Many over-the-counter drug products lack official compendial analytical methods. As a result, the United States Pharmacopeia and the United States Food and Drug Administration are seeking to develop and validate new methods to establish analysis standards for the assessment of the pharmaceutical quality of over-the-counter drug products. Diphenhydramine and phenylephrine hydrochloride oral solution, a combination drug product, was identified as needing a compendial standard. Therefore, an ultra-high-performance liquid chromatography method was developed to separate and quantify the two drug compounds and eleven related organic impurities. As part of a robustness study, the separation was demonstrated using different highperformance liquid chromatography systems and columns from different manufacturers, and showed little dependence with changes in flow rate, column temperature, detection wavelength, injection volume and mobile phase gradient. The method was then validated conformant with the International Council for Harmonisation guidelines. For impurities, adequate specificity, linearity, accuracy and precision were demonstrated. For assay, a slight modification to the injection volume was necessary to achieve adequate analytical performance. With successful development and validation, these methods were shown to be suitable for their intended purpose and may be considered for adoption as compendial procedures.

The United States Pharmacopeia compendium does not currently contain a documentary standard for acetaminophen and diphenhydramine hydrochloride tablets to determine quality. To address this gap, high‐performance liquid chromatography methods for assay and impurities were developed and validated. Marketed products contain different amounts of drug substances per unit (325–500 mg of acetaminophen and 12.5–25 mg of diphenhydramine), so two methods specific to each substance were required. Methods were designed for high throughput by limiting analysis time, and complexity was reduced by utilizing similar materials and instrumental configurations across methods. For each method, specificity, linearity, accuracy, and precision were demonstrated for the assay and impurity determination. Both methods were shown to be fit‐for‐purpose and may be considered for adoption as United States Pharmacopeia compendial standards.