Case Study on Regulatory Approaches for New Degradation Impurity Exceeding ICH Thresholds in Solubilized Ibuprofen Capsules During Stability Testing

The article discusses the identification, isolation, characterization, and toxicology study of a new degradation impurity found in stability samples of Ibuprofen soft gelatin capsules. An unknown impurity was detected during stability analysis, reaching 0.28% level, which prompted further investigation. A preparative method was developed to isolate the impurity quickly, followed by its identification and characterization using spectroscopic techniques. The impurity, named 2,3-dihydroxxypropyl 2-(4-isobutylphenyl)propanoate, was confirmed through various analyses, including HPLC, LC-MS, NMR, and FT-IR. Forced degradation studies suggested that the impurity formation might be due to the reaction of Ibuprofen with Glycerin present in the product. Toxicology studies were conducted to evaluate the safety of Ibuprofen with the impurity, concluding that it posed no significant toxicity concerns. Based on the findings, a specification limit of not more than 0.3% for the impurity was proposed, supported by justification from various studies and guidelines. To the best of our knowledge, this impurity has not been reported in pharmaceuticals elsewhere; it can be helpful in the pharmaceutical industry for regulatory considerations. This would enhance the pharmaceutical industry's perspectives on unknown impurities and knowledge of degradation impurities, which would positively impact pharmaceutical companies' approaches.