ABSTRACT
Crystallization is essentially a molecular recognition process occurring on a grand scale that allows separation and purication of the desired compound to produce high-purity products. The ways in which a molecule is packed in the crystal structure depends on the balance of the intermolecular interactions that it can achieve for a given conformation (Price 2009). Variations in the molecular packing arrangement in the crystal structure of a drug (polymorphic forms) can directly inuence its physical properties such as dissolution rate and stability (Bernstein 2002; Datta and Grant 2004). It is therefore important to understand the relationship between the crystal structure of a drug and the properties of pharmaceutical solids. This will allow for selection of the most suitable crystal form for development into a drug product. Crystal growth morphology (i.e., shape or habit) of crystalline drugs can inuence fundamental properties of the material such as rate of dissolution,
5.1 Introduction .......................................................................................................................... 157 5.2 Intermolecular Interactions in the Crystalline Solid-State .................................................. 158 5.3 Crystal Structure Prediction ................................................................................................. 160
5.3.1 Methodology ............................................................................................................. 160 5.3.2 Conformational Mapping ........................................................................................ 160 5.3.3 Crystal Energy Landscapes ...................................................................................... 162 5.3.4 Entropic and Kinetic Factors ................................................................................... 163 5.3.5 Crystal Structure Solution from Powder X-Ray Diffraction Data............................ 165 5.3.6 Predicting the Formation of Co-crystals ................................................................. 166
5.4 Modeling Crystal Growth Morphology ................................................................................ 167 5.4.1 The Bravais-Friedel-Donnay-Harker Rule and Attachment Energy Models ......... 167 5.4.2 The Effect of Solvent ................................................................................................ 169 5.4.3 The Effect of Supersaturation ................................................................................... 171
5.5 Modeling the Effect of Impurities and Additives on Crystallization ................................... 172 5.5.1 Impurity Interactions at the Crystal Surface ........................................................... 173 5.5.2 Binding Energy Calculations .................................................................................... 175
5.6 Applications in Formulation ................................................................................................ 179 5.6.1 Surface Properties of Pharmaceutical Materials ..................................................... 180 5.6.2 Stabilization of Crystalline Drug Nanosuspensions ................................................. 180
5.7 Concluding Remarks ............................................................................................................ 181 References ...................................................................................................................................... 182
wettability, and compressibility (Yu and York 2000). Crystal shape is also critical to downstream processing of solid drugs, including ltration, drying, particle ow, and milling (Davey and Garside 2000; Wood 2001). The extent of expression of different crystal planes, and therefore functional groups, has been attributed to the dependence of these pharmaceutical properties on crystal growth morphology (Danesh et al. 2000; Heng and Williams 2006).
