Successful Computationally Directed Templating of Metastable Pharmaceutical Polymorphs
Successful Computationally Directed Templating of Metastable Pharmaceutical Polymorphs
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DOI：
10.1021/acs.cgd.8b00765
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发表时间：
2018-09-01
影响因子：
3.8
通讯作者：
Price, Sarah L.
中科院分区：
文献类型：
--
作者：
Case, David H.;Srirambhatla, Vijay K.;Price, Sarah L.
一种利用晶体结构预测（CSP）方法来确定哪个同型结构模板可以通过气相沉积促进预测的多晶的首次结晶的策略被扩展到fenamate家族。甲苯胺酸（MFA）和甲苯苯胺酸（TFA）被用作具有最小化学差异的分子，而氟芬那酸（FFA）在取代基上显示出更大的差异。计算了三种晶体的能量格局，并利用周期电子结构计算来证实可能的同工结构多晶与实验中获得的其他分子晶体的热力学合理性。正如预测的那样，一种新的多晶，TFA形式VI，被升华到同构MFA形式I上，使用最近开发的技术。MFA和TFA形成连续的固溶体，极限结构为MFA I和TFA VI，但同构的MFA/FFA固溶体并没有扩展为新的FFA多晶。发现了TFA和FFA的新型固溶体结构，并将其升华到新的固溶体模板上，得到了新的同构多晶TFA VII。在沉积的早期阶段，将TFA升华到金属表面，得到形式为VIII的TFA。我们合理化了仅TFA新多晶的形成。
A strategy of using crystal structure prediction (CSP) methods to determine which, if any, isostructural template could facilitate the first crystallization of a predicted polymorph by vapor deposition is extended to the fenamate family. Mefenamic acid (MFA) and tolfenamic acid (TFA) are used as molecules with minimal chemical differences, whereas flufenamic acid (FFA) shows greater differences in the substituents. The three crystal energy landscapes were calculated, and periodic electronic structure calculations were used to confirm the thermodynamic plausibility of possible isostructural polymorphs to experimentally obtainable crystals of the other molecules. As predicted, a new polymorph, TFA form VI, was found by sublimation onto isomorphous MFA form I, using a recently developed technique. MFA and TFA form a continuous solid solution with the structure of MFA I and TFA VI at the limits, but the isomorphous MFA/FFA solid solution does not extended to a new polymorph of FFA. The novel solid solution structure of TFA and FFA was found, and a new isomorphous polymorph TFA VII was found by sublimation onto this new solid solution template. Sublimation of TFA onto a metal surface at the early stage of deposition gave TFA form VIII. We rationalize the formation of new polymorphs of only TFA.