A HPLC assay for coating integrity of topiramate sprinkle formulation.

A HPLC method has been developed for the determination of coating integrity of topiramate sprinkle formulation. This method determines the completeness of the sprinkle coating and, indirectly, the completeness of taste masking of the product. This method utilizes a sample preparation where the sprinkles are placed in a specially designed stainless steel basket equipped with a screen, 25-mesh size, at the bottom. Water is used to solubilize any incompletely coated drug. The aqueous solution is analyzed for topiramate using a phenyl column in the reversed-phase mode, isocratic elution, and refractive index detection. This analytical method, for recovered topiramate, provides an indirect measure of drug taste-masking in the sprinkle formulation. It was also used in formulation selection by screening sprinkles beads that contained different amounts of coating to see which formula can best mask the taste with an acceptable level of exposed topiramate drug substance. This method has been validated to meet FDA validation guidelines.

Ion chromatography method and validation for the determination of sulfate and sulfamate ions in topiramate drug substance and finished product.

A stability-indicating assay method has been developed for monitoring topiramate degradation in drug substance and finished product by quantifying sulfamate and sulfate ions. Topiramate in the solid state is stable under ambient conditions but can degrade under stress conditions (elevated temperatures and humidities). This method detects and quantitates sulfamate and sulfate ions (the inorganic part of the decomposition) and in conjunction with an assay method for topiramate and its known organic degradation product provides total molar accountability. The chromatographic system consists of a sodium hydroxide gradient (2-25 mM) and an anion-exchange HPLC column and an anion suppressor. The analysis is complete in 30 min. The method utilizes the same sample preparation as the topiramate assay method which increases sample efficiency and throughput. The method has been validated for analysis of degraded and nondegraded topiramate drug substance and finished product.

Ion-exchange chromatography/electrospray mass spectrometry for the identification of organic and inorganic species in topiramate tablets.

An ion-exchange chromatograph/electrospray ionization mass spectrometer (IC/ESI-MS) was used successfully to identify organic and inorganic species present in topiramate tablets. An ion suppressor is placed between the column and detectors to replace sodium ions in the mobile phase with hydrogen ions supplied by the suppressor. The ensuing combination of the hydrogen ions with the mobile phase hydroxide ions produces water and thus allows simultaneous ion detection by an ion conductivity detector and a mass spectrometer. Analytes, including lactate, glycolate, chloride, formate, sulfate, and oxalate, were unambiguously identified by matching the mass spectra and retention times with those of the authentic compounds. Due to its capability of detecting positive and negative as well as neutral species, ESI-MS provides valuable information which is not available with ion conductivity detection alone. Though the coupling of ion-exchange chromatography to mass spectrometry has been reported previously, this is the first demonstration of IC/ESI-MS for the identification of unknown species in real samples. Finally, with the use of deuterium/carbon-13 labeling and MS/MS techniques, we have confirmed that oxalic acid (HOOC-COOH) is formed from formic acid (HCOOH) at the electrospray interface in the presence of the electric field. This observation not only confirms the identity of an unknown peak, but it also provides new insight into chemistry that can take place during electrospray ionization.