MINIREVIEWSignificance of Controlling Crystallization Mechanisms and Kinetics in Pharmaceutical SystemsNA RRODR GUEZ-HORNEDO*,ANDDENETTEMURPHYContribution from College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065 and Dupont Pharmaceuticals, P.O. Box 80400, Wilmington, Delaware 19880-0400.Received December 23, 1998.Final revised manuscript received April 8, 1999. Accepted for publication April 12, 1999.IntroductionMetastable thermodynamic states are frequently en- countered in pharmaceutical systems, in the intentional or unintentional creation of supersaturation, in the crystal- lization of desired solid-state modifications, and in the control of solid-phase conversions during isolation, manu- facturing, storage, and dissolution.1-4Some 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 crystal- lization 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.5-16What is sur- prising, 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 thermody- namic stability of solid phases, information on crystalliza- tion processes can only be obtained by combining studiesof thermodynamic properties with kinetic measurements. Cases of unwanted or previously unknown nucleation events abound. Dunitz and Bernstein17documented 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,18illustrates the decisive role that nucleation mechanisms and kinetics have on crystallization. Nichols and Frampton19have reported considerable efforts that failed to crystallize the metastable polymorph of paraceta- mol as described in the initial publication of the crystal structure.20The 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 produc- tion of the desired solid-state form(s). It should be empha- sized that the manufacturing process (or storage condition) is responsible for producing particular polymorphs or solvates; the control methods merely determine the out- come.” 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: nrhumich.edu. University of Michigan.Dupont Pharmaceuticals.July 1999 Volume 88, Number 7 1999, American Chemical Society and10.1021/js980490h CCC: $18.00Journal of Pharmaceutical Sciences / 651 American Pharmaceutical AssociationVol. 88, No. 7, July 1999Published on Web 05/19/1999structural approach due to the availability of commercial software for the prediction of crystal structure from mo- lecular structure (ab initio predictions) while kinetic pro- cesses are scarcely investigated. Desiraju22-24and Gave- zzotti25-29have discussed the various methods for crystal structure and polymorphism prediction and the capabilities and shortcomings of the various computer simulation techniques. The main challenge lies in determining the relationships between the molecular aggregation pathways that cause some nuclei to grow and the structure and thermodynamics of the crystalline solids. Recent work from various groups14,30-40highlight the importance of combining computer simulations with experimental methods to in- vestigate the molecular events that lead to crystallization. The purpose of this review is to describe ways in which crystal structure, morphology, and crystallization kinetics can be utilized to reproducibly maintain metastable states and control solid-s