(T1130-10-59) Quality Assessment of Four FDA-Approved Extended-Release Products of Divalproex

Purpose: Seizures remission have been reported in epileptic patients upon switching patients to another drug or another generic of the same drug ^{1, 2}. Shaw & Hartman mentioned “While the drug concentration differences between the brand name drug and each generic formulation are unlikely to be substantial, the differences with generic-to-generic switches will be greater and potentially clinically significant.” The general consensus is that bioequivalence boils down to similarity between the generic and reference products in drug substance concentration per unit dose and in time-dependant release. Here, we show that drug release of Divalproex sodium, an antiepileptic agent that is considered as narrow therapeutic index drug, can significantly change after exposure to storage conditions usually seen as short-lived and insignificant, namely; patients’ in-use and pharmacy dispensing conditions.

Methods: Four bioequivalent extended-release commercial products of Divalproex sodium (250 mg, designated as A, B, C & D) were selected for this study. The products were stored at 30^oC/75% RH in closed pharmacy vials to simulate patients’ in-use, and at ambient conditions (25±0.5^oC/65%RH) in unsealed but closed HDPE containers to simulate pharmacy storage conditions, for 6 and 12 weeks, respectively. The products were analyzed for in-vitro dissolution as well as in-vivo performance in Beagle dogs. Changes in physicochemical properties were studied using near infrared (NIR) chemical imaging, surface morphology (scanning electron microscopy, SEM), Fourier transformed infrared spectroscopy (FTIR), and X-ray powder diffraction (XRPD)^{3, 4}.

Results: A dissolution method with an optimized amount of surfactant (0.8%) was established and used throughout the study. Although all the selected products satisfied the USP drug release limits prior to storage, they exhibited discrepant dissolution profiles both in the rate and extent of drug dissolution (Fig 1). The drug dissolution from tablets stored in pharmacy vials at conditions simulating kitchen and washroom cabinets significantly decreased but remained within USP release limits. When stored in HDPE bottles simulating dispensing conditions, products A, B and C were at the lower acceptance limits, while product D failed the test. The NIR chemical imaging indicated compositional changes in the tablets upon storage. SEM images showed changes in the tablet morphology (Fig 2). The inspection of FTIR spectra showed that all the characteristic absorption bands were retained and, hence, the integrity of the co-ordination compound at all conditions was confirmed. In XRPD, the drug showed intense and distinguishing reflection peak at 7.1^o (Fig 3a). The net peak area for crystalline drug was 203.3. All products contained appreciable amounts of the amorphous form, while, upon storage, transformation to crystalline form occurred at different proportions depending on the conditions (Fig 3b). To assess whether the observed changes in tablets’ quality attributes have an impact on in-vivo performance, the plasma concentrations of Divalproex sodium from Beagle dogs administered two selected products (A & C) before and after storage at ambient conditions were analyzed by UPLC-MS/MS. The results showed comparable average reduction in AUC_0-t after storage by 73.4% and 84.37%, respectively.

Conclusion: The study revealed that bioequivalent Divalproex sodium extended-release products stored at conditions seen as short-lived can significantly affect the quality attributes and in-vivo performance. The study augments the recalls of Divalproex generics due to failure to meet specifications^5-7 and provides evidence to the compositional changes occurring during storage.

References: 1. Shaw SJ, Hartman AL. The controversy over generic antiepileptic drugs. J Pediatr Pharmacol Ther 2010; 15(2): 81-93.
2. Jobst B. The art of switching antiepileptic medications: Keep trying or just let it be. Epilepsy Curr 2013; 13(2): 76-7.
3. Dharani S, Mohamed EM, Khuroo T, Ali HI, Reddy IK, Rahman Z, Khan MA. In-use stability assessment of fda approved metformin immediate release and extended release products for n-nitrosodimethylamine and dissolution quality attributes. Int J Pharm 2022; 623: 121923.
4. Dharani S, Mohamed EM, Rahman Z, Khan MA. Patient in-use stability testing of fda-approved metformin combination products for n-nitrosamine impurity. AAPS PharmSciTech 2024; 25(1): 19.
5. Palmer E. Teva recalls seizure drug; 2016. https://www.fiercepharma.com/manufacturing/teva-recalls-seizure-drug
6. White ME. Anticonvulsant drug recall; 2017. https://www.hmpgloballearningnetwork.com/site/pln/content/anticonvulsant-drug-recall
7. Tumolo J. Divalproex sodium extended-release tablets recalled; 2019. https://www.hmpgloballearningnetwork.com/site/pln/content/divalproex-sodium-extended-release-tablets-recalled

Acknowledgements: Animal study (IACUC 2019-0241) was approved by the Institutional Animal Care and Use Committee (IACUC) of Texas A&M University. The authors have no conflicts of interest.

Fig. 1. Dissolution profiles of four commercial extended-release tablets of Divalproex sodium. The dotted lines represent the USP lower and upper acceptance limits. Patients’ in-use conditions were at 30oC/75% RH in pharmacy vials for 6 weeks.

Fig 2. 3D-Surface Plots by ImageJ generated from SEM Images.1: Initial tablets before storage. 2: After storage for 6 weeks at 30oC/75% RH in pharmacy vials. 3. After storage for 12 weeks at ambient conditions (25±0.5oC/65%RH) in HDPE unsealed containers.

Fig 3. X-Ray Powder Diffraction (a) Representative diffractograms for product C at different storage conditions with controls. (b) The net area of the peak at 7.01o. 1: Initial tablets before storage. 2: After storage for 6 weeks at 30oC/75% RH in pharmacy vials. 3. After storage for 12 weeks at ambient conditions (25±0.5oC/65%RH) in HDPE unsealed containers.