Determination of Ethoxy Content in Ethylcellulose via Relative Quantitative 1 H NMR Spectroscopy

ABSTRACT The research team established a quantitative 1 H NMR method to determine the relative ethoxy content ( EO %) in ethylcellulose using a CDCl 3 /TFA‐d solvent mixture. High‐field NMR spectroscopy enabled direct measurement without the use of internal or external calibrants by integrating the methyl proton signals (δ 1.15 ppm) and the methylene/methine proton signals (δ 2.5–5.5 ppm), and using their equivalent 1 H numbers and corresponding mass fractions for calculations. The EO % was calculated as: EO % = × 100, where r = (I A methyl 1 Hs integral; Iᴃ methylene/methine 1 Hs integral). Round robin multi‐laboratory validation testing showed that the qNMR results deviated by less than 3% from the certificate of analysis (COA) values (44%–51%). The COA values, derived using the pharmacopeial gas chromatography‐flame ionization detection (GC‐FID) method, may be affected by factors related to incomplete derivatization and the volatility and instability of the product (iodoethane) and the inert internal reference standard (n‐octane). Therefore, the qNMR method with its operational simplicity, reduced chemical hazards, and robust performance presents an alternative for quality control of pharmaceutical‐grade ethylcellulose.