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

Significance of the topic

Green and sustainable sample treatment is a central challenge for contemporary analytical chemistry. Sample preparation typically represents the majority of the labor, time, solvent/reagent use, energy demand, and waste generation in analytical workflows, especially in drug analysis of biological matrices. Developing miniaturized, automated, low-waste, and selective sample treatment approaches is therefore essential to reconcile analytical performance (accuracy, precision, sensitivity, throughput) with environmental, operator safety, and economic objectives promoted by Green Analytical Chemistry (GAC). The reviewed article documents recent advances in greening extraction methods, the adoption of alternative solvents and sorbents, and the use of quantitative greenness metrics to guide method selection and improvement.

Objectives and overview of the study

The paper reviews sample preparation techniques applied to drug analysis with emphasis on their environmental and sustainability performance. Objectives include:

• Summarize recent methodological advances in SPE, SPME, LPME and related miniaturized techniques for drugs in biological matrices.
• Describe greener solvents and sorbents (ionic liquids, deep eutectic solvents, bio-based materials, engineered sorbents, MOFs, nanomaterials).
• Discuss how automation, miniaturization and reuse improve green credentials.
• Evaluate representative methods using three greenness/sustainability metrics: AGREEprep, SPMS (Sample Preparation Metric of Sustainability), and HEXAGON.

The review highlights practical trade-offs between analytical figures of merit and sustainability, and it argues for standardized, easy-to-apply metrics that incorporate environmental, economic and performance aspects.

Methodology and used instrumentation

The review compiles and critically evaluates literature examples rather than performing primary experiments. Evaluation uses three complementary metrics:

• AGREEprep: a 10-criteria, score-based tool focused on sample preparation that produces a 0–1 greenness score and a circular pictogram.
• SPMS: an Excel-based sample-preparation-specific metric assessing nine parameters (sample amount, extractant amount/nature, steps, extraction time, energy, waste, reusability, throughput, etc.) with qualitative color-coded outputs.
• HEXAGON: a complementary global metric that balances analytical figures of merit, toxicity/safety, residues, carbon footprint and cost to yield a hexagonal pictogram and a composite score.

Representative analytical instrumentation discussed in the reviewed methods includes:

• Liquid chromatography (HPLC, UHPLC, LC-MS/MS)
• Gas chromatography coupled to mass spectrometry (GC–MS, GC–MS/MS)
• Ion mobility spectrometry (IMS)
• Capillary electrophoresis with TOF-MS
• UV–visible absorbance and diode array detectors
• Direct MS coupling options (e.g., SPME–MS, ambient ionization)

The review also covers diverse extraction devices and platforms (SPE cartridges, pipette-tip SPE, SPME fibers/blades/thin films, stir-bar sorptive extraction, fabric-phase sorptive extraction, micro-paper devices, MOF-functionalized sorbents, magnetic MIPs) and green solvents (ionic liquids, deep eutectic solvents, natural deep eutectic solvents).

Main results and discussion

Key synthesized findings from the literature and metric evaluations are:

• Microextraction techniques (SPME, LPME variants such as DLLME) generally show superior greenness versus conventional off-line SPE because they reduce solvent use, waste, energy and sample volumes and often enable automation and higher throughput.
• SPE remains widely used for clean-up and preconcentration but must be re-designed (miniaturized formats, novel reusable sorbents, solvent-less desorption or low-toxicity elution) to improve green metrics.
• New sorbent materials (MOFs, carbon-based nanomaterials, magnetic MIPs, bio-based polymers) and device manufacturing (3D printing, lab-made extractive phases) expand selectivity and reusability but require careful life-cycle consideration of sorbent synthesis impacts.
• Green solvents (ionic liquids, DES/NADES) are increasingly applied in LPME and as modifiers in sorbent functionalization; they can lower operator risk and fossil solvent dependence but should be assessed for toxicity/biodegradability.
• Integration and on-line coupling of extraction with detectors (e.g., SPME–MS, in-tube SPME coupled to LC) substantially improve greenness by avoiding evaporation steps and lowering analysis time and energy footprint.
• Metric comparisons reveal differences in emphasis: AGREEprep and SPMS focus on sample-preparation-specific parameters, while HEXAGON provides a holistic method-level view including figures of merit and cost. Results vary according to metric assumptions; for instance, SPMS may rate certain MOF-SPE procedures highly due to low extractant volumes and reuse even when AGREEprep scores are moderate because AGREEprep penalizes off-line solvent use more heavily.
• Common penalized practices across metrics include large sample volumes, multiple organic solvents for conditioning/elution, derivatization steps, and labor-intensive off-line operations without automation.

Discussion points emphasize that greenness must be evaluated in a fit-for-purpose context: a method can be intrinsically green yet unsuitable for the analytical question (e.g., single-analyte assays where multianalyte data are needed), leading to false economy. HEXAGON and the White Analytical Chemistry concept encourage balancing greenness with analytical functionality and validation requirements.

Benefits and practical applications of the reviewed methods

• SPME and LPME enable rapid screening in forensic, clinical and environmental drug analysis with reduced solvent use and lower operator exposure, suitable for on-site or high-throughput contexts when coupled to direct MS or portable detectors.
• Miniaturized SPE formats (pipette-tip SPE, disk monoliths) and reusable sorbents reduce waste and cost for routine monitoring while preserving selectivity for drug compounds.
• Advanced sorbent engineering (MOFs, MIPs, magnetic composites) supports selective isolation from complex biological matrices, improving sensitivity and lowering matrix interferences without large solvent volumes.
• Use of DES/NADES and ionic liquids can replace volatile organic solvents in microextraction workflows, improving safety and sustainability when their environmental profiles are appropriate.
• Metric-driven development helps laboratories choose and optimize methods that balance performance, cost, energy use and environmental impacts for regulatory or routine surveillance tasks.

Future trends and possibilities for use

The review outlines several anticipated trends and opportunities:

• Harmonization and user-friendly implementation of greenness metrics (apps, web tools, Excel templates) to simplify adoption in laboratories and industry.
• Expansion of metrics to include water consumption, life-cycle impacts of sorbent manufacture, and explicit economic viability assessments, enabling broader sustainability appraisal.
• Development of truly bio-based, biodegradable sorbents and greener solvent systems whose entire life cycle (synthesis, use, disposal) is favorable.
• Increased coupling of microextraction with ambient and portable MS for rapid, on-site drug screening, reducing transport, central lab load and turnaround time.
• Greater automation and high-throughput SPME workflows to lower operator risk and increase sample throughput while preserving greenness.
• Regulatory uptake of agreed greenness criteria to drive method selection in routine monitoring and forensic workflows.
• Critical assessment of sorbent synthesis impacts and reuse potential to avoid shifting environmental burdens to upstream stages of method production.

Conclusion

Microextraction approaches (SPME, LPME) and redesigned SPE formats with advanced sorbents and greener solvents provide tangible pathways to reduce environmental impact in drug analysis while maintaining or improving analytical performance. The choice and optimization of sample treatment should be guided by fit-for-purpose thinking and quantified greenness assessments. Improvements in metric harmonization, metric accessibility, and inclusion of broader life-cycle and economic considerations will accelerate the adoption of sustainable analytical methods in research, clinical and forensic laboratories.

Used instrumentation

• Liquid chromatography (HPLC, UHPLC) with diode-array or tandem MS detection
• Gas chromatography with MS(/MS)
• Ion mobility spectrometry (IMS)
• Capillary electrophoresis–TOF-MS
• UV–visible/diode-array detectors for simpler applications
• Portable mass spectrometers and direct-coupling ambient ionization sources for on-site screening

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