Changes in methamphetamine impurity profiles induced by tert‐butoxycarbonylation

Abstract

Analysis of impurities in methamphetamine (MA) can be used to characterize MA seizures, investigate the relationship among MA seizures, and provide information on their synthetic routes. Recently, chemically derivatized MA, such as tert‐butoxycarbonyl (t‐Boc) MA, has been seized and attracted attention because routine forensic analysis methods may fail to correctly identify them. Chemical derivatization is a simple method for protection and deprotection of a compound, and protection of MA using t‐Boc can be used to mask the MA. Although t‐Boc derivatization might alter the impurity profile of MA, the actual changes in the impurity profile have not been investigated. In this study, changes in the MA impurity profile with tert‐butoxycarbonylation were explored. MA and some typical impurities were derivatized using di‐tert‐butyl dicarbonate and water. Analysis of the impurities in five MA samples by gas chromatography showed that peaks both appeared and disappeared for the deprotected MA compared with the original MA. However, typical impurities important for characterizing MA seizures were conserved after derivatization and deprotection. Most of the new peaks were speculated to be contaminants introduced during derivatization and deprotection. A peak giving a mass spectrum similar to that of t‐Boc MA was detected in the chromatograms of t‐Boc MA and deprotected MA. Although the origin of this peak was not determined, it might be a marker for the MA involving tert‐butoxycarbonylation. These results indicate that tert‐butoxycarbonylation can alter the MA impurity profile; therefore, care is needed when interpreting results for derivatized MA.

The use of prodrugs as drugs of abuse

“…Substitutions to generate prodrugs for this group are usually done at the terminal N. Labile groups such as acetyl, p‐toluenesulfonyl (p‐tosyl), methoxycarbonyl (n‐Moc), fluorenylmethyloxycarbonyl (Fmoc) and tert‐butoxycarbonyl (t‐Boc) can be used to protect the amine and are easily removable in physiological conditions (Collins et al, 2017; Collins et al, 2018; Mayer et al, 2020; Xu et al, 2020) (Figure 2). The same approach has been found to be useful in masking amphetamine, methamphetamine and MDA (3,4‐methylenedioxyamphetamine), although not all of the possible permutations have been found in the illicit drug market (Johnson & Bogun, 2019; Mayer et al, 2020; Segawa et al, 2023). Two chemically protected precursors of MDMA (t‐Boc‐MDMA and N‐Moc‐MDMA) have been found in MDMA tablets as adulterants but not as stand‐alone compounds, indicating those compounds, while potential prodrugs, are used as precursors in chemical production of MDMA for the illicit market (Croft et al, 2022; O'Reilly et al, 2022) (Figure 3).…”

“…While MDMA prodrugs are thought to be metabolically degradable into MDMA, there are few studies that have evaluated their potential risks or relative potency. There are, however, concerns about the impurity profile of the processes used for chemically protecting this compound (Segawa et al, 2023).…”