydrate crystals. The transformation from BH to A form was observed, however, the transformation rate increased with a decrease in the water addition rate. It is that even when none of the A form was detected by XRD a small amount of fine crystals (A form) is included within the BH crystals and act as seed crystals for the transformation. Furthermore, the change in the molecular structure is related with a dynamic change of the polymorphic crystallization behavior as observed in L-Glu and L-His systems. The dependence of the polymorphic crystallization behavior on the molecular structure was systematically investigated using the newly synthesized BPT esters. It appeared that the conformational flexibility, the size of alkyl group of the esters and the presence of functional group influences the formation of hydrogen bond and the polymorphism. The solvent effect on the polymorphism was also examined in relation to the molecular structure. The functionality of clathrate crystals and the separation efficiency of isomers by clathrate crystals depend on their polymorphic crystallization behavior. The mechanism of the molecular recognition for the guest isomers by the host molecule is clarified. It was also elucidated that the release process of a guest biocide molecule from clathrate crystals includes polymorphic transformation.
