Green and sustainable evaluation of methods for sample treatment in drug analysis

Importance of the topic

Green and sustainable sample treatment is a central challenge for contemporary analytical chemistry. Sample preparation remains the most time- and resource-intensive step in many workflows, particularly in drug analysis of biological specimens where matrix complexity and low analyte concentrations demand clean-up and preconcentration. Driving forces for greening these workflows include reductions in solvent use, waste, operator risk and energy consumption, while maintaining or improving analytical figures of merit and throughput. The reviewed article surveys recent advances and quantifies greenness of sample-treatment approaches using modern metrics to guide method selection and development.

Objectives and overview of the study

The paper aims to collect representative examples of sample-preparation techniques applied to drug analysis and to evaluate their sustainability using three complementary green metrics: HEXAGON (global method assessment combining environmental, economic and analytical performance), AGREEprep (sample-preparation-focused greenness), and SPMS (sample preparation metric of sustainability). The review focuses on solid-phase approaches (SPE and dispersive SPE), solid-phase microextraction (SPME), and liquid-phase microextraction (LPME/DLLME), highlighting strategies to reduce environmental impact (miniaturization, alternative solvents, engineered sorbents, automation) and discussing strengths and limitations of metric tools.

Methodology and green-assessment tools

The authors summarized recent method examples from the literature and applied three metric approaches to evaluate greenness and sustainability:

• AGREEprep: a 10-criterion score (0–1) focused on sample-preparation attributes (e.g., in-field preparation, greener chemicals, miniaturization, waste reduction, energy). Results are shown as a circular pictogram and a single aggregated score.
• SPMS: an Excel-based sample-preparation metric that evaluates nine parameters (sample amount, extractant amount and nature, number of steps, extraction time, post-extraction steps, parallel sample processing, energy consumption, total waste) and flags reusability. SPMS places particular weight on extractant nature and step durations.
• HEXAGON: a holistic hexagonal scoring tool that balances figures of merit, toxicity/safety, residues, carbon footprint and economic cost (penalty-point approach, scored 0–4 per block). HEXAGON produces a pictorial hexagon and an averaged score (Sav) for method comparison.

Used instrumentation

The surveyed literature and evaluations referenced a broad set of analytical platforms and auxiliary equipment commonly combined with the sample treatments:

• Separation and detection: LC-MS/MS, UHPLC-MS/MS, HPLC, GC–MS(/MS), capillary electrophoresis–TOF-MS, LC-DAD, ion mobility spectrometry (IMS), UV–visible spectroscopy.
• Direct and ambient MS interfaces: thermal desorption, direct coupling of SPME to MS, dielectric barrier discharge ionization, DART-like sampling, portable mass spectrometers.
• Sample-preparation devices and supports: SPE cartridges, pipette-tip SPE, metal-organic frameworks (MOFs), molecularly imprinted polymers (MIPs), paper-based analytical devices (PADs), SPME fibers/blades/thin films, fabric phase sorptive extraction (FPSE), stir-bar sorptive extraction (SBSE), and 3D-printed devices.
• Auxiliary equipment: centrifuges, autosamplers, robotics for automation, thermal desorption units and simple detectors used to lower cost and carbon footprint.

Main results and discussion

The review synthesizes observations from multiple case studies and metric evaluations:

• Miniaturized microextraction formats (SPME, LPME/DLLME) generally scored better on greenness than conventional off-line SPE because they reduce solvent volumes, sample consumption, energy use and waste generation. SPMS and AGREEprep reflect these advantages, with SPMS often awarding high marks to miniaturized, low-step procedures.
• Sorbent innovation (bio-based materials, MOFs, engineered carbonaceous sorbents, magnetic phases, and lab-made coatings) can enhance selectivity and permit reuse, improving sustainability. However, greenness gains depend on the environmental footprint of sorbent synthesis—an often under-reported contribution.
• Use of alternative solvents (ionic liquids, deep eutectic solvents, natural deep eutectic solvents) reduces reliance on petroleum-derived extraction solvents; the nature and toxicity of each alternative must still be evaluated within metrics.
• Automation, integration and on-line desorption (e.g., thermal desorption or direct desorption to MS) improve throughput and lower operator risk, often producing better HEXAGON and AGREEprep results by reducing run time, solvent use and waste.
• Metric-specific findings: AGREEprep penalizes off-line SPE and multi-solvent elution steps heavily (lower circular scores). SPMS generally returns favorable evaluations for miniaturized methods because it rewards low step count, low energy and reusability. HEXAGON gives a balanced, holistic image but depends on accurate estimation of carbon footprint and costs; methods using simple instrumentation (IMS, UV–vis) can show strong HEXAGON performance if they meet analytical requirements.
• Some inconsistencies between metrics arise because they emphasize different factors (e.g., extractant nature vs. overall method cost and carbon footprint). The authors recommend careful selection and consistent application of metrics for fair comparisons.

Benefits and practical applications of the methods

• Microextraction (SPME, LPME/DLLME) enables rapid screening, lower sample and solvent consumption, and easier field-deployable workflows—advantages for forensic toxicology, clinical point-of-care testing and environmental monitoring of psychoactive compounds.
• Sorbent engineering and sorbent-miniaturization increase selectivity and reusability, reducing per-sample costs and waste. Magnetic and paper-based devices can simplify workflows and enable low-cost, high-throughput screening.
• Direct coupling of miniaturized extraction to MS shortens analysis time and eliminates chromatographic solvents when appropriate, improving throughput and reducing lab resource demands.

Future trends and opportunities

• Metric refinement and harmonization: a single, user-friendly, broadly accepted metric or interoperable toolset (apps, web interfaces, spreadsheets) is needed to reduce confusion from multiple overlapping metrics and to facilitate regulatory adoption.
• Life-cycle thinking: future metrics should routinely include sorbent synthesis impacts, water usage, full life-cycle inventories and economic viability to capture hidden environmental costs associated with advanced materials.
• Greener sorbent synthesis and waste valorization: development of sorbents and coatings derived from renewable feedstocks or waste streams, with simplified syntheses and known degradability, will support sustainable adoption of high-performance materials.
• Automation, high-throughput microextraction and on-site/portable MS: integration of robotics, autosamplers and portable mass spectrometers with reusable microextraction devices will expand field analysis capacity for drugs and metabolites.
• Fit-for-purpose evaluation: greener methods must still be functionally adequate. Metrics and method selection should prioritize analytical fitness (selectivity, sensitivity and multianalyte capability) in addition to greenness to avoid misapplied minimal methods.

Conclusion

The reviewed literature demonstrates clear movement toward miniaturized, low-solvent sample treatments for drug analysis, driven by engineered sorbents, alternative solvent systems and automation. Microextraction techniques (SPME, LPME) typically present greener footprints than conventional SPE, but comprehensive assessment must include sorbent production, instrument energy demand and method fit-for-purpose. AGREEprep, SPMS and HEXAGON provide complementary perspectives; harmonizing and broadening these tools to include life-cycle and economic indicators will improve method selection and facilitate wider adoption of greener workflows in analytical laboratories.

References

• Martínez-Pérez-Cejuela H, Gionfriddo E, Campíns-Falcó P, Herrero-Martínez JM, Armenta S. Green and sustainable evaluation of methods for sample treatment in drug analysis. Green Anal. Chem. 10 (2024) 100125.
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