Stability study of hard gelatin capsules containing retinoic acid

Retinoic acid (RA) is employed in the therapeutic treatment of acute promyelocytic leukemia (APL). In this paper, the chemical stability and the most favorable storage conditions of RA in hard gelatin capsules containing alpha-lactose monohydrate, used in clinical experimentation, are reported. A secondary goal of this work was to show the usefulness of a robust regression technique, repeated median with replicates (RMWR) in a solid-state shelf life prediction by accelerated studies. The capsules were stored at room temperature and in the freezer. Their residual RA content was assayed for more than 3 years. RA chemical degradation was monitored by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) stability-indicating methods previously validated and able to detect various potential degradation products. Possible physical modifications were checked by dissolution tests and differential scanning calorimetry (DSC) of the content of the capsules. The shelf life was also predicted by an accelerated isothermal method to confirm room temperature results, and the activation energy estimated through this study was 12.5 +/- 1.1 kcal/mol (95% confidence interval). In the conditions of climatic zone II, the shelf life for the capsules stored at room temperature in light-resistant containers was equal to 678 days, while the capsules stored in the freezer retained the initial content of drug after 1289 days. From the results gathered in this study, the usefulness of RMWR for shelf life prediction in the presence of outliers is evident.