Abstract <p>The article focuses on the extraction of low-concentration drugs from their matrix. It is always challenging to extract and detect them with the desired selectivity and sensitivity during analytical method development for low-concentration drugs. Solid-phase extraction (<b>SPE</b>) stands as a cornerstone technique in analytical chemistry, enabling the selective extraction and purification of target compounds from complex polymer matrix mixtures. Its versatility and efficiency have made it indispensable in various fields, including pharmaceuticals, biopharmaceuticals environmental analysis, food safety, and forensic science. This article delves into the fundamentals of SPE, its techniques, and diverse applications in analytical chemistry. The study was performed on a novel dose-similar formulation for levothyroxine sodium extended-release tablets across its dose range. The extraction of levothyroxine sodium became a challenge here for analytical testing due to the active-to-excipient ratio being approximately 1 : 52000 for the lower strength. The study covers a newer concept of extraction, purification, and analysis of levothyroxine sodium using solid-phase extraction.</p>