(M1330-07-44) Patient In-Use Stability of FDA-Approved Delayed-Release Products of Divalproex

Purpose: Divalproex Sodium (DVS) is a long-known antiseizure drug commercially marketed in two delayed-release (DR) forms available from multiple generic sources. DR forms help minimize the gastrointestinal side effects through gastric resistant film coating provided that they remain intact through their use. This is important to enhance drug tolerability and to ensure continuity of treatment. DR-DVS is administered 1-4 times a day, and thus, the pill vial is usually carried along with the patients and is exposed to fluctuations in temperature and humidity

Methods: Five DR tablet products (T-A to T-E) and four DR capsules (sprinkles; C-A to C-D) products were re-packed in amber pill vials with child-resistant caps and stored at 30^oC/75% RH for 1, 2 and 3 months mimicking the multi-months dispensing in pharmacies. In-vitro acid and buffer stages- dissolution was carried out at each time point. Other tests including visual inspection for integrity, surface morphology (scanning electron microscopy), near infrared chemical imaging, and X-ray powder diffraction (XRPD) were also performed to assess changes in physical attributes.

Results: For tablet products, visual signs of damage of the coating layer were observed in the form of stickiness, wrinkling, appearance of pits, and massive rupture (Fig. 1a). On the other hand, none of the capsules showed damage externally, however, the sprinkles inside formed a sticky mass upon storage (Fig. 2a). Dissolution testing was performed initially and at each time point (Fig 1c & 2b). Tablets with visible damage were excluded from dissolution testing and considered as failing specifications. Interestingly, the similarity (f2) and difference (f1) factors showed that all generic tablets were similar initially except for product T-E. After storage all products behaved differently, and none scored well with respect to f1 and f2. DR Capsules were all dissimilar initially (Table 2). NIR chemical imaging indicated compositional changes during storage. Other physical changes were observed in the solid state of the drug captured by XRPD.

Conclusion: The findings of this study explain in part the recalls due to failing dissolution. They also raise concerns about the bioequivalence and safety of DR-DVS during patients’ use. DVS as a narrow therapeutic index drug may require attention to its dispensing regulations.

References: Dharani, S., et al. In-use stability assessment of FDA approved metformin immediate release and extended release products for N-Nitrosodimethylamine and dissolution quality attributes. Int J Pharm 623, 121923 (2022).
2. Dharani, S., Mohamed, E.M., Rahman, Z. & Khan, M.A. Patient In-Use Stability Testing of FDA-Approved Metformin Combination Products for N-Nitrosamine Impurity. AAPS PharmSciTech 25, 19 (2024).


Quality attributes of DR-DVS tablets initially and after storage at in patient’s use conditions. (a) Tablets stored in pharmacy pill amber-colored vials for 1, 2 and 3 months. (b) Drug Release in acid medium (pH 1.2) after 1 h. (c) Dissolution profile in buffer phase (pH 7.5).


Quality attributes of DR-DVS capsules initially and after storage at in patient’s use conditions. (a) Capsules stored in pharmacy pill amber-colored vials for 1, 2 and 3 months. (b) Dissolution profile in buffer phase (pH 7.5) up to 8 h.