Patients in-use stability and safety of repacked delayed-release capsules of sodium divalproex

Divalproex Sodium (DVS) is an antiseizure narrow therapeutic index drug. Despite its effectiveness, the primary reason for reduced compliance and/or treatment discontinuation is intolerance to its gastric side effects. Delayed-release forms to alleviate gastric side effects are available as enteric coated beads (sprinkles) in capsules. Four sprinkles (A-D), marketed as interchangeable, were compared and assessed for quality changes after storage at 30 °C/75%RH in pharmacy vials, and at 40 °C/75% RH and 25 °C/60% RH in HDPE bottles for 3 months. The results revealed that initially, all products differed in their gastric resistance releasing from 3.8 to 39% of the drug. Gastric delivery further increased significantly after storage at higher temperatures to 35-45% among all products. Release also varied initially in buffer medium, especially at 1 h (12.6 ± 1.1, 65.8 ± 0.2, 0.0 ± 0.0 and 10.8 ± 0.3% for products A, B, C and D, respectively), reflecting a controlled release pattern over 4-6 h in three products. Following storage, the drug release increased at all conditions. The capsules parts adhered together, and beads fused into coherent masses in response to environmental changes. The FTIR spectra showed chemical changes in the beads. Overall, the results indicated significant variability among the tested products that could lead to significant side effects, unpredictability in drug absorption and serum level fluctuations, altogether culminating in seizures remittance. The study highlights the pharmaceutical quality as a critical, yet overlooked, player in improving patients' compliance and therapeutic outcomes. Moreover, it draws attention to the importance of reviewing dispensing and storage recommendations for this drug.