Synthesis, characterization, and in vivo evaluation of desvenlafaxine decanoate, a new long-acting injectable antidepressant.

OBJECTIVE

The aim of this study was to design, synthesize, and characterize a novel long-acting injectable antidepressant prodrug, desvenlafaxine decanoate.

SIGNIFICANCE: Long-acting injectable drugs represent a useful approach for the treatment of mental illnesses, since these formulations extend dosing intervals and are beneficial for patients unable to self-administer oral medication or to maintain adherence to treatment. Although some antipsychotic depot formulations are used in clinical practice, there is a lack of studies on long-acting injectable antidepressants.

METHODS

This prodrug was synthesized by esterifying desvenlafaxine with decanoic acid, affording the target compound in 75% yield. Structural characterization was performed by 1H and 13C NMR, high-resolution mass spectrometry (HRMS), and high-performance liquid chromatography (HPLC). An in vivo proof-of-concept study was conducted in mice following intramuscular administration of desvenlafaxine decanoate.

RESULTS

A selective HPLC-DAD method was developed to separate desvenlafaxine succinate and desvenlafaxine decanoate, achieving retention times 6.08 and 15.70 min, respectively. LC-MS/MS analysis of plasma samples collected 2 hours after administration demonstrated significant levels of desvenlafaxine in systemic circulation. The plasma detection was a proof-of-concept for the in vivo hydrolysis of the ester prodrug.

CONCLUSION

These findings support the feasibility of desvenlafaxine decanoate as a promising long-acting injectable antidepressant for patients requiring prolonged maintenance therapy.