Thermal Expansion of Organic Crystals and Precision of Calculated Crystal Density: A Survey of Cambridge Crystal Database

ABSTRACTTrue density is a physical property of both fundamental and practical importance to the study of pharmaceutical powders. True density may be calculated from crystal structure. However, precision of such calculated density is not well understood. Furthermore, thermal expansion properties of organic crystals have rarely been characterized. A survey of Cambridge Crystal Database is conducted to assess (1) precision of calculated crystal density from crystal structure; (2) thermal expansion properties of organic crystals. It is shown that calculated crystal density exhibits, on average, a relative standard deviation (RSD) of ~0.4%. It is found that crystal density generally increases linearly with decreasing temperature provided no phase change occurs. Slope of the line, termed thermal density gradient, of organic crystals ranges between 0.04 and 1.74 mg cm−3 K−1 with an average of ~0.2 mg cm−3 K−1. It is shown that majority polymorph pairs exhibit significantly different thermal expansion behavior and their density—temperature lines can cross. This likely contributes to the less than perfect prediction of relative stability of polymorphs at ambient temperature using the density rule.