For assurance of the quality of active pharmaceutical ingredients (APIs) used for manufacturing medicines, the analytical requirements of the European Pharmacopoeia serve as a guideline and have a binding character. Within a particular timeframe, an API is considered to comply with predefined specifications. If applicable, it can be used for the manufacturing of a finished pharmaceutical product. The objective of the study presented here was to assess the long-term stability of 50 drug substances with an age of 20-30years or even older in some cases. The substances are part of a collection of old pharmaceuticals at the Institute for Pharmacy in Würzburg, Germany, and represent commonly used drug classes containing β-blockers, β-sympathomimetic drugs, anticholinergics, anti-infectives, non-steroidal anti-inflammatory drugs, antipsychotics, antihistaminic drugs, and one antiarrhythmic drug. The content and the degradation profile of the items were determined by means of potentiometric titration and liquid chromatography techniques based on pharmacopoeial approaches for impurity profiling covering all process and degradation related substances. The results of the study show that 44 out of 49 tested substances still complied with specifications of the current pharmacopoeias. For metipranolol, which is not monographed in any pharmacopoeia, a small degradation by hydrolysis was observed. In one lot of ampicillin sodium, atenolol, atropine, penbutolol, and salbutamol, at least one impurity did not meet the acceptance criteria, respectively. Some impurities were not related to degradation. However, a surprisingly high chemical stability of the old drug substances was revealed after more than two decades of storage.