Atomic-level characterization of active pharmaceutical ingredients (API) is crucial in pharmaceutical industry because APIs play an important role in physicochemical properties of drug formulations. However, the analysis of targeted APIs in intact tablet formulations is less straightforward due to the coexistence of excipients as major components and different APIs at dilute concentrations (often below 10 ​wt% loading). Although solid-state (ss) NMR spectroscopy is widely used to investigate short-range order, polymorphism, and pseudo-polymorphism in neat pharmaceutical compounds, the analysis of complex drug formulations is often limited by overlapped signals that originate from structurally different APIs and excipients. In particular, such examples are frequently encountered in the analysis of ¹H ssNMR spectra of pharmaceutical formulations. While the high-resolution in ¹H ssNMR spectra can be attained by, for example, high magnetic fields accompanied by fast magic-angle spinning (MAS) approaches, the spectral complexity associated with the mixtures of compounds hinders the accurate determination of chemical shifts and through-space proximities. Here we propose a fast MAS (70 ​kHz) NMR experiment for the selective detection of ¹H signals associated with an API from a severely overlapped NMR spectrum of a tablet formulation. Spectral simplification is achieved by combining (i) symmetry-based dipolar recoupling ($\text{SR}{4}_1^2$) rotational-echo saturation-pulse double-resonance (RESPDOR) with phase-modulate (PM) saturation pulses, (ii) radio frequency-driven recoupling (RFDR), and (iii) double-quantum excitation using Back-to-Back (BaBa) pulse sequence elements. First, ¹H sites in close proximities to ¹⁴N nuclei of an API are excited using a PM-S-RESPDOR sequence, and simultaneously, the other unwanted ¹H signals of excipients are suppressed. Then, ¹H magnetization transfer to adjacent ¹H sites in the API is achieved by spin diffusion process using a RFDR sequence, which polarizes to ¹H sites within the crystalline API regions of the drug formulation. Next, a PM-S-RESPDOR-RFDR sequence is combined with a Back-to-Back (BaBa) sequence to elucidate local-structures and ¹H–¹H proximities of the API in a dosage form. The PM-S-RESPDOR-RFDR-BaBa experiment is employed in one- (1D) and two-dimensional (2D) versions to selectively detect the ¹H ssNMR spectrum of l-cysteine (10.6 ​wt% or 0.11 ​mg) in a commercial formulation, and compared with the spectra of neat l-cysteine recorded using a standard BaBa experiment. The 2D ¹H double-quantum−single-quantum (DQ-SQ) spectrum of the API (l-cysteine)-detected pharmaceutical tablet is in good agreement with the 2D ¹H DQ-SQ spectrum obtained from the pure API molecule. Furthermore, the sensitivity and robustness of the experiment is examined by selectively detecting ¹H{¹⁴N} signals in an amino acid salt, l-histidine^.H₂O^.HCl.

活性药物成分（API）的原子级表征在制药行业中至关重要，因为API在药物制剂的理化特性中起着重要作用。但是，由于赋形剂作为主要成分和不同的API在稀释浓度下（通常低于10重量％载量）并存，因此完整片剂中靶向API的分析不太直接。尽管固态（ss）NMR光谱已广泛用于研究纯药物化合物的短程顺序，多态性和假多态性，但复杂药物制剂的分析通常受限于来自结构不同的API和赋形剂的重叠信号。特别是在分析^1时经常遇到这样的例子药物制剂的HssNMR光谱。虽然¹ H ssNMR光谱的高分辨率可以通过例如高磁场伴随快速魔角旋转（MAS）方法获得，但与化合物混合物相关的光谱复杂性阻碍了化学位移和化学位移的准确测定。穿越空间。在这里，我们提出了一种快速MAS（70 kHz）NMR实验，用于从片剂制剂的严重重叠NMR光谱中选择性检测与API相关的¹ H信号。通过组合（i）基于对称性的偶极重新耦合（$\text{SR}{4}_{\mathrm{1个}}^2$）具有相位调制（PM）饱和脉冲的旋转回波饱和脉冲双共振（RESPDOR），（ii）射频驱动的再耦合（RFDR）和（iii）使用背对背（-）的双量子激发（ BaBa）脉冲序列元素。首先，使用PM-S-RESPDOR序列激发接近API ¹⁴ N核的¹ H位点，同时抑制其他不希望的赋形剂¹ H信号。然后，通过使用RFDR序列的自旋扩散过程实现¹ H磁化转移到API中的相邻¹ H位置，该过程极化为¹药物制剂的结晶API区域内的H位点。接下来，将PM-S-RESPDOR-RFDR序列与背对背（BaBa）序列结合以阐明剂型中API的局部结构和¹ H – ¹ H邻近度。PM-S-RESPDOR-RFDR-BaBa实验用于一维（1D）和二维（2D）版本中，以选择性检测1-半胱氨酸的¹ H ssNMR光谱（10.6 wt％或0.11 mg）。商购制剂，并与使用标准BaBa实验记录的纯净的1-半胱氨酸光谱进行比较。API的2D ¹ H双量子-单量子（DQ-SQ）光谱（l-半胱氨酸）检测的药物片剂与从纯API分子获得的2D ¹ H DQ-SQ光谱非常吻合。此外，通过选择性检测氨基酸盐1-组氨酸中的¹ H { ¹⁴ N}信号来检验实验的灵敏度和鲁棒性^。^ h ₂ Ø ^。盐酸。