Assessment of lisdexamfetamine dimesylate stability and identification of its degradation product by NMR spectroscopy

• Published in: Drug development and industrial pharmacy 2019-01, Vol.45 (1), p.139-146
• Main Authors: Carlos, Graciela, Magalhães, Alvicler, Isler, Ana Cristina, Comiran, Eloisa, Fröehlich, Pedro Eduardo
• Format: Article
• Language: English
• Subjects: Central Nervous System Stimulants - analysis; Central Nervous System Stimulants - metabolism; degradation product; Drug Stability; lisdexamfetamine dimesylate; Lisdexamfetamine Dimesylate - analysis; Lisdexamfetamine Dimesylate - metabolism; Magnetic Resonance Spectroscopy - methods; NMR; stability; structure elucidation
• ISSN: 0363-9045; 1520-5762
• DOI: 10.1080/03639045.2018.1526185

Lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant indicated for the treatment of the attention-deficit/hyperactivity disorder (ADHD), was subjected to forced degradation studies by acid and alkaline hydrolysis and the degradation profile was studied. To obtain between 10-30% of degraded product, acid and alkaline conditions were assessed with solutions of 0.01 M, 0.1 M, 0.5 M, and 1 M of DCl and NaOD. These solutions were analyzed through 1 H NMR spectra. Acid hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and 4.38%, 9.69%, and 17.75% of degradation LDX, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) DCl. And alkaline hydrolysis produced no degradation in 0.01 M and 0.1 M DCl and a degradation LDX extension of 8.5%, 14.30%, and 22.91%, respectively, in 0.5 M, 1 M (4h) and 1 M (4 + 12 h) NaOD. LDX solutions subjected to 1 M (4 + 12 h) acid and alkaline hydrolysis were evaluated by NMR spectra (1 H NMR, 13 C NMR, HSQC and HMBC). LDX degradation product (DP) was identified and its structure elucidated as a diastereoisomer of LDX: (2R)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl] hexanamide without their physical separation.