Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems

Metastable thermodynamic states are frequently encountered in pharmaceutical systems, in the intentional or unintentional creation of supersaturation, in the crystallization of desired solid-state modifications, and in the control of solid-phase conversions during isolation, manufacturing, storage, and dissolution.1-4 Some examples in which metastable states are encountered include solid solutions, freeze-concentrated solutions, solutions of weak acids or bases exposed to a pH change, solutions prepared by dissolving a solid-state modification with a higher solubility (higher free energy), and residual solutions during filtration, granulation, and drying. Because crystallization provides a way of reducing the free energy of metastable thermodynamic states, the extent to which metastable states can be maintained is determined by the crystallization mechanisms and kinetics.5-16 What is surprising, however, is that despite the important role that crystallization has in process control and in determining solid-phase outcomes, crystallization phenomena are often neglected in the pharmaceutical industry until a problem is encountered. While emphasis is often given to the knowledge of equilibrium phase diagrams with the purpose of identifying the concentration and temperature regions of thermodynamic stability of solid phases, information on crystallization processes can only be obtained by combining studies of thermodynamic properties with kinetic measurements. Cases of unwanted or previously unknown nucleation events abound. Dunitz and Bernstein17 documented cases of “disappearing or elusive polymorphs” that provide evidence for the consequences of poor process control in crystallization of polymorphic systems. The recent shortage in the supply of capsules of the HIV protease inhibitor Norvir (indinavir), due to the sudden formation of a crystalline structure different from the one harvested for months,18 illustrates the decisive role that nucleation mechanisms and kinetics have on crystallization. Nichols and Frampton19 have reported considerable efforts that failed to crystallize the metastable polymorph of paracetamol as described in the initial publication of the crystal structure.20 The critical role of crystallization kinetics in determining the appearance of crystalline modifications is also recognized by the FDA and described in the guidelines for the manufacture of drug substances:21 “Appropriate manufacturing and control procedures (including in-process testing when needed) should be established for the production of the desired solid-state form(s). It should be emphasized that the manufacturing process (or storage condition) is responsible for producing particular polymorphs or solvates; the control methods merely determine the outcome.” Even when the parameters that regulate crystallization phenomena are neglected, the illusion of process control is motivated by a crystallization process that yields the desired productssolid phase modification, shape, or size distributionsand by the robust analytical methods used for solid state characterization. This situation is greatly complicated by the recent emphasis on an exclusively * Corresponding author. Tel: 734-763-0101. Fax: 734-763-2022. e-mail: nrh@umich.edu. † University of Michigan. ‡ Dupont Pharmaceuticals. July 1999