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[资源] 从已知晶体结构设计多晶型产物

P.H. YOUNG, H.Y. ANDO
Analysis of Known Crystals to Design Polymorph Prediction Strategies
JOURNAL OF PHARMACEUTICAL SCIENCES, 2007. 96(5):1203-1236

Computational analysis of known crystals was used to provide insight into polymorph prediction strategies. It was hypothesized that intermolecular crystalline
interactions are inadequately accounted for in current computational strategies. TheQEq method of partial charge assignments was applied to the crystal milieu (CMc) and to the isolated molecule (IMc). For 90 known crystal structures, these two partial charging methods showed that the unit cell energy was almost always lower (more stable) with CMc partial charge assignments. In simulations on a model drug, the CMc charging reranked the unit cell energies of possible polymorphs in a way that aided the identification of physically reasonable packings more easily than IMc. Decomposing the unit cell energy for known crystals showed that the cohesive IMc deviation from CMc was dominant. On the other hand, for simulations, the corresponding IMc conformational component of unit cell energy dominates when conformational adaptive strategies (CA) are used; this was not apparent with rigid-body simulations (RB). Furthermore, evidence is presented that
polymorph strategies that use unit cell energy for optimizing are especially prone to this undesired conformational bias. Suggestions are made for polymorph strategies that might enhance the probability of identifying physically relevant polymorphs in
the future.

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