Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine
Exploring the Experimental and Computed Crystal Energy Landscape of Olanzapine
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DOI：
10.1021/cg301826s
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发表时间：
2013-04-01
影响因子：
3.8
通讯作者：
Florence, Alastair J.
中科院分区：
文献类型：
--
作者：
Bhardwaj, Rajni M.;Price, Louise S.;Florence, Alastair J.
对抗精神病化合物奥氮平的固体形式进行了广泛的实验研究，确定了60种不同的固体形式，包括三种非溶剂化多晶型物，56种结晶溶剂化物和一种无定形相。含有奥氮平的35个实验晶体结构（30个来自本研究，5个来自CSD）的XPac分析表明，它们含有特定的分散结合二聚体结构，该结构可以采用各种排列并容纳不同的溶剂，以产生具有与晶型I相似的中等填充效率的结构。晶体能量图证实奥氮平无法以超过70%的效率进行包装，解释了溶剂在稳定溶剂化物结构中的作用，并确定了一种假设的结构类型，该类型为无法分别获得亚稳态II型和III型提供了解释。计算发现，不包含观察到的二聚体的结构在热力学上是可行的，这表明动力学效应是所有观察到的基于二聚体的结构的原因。因此，这种广泛的筛选可能没有发现奥氮平的所有可能的物理形式，并且可以通过更好地理解动力学在其结晶中的作用来进一步确定形式多样性。
An extensive experimental search for solid forms of the antipsychotic compound olanzapine identified 60 distinct solid forms including three nonsolvated polymorphs, 56 crystalline solvates, and an amorphous phase. XPac analysis of the 35 experimental crystal structures (30 from this work and 5 from the CSD) containing olanzapine show that they contain a specific, dispersion-bound, dimer structure which can adopt various arrangements and accommodate diverse solvents to produce structures with a similar moderate packing efficiency to form I. The crystal energy landscape confirms the inability of olanzapine to pack with an efficiency of more than 70%, explains the role of solvent in stabilizing the solvate structures, and identifies a hypothetical structural type that offers an explanation for the inability to obtain the metastable forms II and III separately. The calculations find that structures that do not contain the observed dimer are thermodynamically feasible, suggesting that kinetic effects are responsible for all the observed structures being based on the dimer. Thus, this extensive screen probably has not found all possible physical forms of olanzapine, and further form diversity could be targeted with a better understanding of the role of kinetics in its crystallization.