Department of Physics, University of Warwick, Coventry, CV4 7AL, UK.
Pfizer Worldwide R&D, Groton, CT, USA.
J Pharm Sci. 2023 Jul;112(7):1915-1928. doi: 10.1016/j.xphs.2023.02.022. Epub 2023 Mar 2.
Lorlatinib is an active pharmaceutical ingredient (API) used in the treatment of lung cancer. Here, an NMR crystallography analysis is presented whereby the single-crystal X-ray diffraction structure (CSD: 2205098) determination is complemented by multinuclear (H, C, /N, F) magic-angle spinning (MAS) solid-state NMR and gauge-including projector augmented wave (GIPAW) calculation of NMR chemical shifts. Lorlatinib crystallises in the P2 space group, with two distinct molecules in the asymmetric unit cell, Z' = 2. Three of the four NH hydrogen atoms form intermolecular hydrogen bonds, N30-H…N15 between the two distinct molecules and N30-H…O2 between two equivalent molecules. This is reflected in one of the NHH chemical shifts being significantly lower, 4.0 ppm compared to 7.0 ppm. Two-dimensional H-C, N-H and H (double-quantum, DQ)-H (single-quantum, SQ) MAS NMR spectra are presented. The H resonances are assigned and specific HH proximities corresponding to the observed DQ peaks are identified. The resolution enhancement at a H Larmor frequency of 1 GHz as compared to 500 or 600 MHz is demonstrated.
洛拉替尼是一种用于治疗肺癌的原料药（API）。在这里，我们进行了一项 NMR 晶体学分析，通过这项分析，我们对单晶 X 射线衍射结构（CSD：2205098）的测定进行了补充，还采用了多核（H、C、/N、F）魔角旋转（MAS）固态 NMR 和包括电测规在内的投影增强波（GIPAW）计算 NMR 化学位移。洛拉替尼结晶于 P2 空间群，在不对称单元胞中包含两个不同的分子，Z'=2。四个 NH 氢原子中的三个形成分子间氢键，两个不同分子之间的 N30-H…N15 和两个等效分子之间的 N30-H…O2。这反映在一个 NHH 化学位移显著降低，为 4.0 ppm，而另一个为 7.0 ppm。我们还呈现了二维 H-C、N-H 和 H（双量子，DQ）-H（单量子，SQ）MAS NMR 谱。对 H 共振进行了分配，并确定了与观察到的 DQ 峰相对应的特定 HH 近程。与 500 或 600 MHz 相比，在 1 GHz 的 H 拉莫尔频率下，分辨率得到了提高。
