Insights into the Polymorphic Structures and Enantiotropic Layer-Slip Transition in Paracetamol Form III from Enhanced Molecular Dynamics
Insights into the Polymorphic Structures and Enantiotropic Layer-Slip Transition in Paracetamol Form III from Enhanced Molecular Dynamics
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DOI：
10.1021/acs.cgd.0c01250
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发表时间：
2021-01-05
影响因子：
3.8
通讯作者：
Tuckerman, Mark E.
中科院分区：
文献类型：
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作者：
Hong, Richard S.;Chan, Eric J.;Tuckerman, Mark E.
Y 可逆的温度介导的固相变化，也称为对映体转变，发生在许多分子晶体中。这些转变是由于在有限温度下通过熵贡献实现自由能稳定而发生的，并且通常会对结晶固体的性质产生重大影响。因此，理解和预测这些转变非常重要。在本研究中，我们利用分子模拟来阐明对乙酰氨基酚晶型 III（晶型 III-m 和 III-o）的斜方晶型和单斜晶型之间的对映异构层滑移相变背后的机制。除了晶体绝热自由能动力学（一种基于MD的晶体系统增强采样方法）之外，我们还使用标准分子动力学（MD）证明，从单斜晶型III-m到斜方晶型III-o的转变是由结构内的局部和动态无序驱动的，而不是完美的晶体到晶体的转变。这些结果表明，斜方晶型 III-o 结构并不作为具有完全对准层的完美斜方晶体存在，而是作为各种未对准层滑移结构的熵稳定的集体系综平均值而存在。总的来说，这些模拟方法明确地处理动态结构紊乱，使我们能够绘制出这种对映异构体随温度变化的自由能图景，并提取对转化潜在机制的关键见解。
Y Reversible temperature-mediated solid phase changes, otherwise known as enantiotropic transformations, occur in many molecular crystals. These transformations take place as a result of the free-energy stabilization through entropic contributions at finite temperatures and can often have significant implications for the properties of crystalline solids. As such, understanding and predicting these transformations is of great importance. In this study, we utilize molecular simulations to elucidate the mechanism behind the enantiotropic layer-slip phase transformation between the orthorhombic and monoclinic versions of paracetamol form III (form III-m and III-o). Using standard molecular dynamics (MD) in addition to crystal adiabatic free-energy dynamics, an MD-based enhanced sampling approach for crystalline systems, we demonstrate that the transformation from the monoclinic form III-m to the orthorhombic form III-o is driven by localized and dynamic disorder within the structure rather than a perfect crystal-to-crystal transition. These results suggest that the orthorhombic form III-o structure does not exist as a perfect orthorhombic crystal with fully aligned layers, but rather, as an entropy-stabilized collective ensemble average of various misaligned layer-slipped structures. Overall, these simulation approaches, which explicitly treat dynamic structural disorder, allowed us to map out the free-energy landscape of this enantiotropic transformation as a function of temperature and extract critical insights into the underlying mechanism of the transformation.