Imipramine, oxidation

Imipramine oxide Oxygenated ring Metabolite of imipramine... 

That there are considerably fewer EC methods for the TCAs as compared with those for the phenothiazine antipsychotics probably reflects the generally higher potentials that are required and the poor EC response of some of the class of drugs. This is particularly true of compounds, such as amitriptyline and nortriptyline (Figure 6.18), that possess no alicyclic nitrogen. The fact that imipramine -oxide produced a response similar to that of imipramine (Figure 6.18) shows that the alicyclic nitrogen is amenable to oxidation. 

Amitriptylin oxide 3-(Dimethylamino) propyl chloride Amitriptyline HCI Ch/orprothixene Clomipramine Cyclobenzaprine Imipramine HCI Oxetorone fumarate Prothipendyl HCI... 

DLs for impurities should correspond to less than 0.1% of the main compound " compounds that take effect in lower amounts may require lower DLs. For example, imipramine N-oxide hydrochloride impurities and salicylamide impurities have been determined at the 0.01% level. DLs and QLs in CE are generally to some extent higher (in concentration) than in HPLC because of the small optical path (50—100 pm) used for ultraviolet (UV) detection and small injected volume (2—20nl) compared with HPLC 10 mm optical length and 10—200 pi injected volume. ... 

A mixed MEKC system employing zwitterionic and non-ionic surfactants was used for the investigation of impurities in imipramine-N-oxide. The non-ionic surfactant improved the resolution keeping the current as low as possible. With this system, four known impurities and... 

Cortisol into 7- 3-hydroxycortisol. Epoxidation Benzene into benzene 1,2-epoxide. N-oxidation Drug containing amino groups can undergo N-oxidation i.e. imipramine into imipramine N-oxide. 0-dealkylation This reaction probably Involves formation of an unstable hydroxy methyl Intermediate I.e. codeine Into morphine. 

Oral contraceptives reduce the clearance of imipramine, probably by reducing hepatic oxidation, and thus increase its half-life. Hydroxylation of amitriptyline is inhibited by contraceptive steroids. The clinical significance is uncertain, but there is at least anecdotal evidence of an increase in antidepressant adverse effects (360). Caution should be exercised when tricyclic antidepressants are used long term in women taking oral contraceptives. 

Imipramine hydrochloride API undergoes oxidation at the benzylic site to form the corresponding benzyl hydroxyl compound (Fig. 98). Subsequent elimination of the hydroxyl occurs to give an extended conjugation in... 

Skjelbo E, Brosen K, Hallas J, et al. The mephenytoin oxidation polymorphism is partially responsible for the N-demethylation of imipramine. Clin Pharmacol Ther 1991 49 18-23. 

Skjelbo E, Gram LF, Brosen K. The N-demethylation of imipramine correlates with the oxidation of (5)-mephenytoin (S/R ratio). A population study. Br J Clin Pharmacol 1993 35 331-334. 

A-Oxidation -Oxidation P-Oxidation Desulfuration Nicotine, dimethylaniline, imipramine Thiobenzamide, phorate, thiourea Diethylphenylphosphine Fonofos Alcohol Dehydrogenase... 

Rapp W, Noren MB, Pedersen F. Comparative trial of imi-pramine N-oxide and imipramine in the treatment of outpatients with depressive syndromes. Acta Psychiatr Scand 1973 49(l) 77-90. 

To avoid the expensive use of deuterated solvents for H/D exchange experiments, Tolonen et al. [21] have described the postcolumn infusion of D2O to facilitate the LC-MS detection and identification of labile protons in a column eluant. Whilst acknowledging the potential limitations with respect to a reduced level of exchange, and hence sensitivity, compared to the use of deuterated mobile-phase solvents, they optimized the column effluent flow rate (via a splitting connector) with the infused D2O flow rate to enable the very useful determination of up to four labile protons. The method was exemplified by the differentiation of hydroxylated metabolites of the alkaloidal drugs imipramine and omeprazole (Figure 13.5) from the N-oxide and sulfone metabolites, respectively [21]. This was a differentiation that could not be achieved by high-resolution mass measurements. 

In this chapter, the application of polarography in the determination of benzodiazepines is emphasized in which this method has played an outstanding role but it can be also useful with some other psychotherapeutics such as fluorine-substituted butyrophenones [240] or those with seven-membered, possibly heterocyclic rings [241] such as in imipramine. In the latter case, anodic oxidation waves are obtained with rotated noble metal electrodes. 

The anti-depressants amitryptyline and imipramine, and their desmethyl analogues, inhibited the enzymic oxidation of both substrates but only at relatively high concentrations. It is significant that iproniazid, which owes its anti-depressant activity to its known inhibition of monoamine oxidase, had no effect on caeruloplasmin. 

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