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In addition to well-known traditional synthetic illicit drugs like cocaine, amphetamines, and heroin, an increasing number of new psychoactive substances (NPS) are appearing on the global drug market. Among them, cathinones represent a prominent class. These amphetamine-like compounds contain a stereogenic center, resulting in the possible presence of two enantiomers. Pure enantiomers of cathinone derivatives are not commonly available, and their production is cost-intensive. Thus, there is very little knowledge about the possible distinct effects of single enantiomers of cathinones. The objective of this study was to evaluate the stability of a set of eight cathinone derivatives, namely 3-methylethcathinone, 3-methylmethcathinone, 4-methylethcathinone, 4-methylmethcathinone, ethylone, 3,4-trimethylene-α-ethylaminovalerophenone, 3,4-tetramethylene-α-pyrrolidinovalerophenone, and 3,4-trimethylene-α-pyrrolidinobutiophenone, over a six-month period. Any racemization that may have occurred under different storage and solution conditions was monitored and compared. Pure enantiomeric fractions were collected on a multi-milligram scale using semi-preparative HPLC under isocratic normal-phase conditions. A Phenomenex Lux® i-Cellulose-5, 5 μm 250 × 10 mm column containing cellulose tris(3,5-dichlorophenylcarbamate) served as the chiral selector. The tests showed that aqueous conditions, pH, temperature, chemical structure, sunlight, and oxygen influence compound stability. The long-term storage of cathinone derivative enantiomers was found to be optimal as solids under deep-freezing conditions or in a slightly acidified solvent where they are protected from air and light.

The enantioselective potential of two macrocyclic glycopeptide-based chiral stationary phases for analysis of 28 structurally diverse biologically active compounds such as derivatives of pyrovalerone, ketamine, cathinone, and other representatives of psychostimulants and antidepressants was evaluated in sub/supercritical fluid chromatography. The chiral selectors immobilized on 2.7 μm superficially porous particles were teicoplanin (TeicoShell column) and modified macrocyclic glycopeptide (NicoShell column). The influence of the organic modifier and different mobile phase additives on the retention and enantioresolution were investigated. The obtained results confirmed that the mobile phase additives, especially water as a single additive or in combination with basic and acidic additives, improve peak shape and enhance enantioresolution. In addition, the effect of temperature was evaluated to optimize the enantioseparation process. Both columns exhibited comparable enantioselectivity, approximately 90% of the compounds tested were enantioseparated, and 30% out of them were baseline enantioresolved under the tested conditions. The complementary enantioselectivity of the macrocyclic glycopeptide-based chiral stationary phases was emphasized. This work can be useful for the method development for the enantioseparation of basic biologically active compounds of interest.

The ongoing development of more and more new psychoactive substances continues to be a huge problem in 2022 affecting the European and international drug market. Through slight alterations in the structure of illicit drugs, a way to circumvent the law is created, as the created derivatives serve as legal alternatives with similar effects. A common way of structure modification is the induction of a halogen residue. Recently, halogenated derivatives of the well-known designer drug 4-methylaminorex appeared on the market and are available in various online shops. In this study, three novel halogenated 4-methylaminorex derivatives, namely 4′-fluoro-4-methylaminorex, 4′-chloro-4-methylaminorex, and 4′-bromo-4-methylaminorex, were purchased online and characterized using nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS), and chiral high-performance liquid chromatography with ultraviolet detection (HPLC-UV). These derivatives possess two stereogenic centers, and analyses revealed that all of them were present as a racemic mixture of the trans diastereomeric form.

Besides the well-known hallucinogenic ketamine, various novel ketamine derivatives are available on the illicit drug market, sold as designer drugs. Minor chemical changes to the parent compound aim to circumvent existing narcotic drug laws while mimicking the effects of the original substance. Ketamine and some of its derivatives possess a chiral centre and therefore exist as two enantiomers. While differences in the effects of S- and R-ketamine are well studied, this is not the case for ketamine derivatives. Therefore, the development and adaptation of suitable enantioseparation methods for those compounds is important to face the problems of the constantly changing drug market. In this study, different chiral separation methods for capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) were tested on 11 ketamine derivatives. Some of them were enantioseparated for the first time due to their novelty. All compounds were at least partially separated on both instruments. HPLC separations were conducted using four different polysaccharide-based chiral stationary phases. Furthermore, an optical rotation detector coupled to the HPLC enabled the determination of the enantiomer elution order. In CE analysis, enantioseparation was achieved using 2% (w/v) acetyl-β-cyclodextrin or carboxymethyl- β-cyclodextrin in 10 mM di-sodium hydrogen phosphate as the background electrolyte in capillary electrophoresis.

Cannabis is globally by far the most widespread illicit drug of abuse. Especially since its legalization in some of the US, controversies about the legal status of cannabis for recreational and medical use have come up. Δ(9)-Tetrahydrocannabinol (Δ(9)-THC), which is the major active ingredient in cannabis products, is mainly responsible for the psychoactive effects. Its inactive biosynthetic precursor tetrahydrocannabinolic acid (THCA) is present in different quantities in fresh and undried cannabis plants. Under influence of drying, temperature and UV exposure it decomposes to Δ(9)-THC. In this study, a quantification of Δ(9)-THC and THCA was carried out to check the stability of cannabis samples. The determination of the degradation of THCA to Δ(9)-THC in 29 cannabis products seized in Austria was monitored by HPLC-UV. Mobile phase consisted of a 25mM triethylammoniumphosphate buffer (pH 3.0) and acetonitrile (36:64). A common LiChrospher(®) 100 RP-18 column was utilized as stationary phase. To check the influence of low as well as high temperature on the degradation process of the cannabinoid THCA to Δ(9)-THC, samples were stored in a freezer or in a drying cabinet for a specified time period. It was shown successfully that high storage temperatures led to a more rapid and complete decomposition of THCA to Δ(9)-THC while at low temperatures only slight or no changes of the percentage distribution were determined.

Several research disciplines require fast, reliable and highly automated determination of pharmaceutically active compounds and their enantiomers in complex biological matrices. To address some of the challenges of Capillary Electrophoresis (CE), such as low concentration sensitivity and performance degradation linked to the adsorption and interference of matrix components, CE in a hydrodynamically closed system was evaluated using the model compounds Pindolol and Propranolol. Some established validation parameters such as repeatability of injection efficiency, resolution and sensitivity were used to assess its performance, and it was found to be broadly identical to that of hydrodynamically opened systems. While some reduction in separation efficiency was observed, this was mainly due to dispersion caused by injection and it had no impact on the ability to resolve enantiomers of model compounds even when spiked into complex biological matrix such as blood serum. An approximately 18- to 23-fold increase in concentration sensitivity due to the employment of wide bore capillaries was observed. This brings the sensitivity of CE to a level similar to that of liquid chromatography techniques. In addition to this benefit and unlike in hydrodynamically opened systems, suppression of electroosmotic flow, which is essential for hydrodynamically closed systems practically eliminates the matrix effects that are linked to protein adsorption.

[Display omitted] •Determination of the active ingredients cathinone and cathine in seized Khat samples.•Comparison of fresh with dried Khat leaves.•Estimation of stability of dried Khat leaves. The consumption of Khat leaves represents an ancient kind of drug abuse mainly observed in Eastern Africa and the Arab Peninsula among adult men. For this purpose, the leaves are directly collected from the shrub “Catha edulis” prior to extensive chewing process. Seizures in Europe are rare, since the leaves have to undergo quick transportation: After a short period of time, the harvested leaves decompose and suffer in decrease of concentration of the active ingredient cathinone, which makes long term transportation difficult. As an alternative, plant material can be dried to increase life period. In the past years, an increasing number of seizures were made by Austrian police, however, the content of cathinone and cathine in dry material is widely unknown. In this work, a seizure of fresh Khat leaves was compared with two seizures of dried material in terms of concentration of cathinone and cathine using LC–MS/MS analysis. For fresh leaves, a purity grade was found to be 0.115-0.158% for cathinone and 0.172-0.192% for cathine, respectively. In contrast, subsequent storage of dried Khat leaves over months led to a dramatic loss of cathinone: Analysis of two seizures revealed that concentration of cathinone dropped to 0.021-0.023%. These findings are intended to serve as a guideline for Justice authorities to estimate the content of the controlled ingredients of Khat leaves in future.

Synthetic cathinones belong to one of the biggest and most popular classes of New Psychoactive Substances. Each year, new derivatives appear on the drug market, traded under various labels like “bath salts” or “legal highs”. In recent years, the emergence of new cathinone derivatives, containing a cyclohexyl residue, has been observed. Since 2021, threads about N-cyclohexylmethylone have been posted in various user forums. A powder sample of N-cyclohexylmethylone purchased by a client was collected in Austria in a local drug checking program and analyzed by GC-MS, LC-HRMS NMR spectroscopy and chiral HPLC. The aim of this study was to provide experimental NMR data of the compound and to determine the chiral status of the sample. Usually, cathinone derivatives are sold as racemic mixtures on the market. Investigation showed that in the sample both enantiomers were present. [Display omitted] •A new methylone derivative was analyzed with GC-MS, LC-HRMS and NMR spectroscopy.•It was identified as N-cyclohexylmethylone.•Chiral HPLC was used to determine, if the sample was sold as racemic mixture.•Both enantiomers were present in the sample.

•New chiral HPLC separation method applicable for a broad spectrum of NPDs.•A Lux® Cellulose-2 column was used in polar organic phase mode.•40 psychoactive compounds were separated into their enantiomers, successfully.•Analysis of real life samples seized by Austrian police.•All tested compounds are traded as racemic mixtures. Since the last decade, the hype of the recreational use of novel psychoactive drugs is still on its top in entire Europe. Every year, new derivatives enter the drug market and enlarge the broad spectrum of misused drugs. Many of these compounds contain a stereogenic centre and therefore two enantiomers exist. It is obvious that the pharmacological potency of the isomers differ as it is already known from various pharmaceutical ingredients. Therefore, the development of analytical methods for the chiral separation of new psychoactive substances is of great medical and forensic interest. The aim of this study was to establish an enantioseparation method, which is applicable at equal conditions for different drug compound classes including cathinones, amphetamines, benzofurans, thiophenes, phenidine and phenidate derivatives. A commercially available Lux® Cellulose-2 column consisting of cellulose tris(3-chloro-4-methylphenylcarbamate) coated on silica gel was found to be appropriate for the chiral separation of the mentioned drug classes. Experiments were performed under isocratic conditions in polar organic phase mode using UV-detection. With a mobile phase consisting of acetonitrile:isopropanol:diethylamine:formic acid (100%) (95:5:0.1:0.1) 40 out of 43 psychoactive compounds were successfully baseline or partially separated. 3-Fluoroamphetamine, 4-fluoroamphetamine and 1-(benzofuran-6-yl)-N-ethylpropan-2-amine were not chirally separated. The established method enabled enantioseparation of a broad spectrum of different psychoactive compounds under equal conditions. Forty of forty-three compounds were separated in their enantiomers, thus this method has a wide applicability for the enantioseparation of novel psychoactive drugs.

The misuse of so called novel psychoactive substances is still a challenging problem worldwide. A special attribute of a lot of these compounds is a chiral centre enabling two possible enantiomers probably related to different pharmacological and toxicological properties. The goal of the present study was to present a simple and isocratic HPLC–UV method for enantioseparation of mainly cathinone and pyrovalerone derivatives as well as selected representatives of amphetamines, ketamines, benzofuries, phenidines, phenidates, morpholines and thiophenes. A Waters Acquity UPC2® Trefoil™ CEL1 2.5 µm, 3.0 × 150 mm column served as chiral stationary phase by means of cellulose tris-(3,5-dimethylphenylcarbamate) as chiral selector. Mobile phases consisted either of n-hexane/n-butanol/diethylamine (100:0.3:0.2) or n-hexane/diethylamine (100:0.2). The method was found to be applicable for rapid simultaneous chiral separations of cathinone derivatives, to determine enantiomeric elution orders, to detect positional isomers and to identify real-life samples. Also, a repeatability study was performed successfully. 78 out of 95 compounds were separated in their enantiomers successfully, 51 of them within 6 min. It was shown that all NPS bought from online vendors or seized by police were traded as racemic mixtures.