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Many active pharmaceutical ingredients exhibit a needle-like (acicular) crystal habit, which can significantly complicate their downstream processing. In this study, the acicular crystal habit of a model active pharmaceutical ingredient, 5-aminosalicylic acid (5-ASA), was modified by addition of selected organic solvents to the typical aqueous crystallization process. 5-ASA was crystallized by a pH shift from 7.5-8 to 4 in the presence of methanol, acetonitrile, acetone, tetramethylurea, tetrahydrofuran or dimethyl sulfoxide at 25% v/v, or butanol at 9% v/v. Changes to the experimentally observed crystal habit are rationalized by considering adsorption energy calculations for the solvent molecules onto the morphologically important crystal faces. The crystal habit was influenced most significantly by organic solvents containing a good H-bond acceptor atom, particularly oxygen in acetone, tetramethylurea, tetrahydrofuran, and dimethyl sulfoxide. Such solvents have strongly stabilizing adsorption energies onto the fast-growing crystal faces, and their presence in solution thereby serves to modify the acicular habit of 5-ASA. The developed knowledge base on crystal interface-solvent interactions can form a basis for further engineering of an optimal crystal habit for 5-ASA., (Copyright © 2018. Published by Elsevier Inc.)

High-throughput crystallisation and characterisation platforms provide an efficient means to carry out solid-form screening during the pre-formulation phase. To determine the crystal structures of identified new solid phases, however, usually requires independent crystallisation trials to produce single crystals or bulk samples of sufficient quantity to carry out high-quality X-ray diffraction measurements. This process could be made more efficient by a robust procedure for crystal structure determination directly from high-throughput X-ray powder diffraction (XRPD) data. Quantum-chemical calculations based on dispersion-corrected density functional theory (DFT-D) have now become feasible for typical small organic molecules used as active pharmaceutical ingredients. We demonstrate how these calculations can be applied to complement high-throughput XRPD data by determining the crystal structure of piroxicam form III. These combined experimental/quantum-chemical methods can provide access to reliable structural information in the course of an intensive experimentally based solid-form screening activity or in other circumstances wherein single crystals might never be viable, for example, for polymorphs obtained only during high-energy processing such as spray drying or milling., (Copyright © 2012 Wiley Periodicals, Inc.)