Stability study of hard gelatin capsules containing retinoic acid

Retinoic acid (RA) is employed in the therapeutic treatment of acute promye locytic leukemia (APL). In this paper, the chemical stability and the most favorable storage conditions of RA in hard gelatin capsules containing alph a-lactose monohydrate, used in clinical experimentation, are reported. A se condary goal of this work was to show the usefulness of a robust regression technique, repeated median with replicates (RMWR) in a solid-state shelf l ife prediction by accelerated studies. The capsules were stored at room tem perature and in the freezer. Their residual RA content was assayed for more than 3 years. RA chemical degradation was monitored by high performance li quid chromatography (HPLC) and thin-layer chromatography (TLC) stability-in dicating methods previously validated and able to detect various potential degradation products. Possible physical modifications were checked by disso lution rests and differential scanning calorimetry (DSC) of the content of the capsules. The shelf life was also predicted by an accelerated isotherma l method to confirm room temperature results, and the activation energy est imated through this study was 12.5 +/- 1.1 kcal/mol (95% confidence interva l). 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 d ays, while the capsules stored in the freezer retained the initial content of drug after 1289 days. From the results gathered in this study, the usefu lness of RMWR for shelf life prediction in the presence of outliers is evid ent.