LC–QTOF-MS Identifies Degradation Products and Process-Related Substances of Brivaracetam

Drugs based on the pharmaceutical organic synthesis intermediate pyrrolidone, according to the authors of a recently published study, are useful for treating conditions such as epilepsy and Alzheimer’s disease—most recently under the generic name brivaracetum (1,2). The study, performed by researchers at China Pharmaceutical University in Nanjing, China, attempts to contribute to the safe administration of this drug in developed nations in whose pharmacopeias it is not yet included.

Woman lying on the floor at home, epilepsy, unconsciousness, faint, stroke, accident or other health problem. | Image Credit: © Tunatura - stock.adobe.com

To do this, as illustrated in the study published in the journal Rapid Communications in Mass Spectrometry, the research team employed a liquid chromatography–quadrupole time-of-flight mass spectrometry (LC–QTOF-MS) method to identify the degradation products, or the unwanted chemicals produced during manufacture, and other process-related substances associated with brivaracetum (1). Stress testing was performed according to International Conference on Harmonisation (ICH) Stability Testing of New Drug Substances and Products (Q1A[R2]) guidelines, and further identification of these impurities’ structures was made by positive electrospray ionization (EI) QTOF–high resolution MS (HRMS), and nuclear magnetic resonance (NMR) spectroscopy (1).

As mentioned, brivaracetum is used to treat conditions including temporal lobe epilepsy, focal (meaning partial) impaired awareness or complex partial seizures, secondarily generalized or bilateral tonic clonic seizures, and focal aware onset seizures, according to the Epilepsy Foundation (3). It is available in tablet, oral liquid, and intravenous (IV) form. But even on the Epilepsy Foundation page, a question about “special concerns” for this still somewhat new drug are not yet known. Yet, the Chinese research team said its affinity to the synaptic vesicle glycoprotein 2A (SV2A) receptor is twice that of levetiracetam, a previous generation drug administered similarly for seizure control (1). This makes the evaluation of brivaracetum’s safety in clinical settings imperative for future deployment.

Ultimately, the researchers uncovered 13 degradation products, and because of the analytical conditions used, they were able to glean information about these products’ origins and pathways. Of the group of 13, three degradation products aligned with impurities that had been previously identified, and two products that had heretofore gone unreported were synthesized and confirmed by NMR spectroscopy (1). Regarding stress testing, brivaracetam was found to be relatively stable under photolytic stress conditions, but acidic, alkaline, oxidative, and thermal stress conditions all revealed some level of instability.

Taking those findings into account, the authors said that while the analytical method they developed was effective, it draws attention to the gap in drug standards for brivaracetum both domestic and foreign (1). Still, they said a liquid chromatography–quadrupole time-of-flight high-resolution mass spectrometry platform will be essential, going forward, not only for evaluations of stability as described in the research, but also quality control during the drug production process and to establish appropriate conditions for storage (1).

References

(1) Xu, K.; Ning, M.; Li, W.; et al. Identification of Degradation Products of Brivaracetam Using Liquid Chromatography Quadrupole Time-of-Flight Tandem Mass Spectrometry: Degradation Pathway Elucidation. Rapid Commun. Mass Spectrom. 2024, 38 (2), e9651. DOI: 10.1002/rcm.9651

(2) Pyrrolidone. Eastman. Eastman Chemical Society, 2024. https://www.eastman.com/en/products/product-detail/71103629/pyrrolidone (accessed 2024-05-13).

(3) Brivaracetam Basic Seizure Medication. Epilepsy Foundation, 2024. https://www.epilepsy.com/tools-resources/seizure-medication-list/brivaracetam (accessed 2024-05-13).