Solriamfetol impurities: Synthesis, characterization, and analytical method (UPLC-UV) validation

Abstract

Given that impurities may affect the quality and safety of drug products, impurity identification and profiling is an integral part of drug quality control and is particularly important for newly developed medications such as solriamfetol, which is used to treat excessive daytime sleepiness. Although the high-performance liquid chromatography analysis of commercial solriamfetol has revealed the presence of several impurities, their synthesis, structure elucidation, and chromatographic determination have not been reported yet. To bridge this gap, we herein identified, synthesized, and isolated eight process-related solriamfetol impurities, characterized them using spectroscopic and chromatographic techniques, and proposed plausible mechanisms of their formation. Moreover, we developed and validated a prompt impurity analysis method based on ultrahigh-performance liquid chromatography with UV detection, revealing that its selectivity, linearity, accuracy, precision, and quantitation limit meet the acceptance criteria of method validation stipulated by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Thus, the developed method was concluded to be suitable for the routine analysis of solriamfetol substances.

Keywords: Impurity analysis; Impurity synthesis; Method validation; Solriamfetol; UPLC.

Graphical abstract

Fig. 1

Structure of solriamfetol hydrochloride.

Fig. 2

Previously reported solriamfetol synthesis methods. (A) Patent US5955499 A [6], (B) patent WO2005033064 A1 [7], and (C) patent WO2020035769 A1 [8]. Cbz: benzyloxycarbonyl; Ms: mesyl.

Fig. 3

Syntheses of imps. 1–8. (A) Imp. 1 ((R)-1-(1-hydroxy-3-phenylpropan-2-yl)urea) from compound I, (B) Imp. 2 ((R)-3-phenyl-2-ureidopropyl carbamate) from compound I, (C) Imp. 3 ((R)-4-benzyloxazolidin-2-one) in five steps starting with compound II, (D) Imp. 4 ((S)-2-amino-N-((R)-1-hydroxy-3-phenylpropan-2-yl)-3-phenylpropanamide) in two steps starting with compounds II and VII, (E) Imp. 5 ((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropyl carbamate) in three steps starting with compound VII, (F) Imp. 6 (N-[(2R)-1-hydroxy-3-phenylpropan-2-yl]dicarbonimidic diamide) in two steps starting with compound XI, (G) Imp. 7 ((2R)-2-(carbamoylamino)-3-phenylpropyl carbamoyl carbamate) from imp. 2, and (H) Imp. 8 ((R)-5-benzylimidazolidine-2,4-dione) from compound XIII. MSA: methanesulfonic acid; MCF: methyl chloroformate; NMM: N-methylmorpholine.

Fig. 3

Syntheses of imps. 1–8. (A) Imp. 1 ((R)-1-(1-hydroxy-3-phenylpropan-2-yl)urea) from compound I, (B) Imp. 2 ((R)-3-phenyl-2-ureidopropyl carbamate) from compound I, (C) Imp. 3 ((R)-4-benzyloxazolidin-2-one) in five steps starting with compound II, (D) Imp. 4 ((S)-2-amino-N-((R)-1-hydroxy-3-phenylpropan-2-yl)-3-phenylpropanamide) in two steps starting with compounds II and VII, (E) Imp. 5 ((R)-2-((R)-2-amino-3-phenylpropanamido)-3-phenylpropyl carbamate) in three steps starting with compound VII, (F) Imp. 6 (N-[(2R)-1-hydroxy-3-phenylpropan-2-yl]dicarbonimidic diamide) in two steps starting with compound XI, (G) Imp. 7 ((2R)-2-(carbamoylamino)-3-phenylpropyl carbamoyl carbamate) from imp. 2, and (H) Imp. 8 ((R)-5-benzylimidazolidine-2,4-dione) from compound XIII. MSA: methanesulfonic acid; MCF: methyl chloroformate; NMM: N-methylmorpholine.

Fig. 4

Results of high-performance liquid chromatography with ultraviolet (HPLC-UV) analysis. Chromatograms of a 1 mg/mL solution of solriamfetol spiked with all impurities (1 μg/mL each) (a) and a blank solution (b). API: active pharmaceutical ingredient.