Growth of the pharmaceutical industry relies on development of new drugs.  Because of the continuing losses of exclusivity on drug products, it is vital for drug companies to constantly develop new products. Yet, drug development cycle of a new drug becomes longer (15 years), more expensive (1 billion dollars), and more difficult (only dozens get approved yearly by FDA). As a result, drug companies rely heavily on cutting-edge technologies to grasp new drug targets and rush their products to the market. Genomics, proteomics, combinatorial chemistry, high-throughput screening, novel delivery systems, materials engineering, and process analytical technology have emerged as key drivers for drug development. The industry also faces the pressure from the consumer and regulatory agency demanding safer, more effective and cheaper drug products, having no choice but to scrutinize every physical, chemical and biological property thoroughly.

Organic crystalline materials play a central role in the pharmaceutical industry as well as in fine chemicals. Physicochemical properties not only affect drug formulation and production, but also have a big impact on the performance and stability of final products. Because the majority of pharmaceutical materials are solid and most of the solid are molecular crystals, controlling crystal growth and consequent materials properties of drug substances and excipients has become one of essential tasks in the industry, demanding a vast amount of investment and raising significant challenges for scientists. It is well known that crystal size, shape, and surface properties greatly influence formulation and unit operations, including flow, blending, granulation, and compaction. Uncontrolled and unexpected properties can lead to product failures. Furthermore, failing to identify or select a right polymorphic form of a drug often causes a product susceptible to phase transformation and instability, resulting in deterioration in bioperformance, putting a patient in jeopardy and throwing a company into a market crisis.

Solid-state organic chemistry is an area where understanding and control of crystal properties of organic materials, including pharmaceutical substances, are carried out. Despite decades of efforts, the crystal growth mechanism is not clearly understood. In particular, how growth environment affects growth morphology and polymorphism remains to be solved.  On the other hand, a significant amount of experimental observations have been made about properties, analysis, preparation, and manufacture of polymorphic systems, especially drug crystals. Polymorph screening of a new drug becomes routine.

Polymorphism of organic crystals states that more than one packing motif of the same compound can exist in solid state, manifested by the variation in melting point, solubility, chemical stability and mechanical strength, just to name a few. Theoretical studies have been focused on thermodynamics and kinetics of crystal growth regarding polymorph formation, resulting in development of several widely-adopted phenomenological and thermodynamic rules (Ostwald rule, phase rule, density rule, etc.). The role of a solvent has been thought as a kinetic factor that may trap a metastable form of a crystal due to its higher solubility in the solvent. However, why a unique crystal structure is formed in a specific solvent remains unanswered, in particular, with regard to the nucleation in which solvent-solute interactions are believed to dictate the packing and conformation of solute molecules.

Crystal structure prediction (CSP) remains a grand challenge in chemistry.  Current prediction efforts rely on a brute-force manner to search all possible packing motifs of molecules in the energy space, unable to take into account the role of solvent-crystal interactions. Due to the limitation of energy models such as force fields to calculate molecular interactions, limited success has been achieved. The energy difference between the most stable form and a metastable form can be too small to be accurately calculated. Using QM (quantum mechanics) may be the only choice for energy evaluation, but how to cut down the number of guessed structures needs to be addressed otherwise computation of an energy space is merely overwhelming. It is even more challenging for organic crystals, where weak intermolecular interactions are dominant, susceptive to polymorphism. In lieu of searching endless combinations of molecules in a periodic pattern, we believe electronic structures of a solvent and crystal surfaces of the polymorph developed in the solvent should match, and therefore finding such matching patterns will produce new insights and inspire new prediction methods.

Growing different polymorphs of organic crystals in solvents has been widely reported. Few attempts, however, can be found in literature illustrating use of additives in nucleation of different forms. Additives do show the potential to stabilize one form over others in a solvent. Collective effects by solvent and additive make it difficult to elucidate and design additives to control polymorphs. Some of recent research reports are extremely intriguing, including using epitaxy, self-assemble monolayer, polymers, capillary and even laser to control crystal forms.

Understanding and controlling of polymorphism play a central role in molecular crystal engineering, which aims to design, synthesize, and characterize molecule-based materials with novel or enhanced properties. Fueled by recent interests in nanotechnology and supra-molecular chemistry, crystal engineering is attracting tremendous attentions from various fields. It is still embryonic, demanding much more fundamental studies. Current approaches based on designing synthons for a specific architecture lie in molecular shape and stereochemistry, not yet to take electronic properties into full account. Any attempt without considering the solvent and/or using additive may be limited.