Crystallization: Impact on the Nature and Properties of the Crystalline Product

Crystallization is usually the final stage in the manufacture of an active pharmaceutical ingredient. The development of a given crystal during the crystallization process proceeds through three consecutive stages, namely, nucleation, crystal growth, and Ostwald ripening. In the nucleation stage, molecules of the substance aggregate to form embryos. If the conditions are such as to allow an embryo to reach a critical size, known as a nucleus, this nuclear aggregate can grow to form a macroscopic crystal. Crystal growth proceeds by successive incorporation of molecules, first onto the surface of the nuclei and subsequently onto the surface of the growing crystals. Provided the solution is supersaturated, this growth process is spontaneous (DG is negative) and is accompanied by an increase in molecular order (DS is negative). According to the Thomson (Kelvin) equation, smaller crystals have a slightly greater solubility than larger crystals. This difference in solubility causes the larger crystals to grow at the expense of the smaller crystals, which tend to dissolve. This phenomenon, whereby the crystal size distribution moves towards increasing size, is termed Ostwald ripening.

During crystal growth and Ostwald ripening, any impurities present in the solution or in the crystals may redistribute themselves between the solution and the crystals and between the crystals themselves. Usually the crystallization process leads to a crystalline product that contains smaller amounts of impurities than the original material, although exceptions are known.