Development and Validation of Stability-Indicating Assay Method for a Novel Oxazolidinone (PH-192) with Anticonvulsant Activity by Using UHPLC-QToF-MS

Abstract

The treatment of seizure disorders with currently available pharmacotherapeutic agents is not optimal due to the failure of some patients to respond, coupled with occurrences of side effects. There is therefore a need for research into the development of new chemical entities as potential anticonvulsant agents, which are different structurally from the existing class of drugs. We recently identified a novel triazolyl-oxazolidinone derivative, PH-192, as a potential anticonvulsant agent. PH-192 demonstrated protection comparable to phenytoin against both chemically- and electrically-induced seizures in rodents with little or no central nervous system side effects. However, PH-192 did not exhibit protection beyond 30 min; therefore, we decide to investigate a stability-indicating assay of PH-192 in plasma and other solutions. A reliable and validated analytical method was developed to investigate the stability of PH-192 for 90 min in human plasma, acidic, basic, and oxidative conditions, using a Waters Acquity ultra high-performance liquid chromatography (UHPLC) system with a quaternary Solvent Manager (H-Class). A simple extraction method indicated that PH-192 was stable in human plasma after 90 min at 37 °C, with more than 90% successfully recovered. Moreover, stress stability studies were performed, and degradants were identified using LC-QToF-MS under acidic, basic, and oxidative simulated conditions.

Keywords

• antimycobacterial activity
• linezolid
• PH-189
• substituted-glycinyl triazolyl-oxazolidinone
• GC-MS
• UPLC