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首页> 外文期刊>Crystal growth & design >Experimental and Mechanistic Study of the Heterogeneous Nucleation and Epitaxy of Acetaminophen with Biocompatible Crystalline Substrates
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Experimental and Mechanistic Study of the Heterogeneous Nucleation and Epitaxy of Acetaminophen with Biocompatible Crystalline Substrates

机译：生物相容性结晶衬底的异质成核乙酰苯甲酰乙酰苯甲酸外延的实验与机械研究

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The presence of different heterogeneous surfaces can directly influence the nucleation kinetics, crystal growth, and morphology of active pharmaceutical ingredients (APIs). However, a mechanistic understanding of heterogeneous nucleation remains lacking. Herein,, we report the use of biocompatible crystalline heterogeneous surfaces to enhance the nucleation rates of the model API compound acetaminophen (APAP). We also report experimental and computational studies of the epitaxial growth mechanism of APAP On different substrates. Five crystalline substrates, namely, D galactose (DGAL), the alpha and beta forms of D-mannitol (DMAN), alpha-lactose monohydrate (LMH), and xylitol (XYL) were selected because they contain a similar functionality: a high density of hydroxyl groups per molecule. We measured the induction-times in the presence of the substrates and used the results to rank the substrates based on their ability to enhance the nucleation of APAP. While all selected substrates enhanced the nucleation rates, XYL was particularly effective and enhanced the nucleation rate by a factor of 10 (average induction time: 85 min) relative to bulk nucleation (average induction time: 885 min). To determine the mechanism underbiing the enhanced heterogeneous nucleation, we analyzed grown crystals using single crystal X-ray diffraction (SCXRD) and developed computational models of APAP substrate interactions. Previously developed computational techniques, which are based solely on the level of lattice matching (geometric term) and ignore the importance of chemical interactions (energy term) between the crystallizing API and the substrate, were not effective in predicting and explaining our experimental results. Herein, we present a novel computational method that contains both energy and geometry terms to describe the nucleation of APAP on different crystalline substrates. First, we studied the energetics of the association of a single APAP molecule and a substrate. We found that an increase in the association energy is related to an increase in the effectiveness of the substrate for enhancing the nucleation rate. We next developed a method based on molecular dynamics (MD) simulations of the interaction between the different crystal faces of APAP and the substrates. The method predicted the epitaxial growth of the crystal face (001)(APAP) on top of the selected substrates based on strong hydrogen bond interactions with the substrates. The growth of the crystal face (001)(APAP) was confirmed by SCXRD.
机译：不同的异质表面的存在可以直接影响活性药物成分（API）的成核动力学，晶体生长和形态。然而，对异质成核的机械理解仍然缺乏。在此，我们报告使用生物相容性结晶异质表面，以增强模型API化合物乙酰氨基酚（APAP）的成核速率。我们还报告了对不同底物上APAP外延生长机制的实验和计算研究。选择五种结晶底物，即D半乳糖（DGAL），D-甘露醇（DMAN），α-乳糖一水合物（LMH）和木糖醇（XEL）的α和β形成，因为它们含有类似的功能：高密度每分子的羟基。我们在底物存在下测量诱导时间，并使用结果基于其增强APAP成核的能力来对基材进行排序。虽然所有选定的基质增强了成核速率，但Xyl特别有效，相对于散装成核（平均诱导时间：885min），Xyl特别有效并增强了10倍（平均诱导时间：85分钟）。为了确定抑制增强的异构成核的机制，我们使用单晶X射线衍射（SCXRD）分析生长的晶体，并开发了APAP衬底相互作用的计算模型。以前开发的计算技术仅基于格子匹配（几何术语）的水平并忽略结晶API和衬底之间的化学相互作用（能量术语）的重要性，在预测和解释我们的实验结果方面无效。这里，我们提出了一种新的计算方法，其包含能量和几何术语来描述APAP对不同结晶基质上的核心。首先，我们研究了单个APAP分子和基材的关联的能量。我们发现，关联能量的增加与基材的有效性的增加有关，以提高成核速率。接下来，我们开发了一种基于APAP和基板的不同晶面之间的分子动力学（MD）模拟的方法。该方法基于与基材的强氢键相互作用，预测晶体面（001）（APAP）的外延生长在所选基板的顶部。 SCXRD证实了晶体面（001）（APAP）的生长。

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