Zheng Zhaoxi, Su Yongchao, Schmidt-Rohr Klaus
Department of Chemistry, Brandeis University, Waltham, Massachusetts, USA.
Analytical Research and Development, Merck & Co., Inc., Rahway, New Jersey, USA.
Magn Reson Chem. 2023 Nov;61(11):595-605. doi: 10.1002/mrc.5390. Epub 2023 Aug 30.
Hydroxypropyl methylcellulose acetyl succinate (HPMCAS) is widely used as a pharmaceutical excipient, making a detailed understanding of its tunable structure important for formulation design. Several recently reported peak assignments in the solid-state C NMR spectrum of HPMCAS have been corrected here using peak integrals in quantitative spectra, spectral editing, empirical chemical-shift predictions based on solution NMR, and full spectrum simulation analogous to deconvolution. Unlike in cellulose, the strong peak at 84 ppm must be assigned to C2 and C3 methyl ethers, instead of regular C4 of cellulose. The proposed assignment of signals at <65 ppm to OCH sites, including C5 of cellulose, could not be confirmed. CH spectral editing showed two resolved OCH bands, a more intense one from O-CH ethers of C6 at >69 ppm and a smaller one from its esters and possibly residual CH -OH groups, near 63 ppm. The strong intensities of resolved signals of acetyl, succinoyl, and oxypropyl substituents indicated the substitution of >85% of the OH groups in HPMCAS. The side-group concentrations in three different grades of HPMCAS were quantified.
羟丙基甲基纤维素乙酰琥珀酸酯（HPMCAS）作为一种药用辅料被广泛使用，因此详细了解其可调节结构对于制剂设计很重要。本文利用定量光谱中的峰积分、光谱编辑、基于溶液核磁共振的经验化学位移预测以及类似于去卷积的全谱模拟，对最近报道的HPMCAS固态碳核磁共振谱中的几个峰归属进行了校正。与纤维素不同，84 ppm处的强峰必须归属于C2和C3甲基醚，而不是纤维素的常规C4。将<65 ppm处的信号归属于包括纤维素C5在内的OCH位点这一建议无法得到证实。碳氢光谱编辑显示出两个分辨出的OCH谱带，一个较强的谱带来自C6的O-CH醚，在>69 ppm处，另一个较小的谱带来自其酯以及可能的残留CH-OH基团，在63 ppm附近。乙酰基、琥珀酰基和羟丙基取代基的分辨信号强度很强，表明HPMCAS中>85%的羟基被取代。对三种不同等级的HPMCAS中的侧基浓度进行了定量。
