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The site of protonation in a molecule can greatly affect the fragments observed in product ion MS/MS spectra. In electrospray positive ionization mass spectra, protonation usually occurs predominantly on the most basic site on the molecule to produce the thermodynamically favored protonated species. However, the literature is unclear whether liquid phase or gas phase thermodynamics has the greater influence. This paper describes the protonation and fragmentation behavior of crizotinib and two of its impurities. Crizotinib has two possible protonation sites, a pyridine nitrogen and a secondary amine, piperidine nitrogen; the former is the favored site in the gas phase and the latter the more favored site in the liquid phase. The impurities contain alkyl substitution on the piperidine nitrogen, producing tertiary amine species. Literature precedence suggests that in the liquid phase, the piperidine nitrogen is still the most basic site but, in the gas phase, the pyridine nitrogen and the piperidine nitrogen have very similar basicities. Fragmentation data for the three molecules suggest that the secondary and tertiary amines protonate preferentially and almost exclusively on different sites. We propose that the secondary amine protonates on the piperidine nitrogen (influenced by solution thermodynamics) and the two tertiary amine structures protonate on the pyridine nitrogen because of steric hindrance at the most basic site of the molecule, allowing kinetic control of the protonation process.

A capillary gas chromatography column directly interfaced to a mass spectrometer was used for the analysis of sixteen benzodiazepines. The thermal stability of the drugs was found to be related to their chemical structure. Nine of the benzodiazepines were thermally unstable indicating that care should be taken in the interpretation of gas chromatographic data from this class of drugs. The unstable benzodiazepines were: ketazolam which decomposes to diazepam; N-4 oxides (chlordiazepoxide and demoxepam) which lose an oxygen radical; aromatic 7-nitro compounds (nitrazepam and clonazepam) which are partially reduced to the corresponding amine; alpha-hydroxy ketones (lorazepam and oxazepam) which decompose with the loss of water and N-methyl-alpha-hydroxy ketones (lormetazepam and temazepam) which partially decompose with the loss of a hydrogen molecule to produce the corresponding alpha, beta-diketones. Few problems were encountered in distinguishing the drugs by their mass spectra, the exceptions being ketazolam which decomposes to diazepam and demoxepam which decomposes to desmethyldiazepam. In general, good spectra were obtained from 20-50 ng of drug injected. However, for those compounds where the decompositions were not quantitative (nitrazepam, clonazepam, lormetazepam, temazepam) detection limits were poor.

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