Molecular Dynamics Electric Field Crystallization Simulations of Paracetamol Produce a New Polymorph,Crystal Growth & Design

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Molecular Dynamics Electric Field Crystallization Simulations of Paracetamol Produce a New Polymorph
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2017-06-07 00:00:00 , DOI: 10.1021/acs.cgd.7b00356
Conor Parks ₁ , Andy Koswara ₁ , Hsien-Hsin Tung ₂ , Nandkishor Nere ₂ , Shailendra Bordawekar ₂ , Zoltan K. Nagy ₁ , Doraiswami Ramkrishna ₁

Affiliation

Using molecular dynamics simulations, we demonstrate the ability of high intensity, 1.5 V/nm, static electric fields to induce the formation of a new polymorph of paracetamol, one of the most important fever and pain suppressants in the world. In the newly produced polymorphic form, paracetamol molecules adopt a spatial orientation that maximizes the alignment between the electric dipole and the applied electric field vector. As the properties of crystalline materials are ultimately determined by the conformational and packing patterns of molecules in the solid state, it is predicted that electric fields have the potential to spur the creation of never before seen materials with potential novel properties such as increased drug efficacy in vivo. Paracetamol nanocrystal growth and dissolution dynamics are systematically investigated as a function of the applied electric field intensity and temperature. It is shown that the electric field suppresses the growth rate of supersaturated paracetamol nanocrystals, and can both increase and inhibit the dissolution rates of undersaturated paracetamol nanocrystals. This shows that molecular dynamics predicts that electric fields are a useful control variable for the manipulation of crystal size distributions and crystallization dynamics. Analysis of the crystal morphology under the presence of the electric field shows that paracetamol nanocrystals adopt an electric field intensity dependent morphology. Finally, the new polymorph is shown to be metastable in the absence of the electric field with increased aqueous solubility and hence potentially bioavailability relative to form I and II. The new form is stabilized at short times through a temperature quench, but requires longer application of the electric field to maintain the new polymorph during crystallization.

中文翻译：

扑热息痛的分子动力学电场结晶模拟产生新的多晶型物

使用分子动力学模拟，我们证明了高强度，1.5 V / nm的静电场具有诱导对乙酰氨基酚新多晶型物形成的能力，对乙酰氨基酚是世界上最重要的发烧和止痛药之一。在新产生的多晶型物形式中，扑热息痛分子采用的空间取向可使电偶极子与施加的电场矢量之间的排列最大化。由于晶体材料的性质最终取决于固态分子的构象和堆积模式，因此可以预测，电场有可能刺激产生从未见过的材料，这些材料具有潜在的新特性，例如增加药物的药效。体内。系统地研究了扑热息痛纳米晶体的生长和溶解动力学随施加的电场强度和温度的变化。结果表明，电场抑制了过饱和对乙酰氨基酚纳米晶体的生长速率，并且可以增加和抑制过饱和对乙酰氨基酚纳米晶体的溶解速率。这表明分子动力学预测电场是控制晶体尺寸分布和结晶动力学的有用控制变量。在电场存在下的晶体形态分析表明，扑热息痛纳米晶体采用电场强度依赖性形态。最后，新的多晶型物在不存在电场的情况下显示为亚稳态，具有增加的水溶性，因此相对于形式I和II具有潜在的生物利用度。新的形式通过温度骤冷在短时间内稳定下来，但是需要更长的电场施加时间才能在结晶过程中保持新的多晶型物。

更新日期：2017-06-07

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