A Practical Guide to CHEM21 Solvent Greenness Assessment for Sustainable Research and Development

Chloe Mitchell Nov 26, 2025 57

This article provides a comprehensive guide to the CHEM21 Solvent Selection Guide, a globally recognized framework developed by a European consortium for assessing solvent sustainability.

A Practical Guide to CHEM21 Solvent Greenness Assessment for Sustainable Research and Development

Abstract

This article provides a comprehensive guide to the CHEM21 Solvent Selection Guide, a globally recognized framework developed by a European consortium for assessing solvent sustainability. Tailored for researchers, scientists, and drug development professionals, it details the methodology for scoring solvents based on Safety, Health, and Environment (SHE) criteria aligned with the Global Harmonized System (GHS). The content covers foundational principles, practical application of the selection tool, strategies for troubleshooting and optimizing solvent choices, and a comparative analysis with other green metrics. The guide aims to empower scientists to make informed, data-driven decisions that minimize the environmental impact of chemical processes, particularly in pharmaceutical development where solvents can constitute over half of the material mass used.

Understanding the CHEM21 Framework: Principles and Pillars of Green Solvent Selection

THE ORIGIN AND MISSION OF THE CHEM21 CONSORTIUM

The CHEM21 Consortium (Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries) is a European public-private partnership established to promote sustainable manufacturing in the chemical and pharmaceutical sectors [1]. It was formed under the Innovative Medicines Initiative (IMI) and comprises a consortium of six pharmaceutical companies from the European Federation of Pharmaceutical Industries and Associations (EFPIA), ten universities, and five small to medium enterprises [1]. Its core mission is to develop and embed sustainable biological and chemical methodologies, supported by research projects and educational training packages to instill these principles in future scientists [1].

The CHEM21 Solvent Selection Guide

A key output of CHEM21 is its solvent selection guide, which provides a standardized framework for choosing greener solvents. The guide categorizes solvents based on explicit Safety, Health, and Environment (SH&E) criteria aligned with the Globally Harmonized System (GHS) and European regulations [1] [2]. Solvents are ranked into four categories, as shown in the table below.

Table 1: CHEM21 Solvent Ranking Categories

Category Description Example Instruction
Recommended Preferred, greener solvents Test first in a screening exercise, provided no chemical incompatibility exists [1].
Problematic Solvents with specific scale-up constraints Can be used in the lab, but implementation at production scale requires specific measures or significant energy consumption [1].
Hazardous Solvents with significant constraints Substitution during process development is a priority due to very strong constraints on scale-up [1].
Highly Hazardous Solvents to be avoided Avoided even in the laboratory [1].

The Quantitative Assessment Framework

The CHEM21 guide employs a quantitative scoring system from 1 to 10 for Safety, Health, and Environment, with 10 representing the highest hazard. The scores are combined to provide an overall preliminary ranking [1]. The specific criteria for each category are detailed below.

Table 2: CHEM21 Safety, Health, and Environment (SH&E) Scoring Criteria

Category Core Basis for Scoring Key Scoring Parameters
Safety Flammability and physical hazards [1]. Primarily based on flash point (e.g., >60°C scores 1; <-20°C scores 7) [1]. Score is incremented for low auto-ignition temperature (<200°C), high electrostatic charge risk (resistivity >10^8 Ω m), or peroxide-forming ability [1].
Health Occupational hazard [1]. Based on GHS hazard statements (e.g., H330 "fatal if inhaled" scores 9; H332 "harmful if inhaled" scores 4) [1]. One point is added if the solvent's boiling point is <85°C, increasing the risk of inhalation exposure [1].
Environment Environmental impact and toxicity [1]. A 10-point criteria system is used, with the highest hazard dictating the final score (3, 5, or 7) [1]. Considers factors like environmental toxicity (e.g., H400 "very toxic to aquatic life") and boiling point [3].

Experimental Protocol for Solvent Greenness Assessment Using CHEM21 Principles

This protocol outlines how to use the CHEM21 methodology to select a greener solvent for a chemical process, using the replacement of xylene in a painting varnish as a model application [2].

1. Initial Solvent Selection and SH&E Assessment

  • Objective: Identify potential substitute solvents and perform an initial hazard screening.
  • Procedure:
    • Define Target Properties: Use software tools (e.g., SUSSOL) or Hansen Solubility Parameters (HSP) to generate a list of candidate solvents with physical properties similar to the target solvent (e.g., xylene) [2].
    • Apply CHEM21 Screening: Evaluate each candidate solvent using the CHEM21 SH&E criteria [2].
    • Shortlist Solvents: Eliminate all solvents with a health score greater than 3 (on the 1-10 scale) or any score of 10, which indicates a highly hazardous substance [2]. This yields a shortlist of potentially viable and greener alternatives.

2. Determination of Hansen Solubility Parameters (HSP)

  • Objective: Experimentally determine the solubility sphere of the material (e.g., a resin) to guide solvent selection based on solubility.
  • Materials:
    • The material to be dissolved (e.g., Dammar resin, Paraloid B72).
    • A range of 15-20 test solvents with known HSP values, covering a broad Hansen space [2].
  • Procedure:
    • Prepare small-scale vials (e.g., 2-4 mL) with a fixed mass of the resin.
    • Add a fixed volume of each test solvent to the vials and agitate for 24 hours.
    • Visually assess and score the solubility result (e.g., 1 for complete dissolution, 0 for no dissolution).
    • Input the solubility data and the known HSP of the test solvents into HSPiP (Hansen Solubility Parameters in Practice) software.
    • The software will calculate the Hansen Solubility Parameters (δD, δP, δH) for the resin and define the radius of its solubility sphere [2].

3. Final Solvent Selection and Varnish Preparation

  • Objective: Select the best solvent and prepare the final resin solution.
  • Procedure:
    • Use the HSPiP software to identify solvents from the CHEM21 shortlist that fall within the solubility sphere of the resin [2].
    • Prepare resin solutions using the selected alternative solvents and a control with the original solvent (e.g., xylene).
    • Proceed to application-specific testing (e.g., on test boards or actual artworks) to evaluate working properties, film formation, and aesthetic results [2].

G Start Start: Identify Target Solvent for Replacement (e.g., Xylene) Step1 1. Initial Solvent Selection Generate candidate list using SUSSOL or HSP tools Start->Step1 Step2 2. CHEM21 SH&E Screening Score candidates on Safety, Health, and Environment criteria Step1->Step2 Step3 3. Experimental HSP Determination Determine solubility sphere of the resin using test solvents Step2->Step3 Step4 4. Final Solvent Selection Overlap CHEM21 shortlist with resin's solubility sphere Step3->Step4 Step5 5. Application Testing Prepare varnish and test working properties and performance Step4->Step5 End End: Implement Greener Solvent Step5->End

Diagram 1: CHEM21 Solvent Selection Workflow. This diagram illustrates the systematic process for selecting greener solvents, integrating computational screening with experimental validation.

The Scientist's Toolkit: Research Reagent Solutions

The following table details key tools and materials used in the CHEM21-guided solvent selection process.

Table 3: Essential Research Reagents and Tools for CHEM21 Assessment

Tool / Material Function / Description Role in the CHEM21 Workflow
SUSSOL Software [2] A software tool that uses a database of 500 solvents and a clustering algorithm to suggest alternative solvents based on similarity in physical properties. Enables the initial, data-driven generation of candidate solvents to replace a target solvent.
HSPiP Software [2] Software for calculating Hansen Solubility Parameters, which predict whether one material will dissolve in another. Used to determine the solubility sphere of a resin and identify which candidate solvents will effectively dissolve it.
Test Solvent Kit A curated collection of solvents with known, diverse Hansen Solubility Parameters (δD, δP, δH). Essential for the experimental determination of a resin's HSP through solubility testing.
CHEM21 Selection Guide [1] The guide itself, providing the ranked solvent lists and the explicit SH&E scoring criteria. Serves as the primary reference for assessing and comparing the greenness of candidate solvents.
GHS/CLP Regulation Data [1] Safety Data Sheets (SDS) and regulatory classifications from the Globally Harmonized System. Provides the necessary hazard statements (e.g., H-codes) required to assign accurate CHEM21 Health and Safety scores.
4-Fluorodeprenyl4-Fluorodeprenyl|CAS 103596-43-6|MAO-B Inhibitor
7-(2-Hydroxypropoxy)theophylline7-(2-Hydroxypropoxy)theophylline|CAS 19729-83-07-(2-Hydroxypropoxy)theophylline for research. Explore its applications as a theophylline derivative. For Research Use Only. Not for human or veterinary use.

Environment, Health, and Safety (EHS), also referred to as SHE, represents a multidisciplinary field focused on implementing measures to preserve the health and safety of workers while protecting the surrounding environment [4]. This framework encompasses the laws, policies, programs, and practices designed to protect the well-being of employees, customers, and the environment within an organization [5]. The SHE approach forms a holistic system for risk management and responsible business operations, with particular significance in chemical and pharmaceutical industries where solvent use represents at least half of the materials used in chemical processes [1].

The historical development of formal SHE management systems gained momentum following industrial tragedies such as the 1984 Bhopal disaster, which highlighted the catastrophic consequences of inadequate safety and environmental controls [4]. Today, SHE has evolved into a strategic priority for organizations worldwide, with health and safety ranking as the #1 concern among corporate directors globally according to a 2024 survey [5]. In the specific context of solvent selection and greenness assessment, the SHE framework provides the foundational principles for evaluating and mitigating the potential hazards associated with chemical substances throughout their lifecycle.

The CHEM21 Solvent Selection Guide and SHE Integration

The CHEM21 selection guide was developed by a European consortium of pharmaceutical companies, universities, and small to medium enterprises as part of the Innovative Medicines Initiative (IMI) to promote sustainable biological and chemical methodologies [1] [3]. This guide represents one of the most comprehensive tools for assessing solvent greenness from a SHE perspective, aligning with the Global Harmonized System (GHS) and European regulations [1]. The primary objective of the CHEM21 guide is to provide researchers with a standardized methodology for comparing the sustainability of solvents used in chemical processes, particularly relevant for drug substance synthesis where solvents typically constitute 50-80% of the total mass of materials used [1].

The guide employs a straightforward classification system that ranks solvents into four categories:

  • Recommended (or preferred): Solvents to be tested first in screening exercises, assuming no chemical incompatibility with process conditions
  • Problematic: Solvents that can be used in laboratory or kilolab scale but require specific measures or significant energy consumption at pilot plant or production scale
  • Hazardous: Solvents where constraints on scale-up are substantial, making substitution during process development a priority
  • Highly hazardous: Solvents to be avoided, even in laboratory settings [1]

This classification system enables researchers and process chemists to make informed decisions early in development stages, potentially avoiding costly solvent substitutions later in the development pipeline.

SHE Pillars in Solvent Assessment

The CHEM21 guide evaluates solvents based on explicit Safety, Health and Environment (SH&E) criteria, with each category scored from 1 to 10 (10 representing the highest hazard) and associated with a color code (green for 1-3, yellow for 4-6, and red for 7-10) [1]. This scoring system directly corresponds to the three SHE pillars, creating a standardized assessment framework.

Table 1: CHEM21 Safety Scoring Criteria Based on Flammability and Physical Hazards

Basic Safety Score Flash Point (°C) GHS Classification Additional Increments
1 >60 — +1 for each: AIT < 200°C, Resistivity > 10⁸ Ω·m, Peroxide formation (EUH019)
3 24 to 60 H226
4 23 to 0 H225 or H224
5 -1 to -20 H225 or H224
7 < -20 H225 or H224

Source: Adapted from CHEM21 Selection Guide [1]

The Safety criterion primarily addresses flammability hazards based on flash point (FP) and boiling point (BP) characteristics, aligned with GHS/CLP regulations [1]. As shown in Table 1, the basic safety score increases as the flash point decreases, with additional increments applied for specific hazards such as low auto-ignition temperature (AIT < 200°C), ability to accumulate electrostatic charges (resistivity > 10⁸ Ω·m), or tendency to form explosive peroxides (hazard statement EUH019) [1]. For example, diethyl ether receives a combined safety score of 10 due to its extremely low flash point (-45°C) combined with multiple additional hazards including low auto-ignition temperature and peroxide formation potential [1].

Table 2: CHEM21 Health Scoring Based on GHS/CLP Hazard Statements

Health Score GHS/CLP Hazard Statements Boiling Point Adjustment
2 H319, H315, H335, H336 +1 if BP < 85°C
4 H317, H320, H335, H336
6 H301, H311, H331, H314
7 H330, H310, H370, H371
9 H340, H350, H360

Source: Adapted from CHEM21 Selection Guide [1] [3]

The Health criterion reflects occupational hazards and is based primarily on GHS/CLP hazard statements as outlined in Table 2 [1]. The scoring system accounts for the relative severity of health hazards, where H330 ("fatal if inhaled") represents a more severe hazard than H331 ("toxic if inhaled"), which in turn exceeds H332 ("harmful if inhaled") [1]. Additionally, the system incorporates a volatility adjustment where one point is added to the health score if the solvent's boiling point is lower than 85°C, reflecting the increased occupational exposure risk with volatile solvents [1]. This adjustment results in volatile carcinogens such as benzene and 1,2-dichloroethane receiving the maximum health score of 10 [1].

The Environment criterion focuses on environmental impact and persistence, utilizing a simplified scoring system based primarily on boiling point ranges and associated GHS environmental hazard statements (Table 3) [3]. Solvents with boiling points between 70-139°C generally receive the most favorable environmental scores, while those boiling below 50°C or above 200°C typically score poorly due to increased environmental dispersion or persistence, respectively [3].

Table 3: CHEM21 Environmental Scoring Criteria

Environmental Score Boiling Point Range (°C) GHS Environmental Hazard Statements
3 70 to 139 No H4xx assigned
5 50 to 69 or 140 to 200 H412, H413
7 <50 or >200 H400, H410, H411

Source: Adapted from CHEM21 Selection Guide [3]

Experimental Protocols for Solvent Assessment

Protocol 1: SHE-Based Solvent Selection for Process Development

Purpose: To systematically evaluate and select solvents for chemical processes based on SHE criteria using the CHEM21 guide.

Materials:

  • CHEM21 solvent selection guide
  • Safety Data Sheets (SDS) for candidate solvents
  • Physical property data (flash point, boiling point, vapor pressure)
  • GHS/CLP classification data
  • Process temperature and pressure parameters

Procedure:

  • Compile solvent candidate list: Identify all solvents chemically compatible with the reaction system based on solubility parameters and mechanistic considerations.
  • Gather SHE data: For each candidate solvent, collect the following data:
    • Flash point, boiling point, and auto-ignition temperature
    • GHS/CLP hazard statements for health and environmental hazards
    • Vapor pressure and occupational exposure limits (where available)
    • Environmental fate data (biodegradability, bioaccumulation potential)
  • Apply CHEM21 scoring: Calculate safety, health, and environmental scores for each solvent using the criteria in Tables 1-3.
  • Categorize solvents: Classify each solvent as recommended, problematic, hazardous, or highly hazardous based on combined SHE scores.
  • Process compatibility assessment: Evaluate the top-ranked "recommended" solvents for technical compatibility with process requirements (reaction efficiency, separation, recovery).
  • Lifecycle considerations: For final candidate solvents, assess broader environmental impacts including production energy requirements and waste management implications.
  • Document selection rationale: Record the SHE assessment and final solvent selection with justification based on both technical and SHE criteria.

Expected Outcomes: Identification of solvents that provide optimal balance between process performance and SHE considerations, with documentation demonstrating due diligence in solvent selection.

Protocol 2: Workplace Exposure Assessment for Solvent Handling

Purpose: To quantitatively assess workplace exposure to solvents during handling and manufacturing operations.

Materials:

  • Passive diffusion samplers (e.g., Radiello passive samplers)
  • Personal protective equipment (PPE)
  • Sampling pumps (for active sampling comparison)
  • Thermal desorption tubes
  • Gas chromatography with flame ionization detector (GC-FID) or mass spectrometry (GC-MS)
  • Temperature-controlled storage (<5°C)
  • Worksheet for activity recording

Procedure:

  • Study design: Define sampling strategy based on work tasks, duration, and frequency of solvent handling operations.
  • Sampler preparation: According to manufacturer specifications, prepare passive samplers while wearing appropriate PPE in a clean environment.
  • Participant instruction: Verbally instruct operators on proper use of passive samplers, including:
    • Correct attachment to lapel or breathing zone
    • Proper opening and closing procedures
    • Completion of activity worksheets recording sampling times, tasks performed, and solvents handled
  • Sample collection: Conduct measurements over consecutive workdays, covering at least 80% of the work shift [6].
  • Sample storage and transport: Store samples at <5°C immediately after collection and transport to analytical laboratory under temperature-controlled conditions.
  • Chemical analysis:
    • Extract samples using appropriate solvent (e.g., CSâ‚‚ for VOC analysis)
    • Analyze using GC-FID or GC-MS with DB-624 or equivalent column
    • Quantify concentrations using internal standard method and calibration curves
  • Data interpretation:
    • Calculate time-weighted average exposures
    • Compare with occupational exposure limits
    • Identify tasks and conditions associated with highest exposure levels
  • Control implementation: Based on findings, implement appropriate engineering controls, administrative controls, or PPE to maintain exposures below acceptable limits.

Expected Outcomes: Quantitative exposure assessment data enabling evidence-based decisions on exposure control measures and verification of compliance with occupational exposure limits.

SHE Implementation Workflows

The integration of SHE principles into solvent selection and assessment processes requires systematic implementation. The following workflow diagrams visualize the key procedural relationships and decision pathways.

SHE_Workflow cluster_CHEM21 CHEM21 Assessment Elements Start Process Development Requirement SHEPolicy Establish SHE Policy Start->SHEPolicy SolventID Identify Solvent Candidates SHEPolicy->SolventID SHEAssessment Conduct SHE Assessment (CHEM21 Scoring) SolventID->SHEAssessment TechEvaluation Technical Performance Evaluation SHEAssessment->TechEvaluation Safety Safety Scoring (Flammability/Physical Hazards) SHEAssessment->Safety SHECompliance Verify SHE Compliance TechEvaluation->SHECompliance Implementation Implement with Controls SHECompliance->Implementation Monitoring Continuous Monitoring Implementation->Monitoring Optimization Process Optimization Monitoring->Optimization Feedback Loop Optimization->SHEAssessment Iterative Improvement Health Health Scoring (GHS Hazard Statements) Safety->Health Environment Environmental Scoring (Persistence/Toxicity) Health->Environment Classification Solvent Classification (Recommended/Problematic/Hazardous) Environment->Classification

Figure 1: SHE Integration in Solvent Selection Workflow

SHE_Pillars cluster_Safety Safety Pillar cluster_Health Health Pillar cluster_Environment Environment Pillar SHE SHE Management System cluster_Safety cluster_Safety SHE->cluster_Safety cluster_Health cluster_Health SHE->cluster_Health cluster_Environment cluster_Environment SHE->cluster_Environment S1 Flammability Control (Flash Point Management) S2 Physical Hazard Mitigation (Static Control, Peroxide Prevention) S3 Process Safety Management (Reaction Hazard Assessment) S4 Engineering Controls (Ventilation, Explosion Protection) H1 Exposure Assessment (Workplace Monitoring) H2 Hazard Communication (GHS Labeling, SDS) H3 Health Surveillance (Medical Monitoring) H4 Control Implementation (PPE, Administrative Controls) E1 Waste Management (Recycling, Treatment) E2 Emission Control (Air, Water Protection) E3 Environmental Impact Assessment (Persistence, Toxicity) E4 Resource Efficiency (Solvent Recovery, Energy Reduction)

Figure 2: Interrelationship of SHE Pillars in Solvent Management

Research Reagent Solutions and Materials

Table 4: Essential Materials for Solvent SHE Assessment

Category Item/Reagent Specification Function in SHE Assessment
Assessment Tools CHEM21 Selection Guide Current version Provides standardized scoring system for solvent SHE performance
GHS/CLP Classification Database Updated regulatory data Supplies hazard statements for health and environmental scoring
Physical Property Database Contains FP, BP, VP data Enables safety scoring and volatility assessments
Analytical Materials Passive Diffusion Samplers Radiello or equivalent Collects personal exposure samples for workplace monitoring
GC-FID/MS System DB-624 or equivalent column Quantifies solvent concentrations in exposure assessment
Thermal Desorption Tubes Standard sorbent materials Alternative sampling method for VOC analysis
Reference Materials Certified Reference Standards Analytical grade purity Enables calibration and quantification in exposure monitoring
SDS Documentation Manufacturer-provided Supplies hazard information and handling precautions
Safety Equipment Personal Protective Equipment Lab-appropriate Protects researchers during solvent handling and assessment
Flammable Storage Cabinets Certified safety design Secure storage for solvent samples and references
Ventilation Systems Fume hoods, local exhaust Controls airborne exposures during experimental work

The Three-Pillar Approach to Safety, Health, and Environment (SHE) provides a comprehensive framework for evaluating solvent greenness within the context of the CHEM21 guide. By integrating systematic SHE assessment early in process development, researchers and drug development professionals can make informed decisions that balance technical requirements with safety, health, and environmental considerations. The experimental protocols and workflows presented in this document offer practical methodologies for implementing SHE principles in solvent selection and workplace exposure assessment. As regulatory pressures and sustainability expectations continue to evolve, robust SHE integration will remain essential for responsible chemical process development in pharmaceutical and related industries.

Decoding the GHS/CLP Alignment for Standardized Hazard Assessment

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) provides a universal framework for classifying chemical substances and mixtures according to their physical, health, and environmental hazards. Developed by the United Nations, GHS establishes standardized hazard communication elements, including pictograms, signal words, and hazard statements, to ensure consistent safety information across international borders. As a non-binding international standard, GHS operates on a "building blocks" approach, allowing individual countries and regions to select which provisions to implement within their own legislation [7].

The CLP Regulation (Classification, Labelling and Packaging, Regulation (EC) No 1272/2008) is the European Union's binding legislation that implements GHS within its jurisdiction [8] [7]. Enforced from January 2009, CLP fully aligns with GHS principles while incorporating specific regional adaptations to address unique EU safety concerns. This regulation directly replaced previous EU directives on dangerous substances and preparations, establishing a unified system for hazard identification and communication throughout the European market [8]. For researchers applying the CHEM21 solvent selection guide, understanding the nuanced relationship between these two systems is fundamental for accurate solvent greenness assessment and regulatory compliance.

Comparative Analysis: GHS vs. CLP

Core Alignment Principles

GHS and CLP share the fundamental objective of ensuring that chemical hazards are clearly identified and effectively communicated to users. Both systems employ identical hazard communication elements, including:

  • Pictograms: Red diamond-shaped symbols with black hazard symbols on a white background [8]
  • Signal words: "Danger" or "Warning" to indicate the relative level of hazard severity
  • Hazard statements: Standardized phrases describing the nature and degree of a hazard (e.g., H226 for flammable liquids) [7]
  • Precautionary statements: Measures to minimize or prevent adverse effects from exposure [8]

This alignment ensures a consistent understanding of chemical hazards and facilitates the global trade of chemicals while maintaining high safety standards within the EU [8].

Key Divergences in Implementation

Despite their common foundation, significant differences exist between the purely international GHS system and its European implementation through CLP. These divergences primarily manifest in two key areas: the adoption of specific hazard categories and the introduction of supplementary EU-specific hazards.

Table 1: GHS Hazard Classes Not Fully Adopted in CLP

Hazard Class GHS Category CLP Status Rationale for Omission
Flammable liquids Category 4 (H227) Not adopted Considered to indicate negligible hazard level [7]
Acute toxicity Category 5 (H303, H313, H333) Not adopted Considered to indicate negligible hazard level [7]
Skin irritation Category 3 (H316) Not adopted Considered to indicate negligible hazard level [7]
Eye irritation Category 2B (H320) Not adopted Considered to indicate negligible hazard level [7]
Aspiration hazard Category 2 (H305) Not adopted Considered to indicate negligible hazard level [7]
Hazard to aquatic environment Acute categories 2 & 3 (H401, H402) Not adopted Considered to indicate negligible hazard level [7]

The CLP Regulation introduces several EU-specific hazard classes that have no direct equivalent in the UN GHS framework. These additional classifications address environmental and health concerns of particular relevance to European chemical safety policies.

Table 2: EU-Specific Hazard Classes under CLP

Hazard Class Categories EUH Codes
Endocrine disruptors For human health (Cat. 1 & 2) EUH380, EUH381 [7]
Endocrine disruptors For the environment (Cat. 1 & 2) EUH430, EUH431 [7]
Persistent, Bioaccumulative, Toxic (PBT) - EUH440 [7]
Very Persistent, Very Bioaccumulative (vPvB) - EUH441 [7]
Persistent, Mobile, Toxic (PMT) - EUH450 [7]
Very Persistent, Very Mobile (vPvM) - EUH451 [7]

G GHS GHS GHS_Blocks GHS Building Blocks GHS->GHS_Blocks CLP CLP Adopted Adopted Categories CLP->Adopted EU_Specific EU-Specific Hazards CLP->EU_Specific GHS_Blocks->Adopted Not_Adopted Omitted Categories GHS_Blocks->Not_Adopted

Figure 1: GHS to CLP Implementation Pathway. CLP adopts selected GHS categories while introducing unique EU-specific hazard classifications.

CHEM21 Solvent Assessment Methodology

Integration of GHS/CLP in Greenness Evaluation

The CHEM21 solvent selection guide employs a sophisticated scoring system that directly incorporates GHS/CLP hazard statements to evaluate solvent sustainability. This methodology transforms qualitative hazard information into quantitative scores across three critical domains: safety, health, and environmental impact. Each domain is scored from 1-10, with higher values representing greater hazard levels, and color-coded (green=1-3, yellow=4-6, red=7-10) for rapid visual assessment [9].

The health score derivation relies extensively on GHS/CLP H3xx statements, which communicate specific health hazards. The scoring follows a structured hierarchy based on the severity of these statements.

Table 3: CHEM21 Health Score Criteria Based on GHS/CLP Statements

Health Score CMR Properties STOT/Acute Toxicity Irritation
2 H341, H351, H361 (CMR cat. 2) - -
4 H340, H350, H360 (CMR cat. 1) - -
6 - H304, H371, H373 H315, H317, H319, H335, EUH066
7 - H334 H318
9 - H370, H372 H314

CMR: Carcinogen, Mutagen, or Reprotoxic; STOT: Specific Target Organ Toxicity

For solvents with incomplete REACH registration data, the CHEM21 guide applies a default health score of 5 (if boiling point ≥85°C) or 6 (if boiling point <85°C), unless the supplier provides more stringent H3xx statements [9]. This approach ensures consistent assessment even with limited data availability.

Safety and Environmental Scoring Protocols

The safety score in the CHEM21 guide primarily derives from physical properties with contributions from specific GHS/CLP statements. The base safety score is determined by flash point ranges, with additional points added for specific hazardous properties.

Table 4: CHEM21 Safety Score Calculation Methodology

Base Safety Score Flash Point (°C) GHS Statements
1 > 60 -
3 23 to 60 H226
4 22 to 0 -
5 -1 to -20 -
7 < -20 H225 or H224

Additional +1 to safety score for each: Auto-ignition temperature <200°C, Resistivity >10⁸ ohm.m, Ability to form peroxides (EUH019)

The environmental score incorporates both the volatility of the solvent (based on boiling point) and GHS H4xx environmental hazard statements. The score reflects the most stringent of these factors, addressing both atmospheric impact and aquatic toxicity [9].

G Start Solvent Assessment Safety Safety Score Flash Point + GHS Start->Safety Health Health Score GHS H3xx Statements Start->Health Environment Environment Score BP + GHS H4xx Start->Environment Combine Combine Scores Safety->Combine Health->Combine Environment->Combine Ranking Final Ranking Combine->Ranking

Figure 2: CHEM21 Solvent Assessment Workflow. The methodology integrates GHS/CLP data across three assessment domains to determine final solvent ranking.

The CHEM21 guide combines individual safety, health, and environmental scores to generate an overall solvent ranking that guides researchers toward more sustainable choices. The combination follows specific rules that emphasize the most hazardous properties.

Table 5: CHEM21 Overall Solvent Ranking Criteria

Score Combination Default Ranking Examples After Review
One score ≥ 8 Hazardous Chloroform (Highly Hazardous)
Two "red" scores (7-10) Hazardous Pyridine (Hazardous)
One score = 7 Problematic Benzyl alcohol (Problematic)
Two "yellow" scores (4-6) Problematic Cyclohexanone (Problematic)
Other combinations Recommended Acetone, Ethanol (Recommended)

The ranking system incorporates expert review to address limitations of purely GHS-based scoring. For instance, chloroform receives a default "Problematic" ranking but was elevated to "Highly Hazardous" based on its very low occupational threshold limits, demonstrating how professional judgment refines automated scoring [9].

Experimental Protocols for Solvent Assessment

Protocol 1: GHS/CLP-Based Hazard Scoring

This protocol provides a standardized methodology for determining CHEM21 safety, health, and environmental scores based on available GHS/CLP data.

Materials and Equipment:

  • Safety Data Sheets (SDS) from supplier with GHS/CLP classification
  • CHEM21 Solvent Selection Guide spreadsheet tool [9]
  • Physical property data (flash point, boiling point, auto-ignition temperature)

Procedure:

  • Compile GHS/CLP Statements: Extract all H-codes and EUH-codes from Section 2 of the SDS
  • Determine Safety Score:
    • Record flash point and identify base score from Table 4
    • Add +1 for each: auto-ignition temperature <200°C, resistivity >10⁸ ohm.m, peroxide formation (EUH019)
  • Calculate Health Score:
    • Identify the most severe H3xx statement using Table 3 hierarchy
    • Add +1 if boiling point <85°C
  • Establish Environmental Score:
    • Determine score based on boiling point range (<50°C=7, 50-69°C=5, 70-139°C=3, etc.)
    • Compare with H4xx statement score (H412/H413=5, H400/H410/H411=7)
    • Apply the more stringent of the two scores
  • Apply Defaults if Needed: Use default scores (Health=5/6, Environment=5) if REACH registration incomplete and no supplier statements available

Quality Control: Verify scores against the interactive CHEM21 solvent selection tool and consult occupational hygiene experts for final ranking decisions, particularly for solvents with limited data.

Protocol 2: Green Solvent Alternative Assessment

This protocol employs machine learning approaches to identify sustainable solvent alternatives while ensuring GHS/CLP compliance.

Materials and Equipment:

  • GreenSolventDB database (10,189 solvent metrics) [10]
  • Hansen solubility parameters for target and alternative solvents
  • CHEM21 assessment tools [9]

Procedure:

  • Profile Hazardous Solvent: Complete GHS/CLP-based hazard scoring per Protocol 1 for the solvent to be replaced
  • Identify Alternatives:
    • Query GreenSolventDB for solvents with similar Hansen solubility parameters
    • Apply machine learning models (Gaussian Process Regression recommended) to predict greenness metrics [10]
  • Rank Alternatives: Sort candidates by CHEM21 overall ranking, prioritizing "Recommended" solvents
  • Verify Performance: Conduct laboratory testing to confirm solubility performance of top candidates
  • Validate Compliance: Ensure final selection meets all CLP requirements for target market, including EU-specific hazard classes if applicable

Case Study Application: For benzene replacement, this methodology successfully identifies 2-methyltetrahydrofuran as a greener alternative with comparable solvation properties and improved GHS/CLP profile [10].

Research Toolkit for Solvent Assessment

Table 6: Essential Research Tools for GHS/CLP-Compliant Solvent Assessment

Tool/Resource Function Source/Access
CHEM21 Solvent Selection Guide Scores solvents based on safety, health, and environmental criteria from GHS/CLP data [9] ACS GCI Pharmaceutical Roundtable
Interactive Solvent Selection Tool Allows solvent selection based on Principal Component Analysis of physical properties [11] ACS Green Chemistry Institute
GreenSolventDB Machine learning-generated database of green solvent metrics for 10,189 solvents [10] Adv Sci (Weinh.) 2025
Process Mass Intensity (PMI) Calculator Determines PMI value by accounting for raw material inputs and API outputs [11] ACS GCI Pharmaceutical Roundtable
CLP Regulation Annex VI Official list of harmonized classification and labelling of substances [8] ECHA Website
GHS Revision 10 Latest UN GHS standards informing future regulatory updates [12] UNECE Website
3-ethyl-2-methylhept-2-ene3-Ethyl-2-methylhept-2-ene|C10H20|CAS 19780-61-1
Gossyplure(Z,Z)-Gossyplure|52207-99-5|Insect Pheromone(Z,Z)-Gossyplure is a sex pheromone for pink bollworm mating disruption research. For Research Use Only. Not for human or veterinary use.

The strategic alignment between GHS and CLP establishes a robust foundation for standardized chemical hazard assessment, while regional adaptations require careful navigation for global compliance. The CHEM21 solvent selection guide successfully leverages this aligned framework to transform GHS/CLP hazard statements into actionable green chemistry metrics. By integrating these protocols into solvent selection workflows, researchers and drug development professionals can systematically advance solvent sustainability while maintaining regulatory compliance across jurisdictions. The continued evolution of both GHS standards and assessment methodologies promises further refinement of green chemistry practices in pharmaceutical development and manufacturing.

Within the framework of the CHEM21 guide research, solvent selection is a critical component for advancing green chemistry in the pharmaceutical industry. Interpreting the final ranking of solvents—categorizing them as recommended, problematic, or hazardous—is not a trivial task and requires a multi-fetric evaluation. This assessment synthesizes data on environmental, health, and safety (EHS) profiles, life cycle impacts, and technical performance to guide researchers and drug development professionals toward more sustainable laboratory and manufacturing practices [13]. The goal is to move beyond historical, often short-sighted solvent substitution strategies, such as replacing benzene with toluene, without fully considering the latter's own suspected hazards, including potential damage to unborn children and organs [13]. A modern, comprehensive approach, as embodied by the CHEM21 project, seeks to provide a balanced and scientifically robust framework for these critical decisions, integrating regulatory compliance with fundamental green chemistry principles.

Quantitative Solvent Assessment and Classification

Structured Solvent Ranking Tables

A comprehensive solvent assessment involves scoring and ranking based on a suite of quantitative and qualitative indicators. The following tables provide a structured overview of how solvents can be classified, summarizing key hazard information and regulatory status to aid in interpretation.

Table 1: Classification of Common Solvents Based on Assessment Guides

Solvent CHEM21 / GSK Category Key Health & Safety Hazards Environmental Concerns Common Regulatory Restrictions
Ethanol Recommended Flammable, Irritant [14] Low cumulative energy demand (CED) [13] Generally compliant
Heptane Recommended Flammable, Irritant [14] Low CED, but high aquatic toxicity potential [13] [15] Generally compliant
Acetone Recommended Flammable, Irritant [14] - Generally compliant; listed as F003 spent solvent [16]
Ethyl Acetate Recommended Flammable, Irritant [14] - Generally compliant; listed as F003 spent solvent [16]
Toluene Problematic Flammable, Irritant, Suspected reproductive toxicant [13] [14] - REACH restrictions; suspected of damaging the unborn child [13]
Diethyl Ether Problematic Flammable, Narcotic, Peroxide formation [14] - -
N-Methyl-2-pyrrolidone (NMP) Problematic Reproductive toxicity [13] - REACH Substance of Very High Concern (SVHC) [13]
Dichloromethane (DCM) Hazardous Carcinogenic, Irritant [14] Ozone-depleting [13] REACH SVHC; IARC likely carcinogen [13]
Benzene Hazardous Carcinogenic [14] - -
Chloroform Hazardous Narcotic, Irritant [14] - REACH SVHC; IARC likely carcinogen [13]
1,4-Dioxane Hazardous - - Not recommendable from environmental perspective [15]
N,N-Dimethylformamide (DMF) Hazardous Reproductive toxicity [13] - REACH SVHC [13]

Table 2: Quantitative Exposure and Hazard Limits for Selected Solvents

Solvent Workplace Exposure Limit (8-hr TWA) Flash Point (°C) Explosive Limits (% in air) GHS Hazard Pictograms
Acetone 500 ppm / 1500 ppm [14] -20.7 [14] 2.6 - 12.8 [14] Flammable, Irritant
Methanol Not specified 11 [14] 6.7 - 36.0 [14] Flammable, Health Hazard, Toxic
Toluene Not specified 16 [14] 1.2 - 7.1 [14] Flammable, Irritant, Health Hazard
Dichloromethane 100 ppm [14] Above 100 [14] Not specified Irritant, Health Hazard
n-Hexane 20 ppm [14] -26 [14] 1.2 - 7.4 [14] Flammable, Irritant, Environ. Hazard

Interpretation of Ranking Criteria

The classification of a solvent as "Recommended" hinges on a favorable balance across multiple domains. Simple alcohols (e.g., methanol, ethanol) and alkanes (e.g., heptane, hexane) are often placed in this category due to their relatively low environmental impact scores and well-understood safety profiles [15]. From a technical perspective, these solvents must also demonstrate effective performance in their intended application, such as sufficient solubility power for a given API synthesis.

Solvents are elevated to "Problematic" status when they possess significant, but often manageable, hazards. Toluene and diethyl ether are prime examples. Toluene's status as a suspected reproductive toxicant and ether's tendency to form explosive peroxides necessitate rigorous control measures [13] [14]. Their use often requires additional engineering controls, specialized personal protective equipment (PPE), and strict administrative procedures. The "Hazardous" category is reserved for solvents with severe and often irreversible impacts on human health or the environment. Dichloromethane (DCM), benzene, chloroform, and 1,4-dioxane fall into this group. DCM and benzene are recognized carcinogens, while DCM additionally contributes to ozone depletion [13] [14]. The use of these solvents is increasingly restricted under regulations like REACH, and their substitution is a high priority in green chemistry programs [13].

Experimental Protocols for Solvent Ranking and Validation

Protocol 1: Solvent Greenness Assessment Using Selection Guides

This protocol outlines the steps for systematically evaluating and ranking solvents for a specific chemical process using established guide.

  • Objective: To assign a greenness category (Recommended, Problematic, Hazardous) to candidate solvents for a given synthesis or formulation step.
  • Principles: The assessment is based on a combined evaluation of Environmental, Health, and Safety (EHS) criteria and Life Cycle Assessment (LCA) principles, as embodied by the CHEM21 and GSK solvent selection guides [13].

Step-by-Step Methodology:

  • Define Solvent List: Compile a list of all solvents that are technically feasible for the intended chemical process (e.g., reaction, crystallization, extraction).
  • Consult Selection Guide: Cross-reference the solvent list with a current solvent selection guide (e.g., CHEM21, GSK, Pfizer). Record the preliminary category for each solvent.
  • Detailed Hazard Check: For each solvent, consult the Safety Data Sheet (SDS) and regulatory lists (e.g., REACH SVHC, EPA F-list [16] [13]). Document specific hazards:
    • Health: Carcinogenicity, mutagenicity, reproductive toxicity (e.g., DMF, NMP), acute toxicity [13] [14].
    • Safety: Flash point, explosive limits, peroxide formation potential (e.g., diethyl ether) [14].
    • Environment: Biodegradability, aquatic toxicity, ozone depletion potential (e.g., DCM), global warming potential [13].
  • Check Regulatory Status: Verify if the solvent is subject to usage restrictions or authorization requirements under regulations like REACH [13].
  • Assign Final Category: Synthesize the information from steps 2-4 to assign a final category:
    • Recommended: Low EHS burden, no major regulatory restrictions.
    • Problematic: Significant but manageable hazards; requires specific controls.
    • Hazardous: Severe health/environmental hazards; subject to regulatory restrictions; substitution is required.
  • Documentation: Record the rationale for the categorization of each solvent, citing the specific hazards and regulatory findings.

Protocol 2: Computational Solvent Performance and Sustainability Screening

This protocol describes the use of data-driven platforms and machine learning models to predict solvent performance (e.g., solubility) and integrate this with sustainability metrics, as exemplified by the SolECOs platform [17].

  • Objective: To identify an optimal solvent that balances high process efficiency (e.g., high API solubility) with a superior environmental profile.
  • Principles: Leverage machine learning (ML) models trained on large solubility datasets and couple predictions with standardized LCA indicators [17] [18].

Step-by-Step Methodology:

  • Input API Data: Define the target Active Pharmaceutical Ingredient (API) by its structure. Generate or calculate a set of molecular descriptors (e.g., using tools within the platform).
  • Select Solvent Candidates: Choose from a pre-defined list of industrially relevant solvents and their binary mixtures within the platform (e.g., the 30 solvents in SolECOs) [17].
  • Run Solubility Prediction: Execute the ML models (e.g., Polynomial Regression Model-based Multi-Task Learning Network - PRMMT, or FastSolv) to obtain predicted solubility profiles for the API in the candidate solvents across a temperature range [17] [18].
  • Generate Sustainability Ranking: The platform automatically calculates sustainability scores for each solvent candidate using defined metrics (e.g., 23 Life Cycle Impact indicators from ReCiPe 2016 and the GSK sustainable solvent framework) [17].
  • Multi-criteria Decision Analysis: Review the platform's output, which provides a multidimensional ranking of solvents based on both predicted solubility (performance) and sustainability score.
  • Experimental Validation: For the top-ranked solvent(s), conduct laboratory-scale crystallization experiments to validate the predicted solubility and resulting crystal properties (e.g., yield, polymorphism). Compare results with predictions [17].

Visualization of the Solvent Assessment Workflow

The following diagram illustrates the logical sequence and decision points in a comprehensive solvent assessment process, integrating both guide-based and computational screening methods.

solvent_workflow start Start: Identify Need for Solvent input Input: - Target API/Process - Technical Requirements start->input guide_screen Step 1: Preliminary Greenness Screening input->guide_screen comp_screen Step 2: Computational Performance Screening input->comp_screen hazard_check Detailed Hazard & Regulatory Check guide_screen->hazard_check comp_screen->hazard_check For viable candidates multi_crit Multi-Criteria Decision Analysis hazard_check->multi_crit rank Final Ranking: Recommended, Problematic, Hazardous multi_crit->rank validate Experimental Validation rank->validate For top-ranked solvents implement Implement & Monitor validate->implement

Solvent Assessment Workflow

This section details key databases, software tools, and regulatory resources essential for conducting a thorough solvent assessment.

Table 3: Essential Resources for Solvent Selection and Assessment

Tool / Resource Name Type Primary Function in Solvent Assessment Key Features / Data Provided
SolECOs Platform [17] Data-Driven Software Platform Sustainable solvent selection for pharmaceutical crystallization. Predicts solubility for 1186 APIs in 30 solvents; integrates ML models & LCA indicators (ReCiPe 2016, GSK framework).
FastSolv / ChemProp Models [18] Machine Learning Model Predicts molecule solubility in organic solvents. Uses molecular embeddings; accounts for temperature effects; publicly available.
BigSolDB [18] Database Training and benchmarking data for solubility prediction models. Compiled solubility data from nearly 800 published papers for ~800 molecules in >100 solvents.
EPA F-List (e.g., F001-F005) [16] Regulatory List Identifies spent solvents classified as hazardous waste. Lists common spent halogenated (e.g., trichloroethylene) and non-halogenated (e.g., xylene, acetone) solvents.
REACH SVHC List [13] Regulatory List Identifies Substances of Very High Concern subject to authorization. Includes solvents like DMF, NMP, DMAc, and various chlorinated solvents.
GSK/Pfizer/CHEM21 Solvent Selection Guides [13] Assessment Guide Categorizes solvents based on EHS profiles. Provides a ranked list of solvents from "Preferred" to "Undesirable".
EHS Assessment Tool (ETH Zurich) [13] Spreadsheet Tool Numerically ranks solvent greenness based on EHS criteria. Free spreadsheet; combines hazard codes and exposure limits into a single score.

The Critical Role of Solvent Selection in Sustainable Pharmaceutical Manufacturing

Solvent selection is a pivotal determinant of sustainability in pharmaceutical manufacturing, influencing process efficiency, environmental impact, and regulatory compliance. Solvents typically constitute 80-90% of the total mass utilization in active pharmaceutical ingredient (API) synthesis and can account for as much as 80% of the life cycle process waste [19] [20]. Driven by stringent regulations such as REACH and industry initiatives like the Green Pharmacy Initiative, pharmaceutical companies are increasingly adopting green chemistry principles that prioritize safer, more sustainable solvent systems [13] [17]. This application note details practical frameworks, experimental protocols, and assessment tools for implementing sustainable solvent selection within the context of the CHEM21 guide, providing scientists with methodologies to advance greener pharmaceutical manufacturing.

Solvent Greenness Assessment Frameworks

The CHEM21 Solvent Selection Guide

The CHEM21 Selection Guide represents a standardized approach for evaluating solvent environmental, health, and safety (EHS) profiles, aligned with the Globally Harmonized System (GHS) of Classification and Labelling of Chemicals [3]. This framework categorizes solvents into three tiers—Recommended, Problematic, or Hazardous—based on integrated safety, health, and environmental scores.

  • Safety Scoring: Evaluates flammability (flash point), auto-ignition temperature, peroxide formation potential, and decomposition energy. For example, solvents with flash points >60°C score 1 (preferable), while those <-20°C score 7 (hazardous) [3].
  • Health Scoring: Derived from GHS hazard statements, with additional points added for low boiling points (<85°C) indicating higher inhalation exposure risk [3].
  • Environmental Scoring: Based on boiling point ranges and GHS environmental hazard statements (H400-H413), with scores of 3, 5, or 7 assigned accordingly [3].
Complementary Assessment Metrics

Multiple quantitative frameworks exist to complement the CHEM21 guide, providing holistic sustainability perspectives:

  • Life Cycle Assessment (LCA): Comprehensive methodology evaluating environmental impacts across the solvent's entire life cycle, from raw material extraction to disposal [20]. The ReCiPe 2016 method incorporates 23 midpoint and endpoint impact indicators for robust comparative analysis [17].
  • Process Mass Intensity (PMI): Preferred metric of the ACS Green Chemistry Institute Pharmaceutical Roundtable, calculated as the total mass of materials used per mass of product obtained, emphasizing resource efficiency [20].
  • Cumulative Energy Demand (CED): Assesses the total energy required for solvent production, including credits for recycling via distillation or energy recovery via incineration [13].
  • Green Environmental Assessment and Rating for Solvents (GEARS): Novel metric integrating ten parameters including toxicity, biodegradability, renewability, and cost into a single score [21].

Table 1: Comparison of Major Solvent Assessment Frameworks

Framework Key Metrics Output Primary Application
CHEM21 Guide Safety, Health, Environment Categorical (Recommended/Problematic/Hazardous) Initial solvent screening
EHS (ETH Zurich) Environmental, Health, Safety hazards Numerical score (0-9, lower=greener) Process development
GSK SSG Environmental, Health, Safety, Waste Score (0-10, lower=greener) Pharmaceutical process design
GEARS Ten parameters including renewability, efficiency, cost Overall score (0-100, higher=greener) Comprehensive solvent evaluation
LCA Multiple impact categories (ReCiPe 2016) Environmental impact profiles Comparative sustainability analysis

Experimental Protocols for Sustainable Solvent Selection

Computational Screening Workflow

Purpose: To efficiently identify potential green solvent candidates for API crystallization using predictive modeling before experimental verification.

Materials:

  • Solubility database (e.g., SolECOs platform containing 30,000+ data points for 1186 APIs in 30 solvents) [17]
  • Machine learning models (Polynomial Regression Model-based Multi-Task Learning Network/PRMMT, Point-Adjusted Prediction Network/PAPN, Modified Jouyban-Acree-based Neural Network/MJANN for binary systems) [17]
  • Hansen Solubility Parameters data
  • CHEM21 Solvent Selection Guide
  • Life Cycle Assessment software (e.g., SimaPro)

Procedure:

  • Input API Characterization: Calculate 347 molecular descriptors from 3D molecular structure of target API [17].
  • Solubility Prediction: Apply appropriate ML model (PRMMT for general screening, PAPN for specific temperatures, MJANN for binary solvent systems) to predict API solubility in candidate solvents [17].
  • Sustainability Assessment: Rank solvent candidates using integrated sustainability metrics (CHEM21, GSK SSG, LCA indicators) [17].
  • Uncertainty Quantification: Evaluate prediction reliability through probability distributions of residuals [17].
  • Candidate Selection: Identify optimal solvents balancing solubility performance and sustainability metrics.

G Start Start Solvent Selection CharAPI Characterize API Molecular Structure Start->CharAPI Predict Predict Solubility Using ML Models CharAPI->Predict Assess Assess Sustainability (CHEM21, LCA) Predict->Assess Select Select Optimal Solvent Candidates Assess->Select Validate Experimental Validation Select->Validate End Implement Green Process Validate->End

Laboratory-Scale Green Solvent Validation

Purpose: Experimentally verify computational predictions for API crystallization in selected green solvents.

Materials:

  • API compound (e.g., paracetamol, meloxicam, piroxicam, cytarabine) [17]
  • Candidate green solvents (e.g., ethyl lactate, dimethyl isosorbide, ethanol-water mixtures) [22]
  • Standard laboratory equipment: jacketed reactor, temperature control system, vacuum filtration apparatus, analytical HPLC
  • CHEM21 Solvent Selection Guide for reference

Procedure:

  • Solvent Preparation: Obtain and characterize purity of candidate green solvents. For binary mixtures, prepare precise volumetric ratios.
  • Solubility Determination: Use shake-flask method at controlled temperatures (typically 10-50°C) to establish experimental saturation concentrations [17].
  • Crystallization Trials: Conduct cooling crystallization with controlled temperature ramp (0.1-1.0°C/min) from saturation point [17].
  • Product Characterization: Analyze crystal form (polymorphism) by PXRD, purity by HPLC, yield by gravimetric analysis [17].
  • Solvent Recovery: Implement distillation to recover and reuse solvent, calculating recovery efficiency [13].
  • Green Metrics Calculation: Determine Process Mass Intensity (PMI), E-factor, and applicable sustainability scores for the process [20].

The Scientist's Toolkit: Research Reagent Solutions

Table 2: Essential Materials for Green Solvent Research

Reagent/Material Function/Application Green Credentials CHEM21 Category
Ethyl Lactate Bio-based solvent for reactions and extraction Derived from renewable resources, biodegradable [22] Recommended
Dimethyl Isosorbide Green solvent for synthesis, particularly semicarbazones [22] Renewable origin, low toxicity, used in cosmetics [22] Recommended
Ethanol-Water Mixtures Crystallization medium Reduced toxicity, lower VOC emissions vs pure organic solvents [3] Recommended
Supercritical COâ‚‚ Extraction and separation medium Non-flammable, non-toxic, easily recyclable [23] Recommended
Ionic Liquids Tunable solvents for specialized applications Negligible vapor pressure, highly customizable [23] Case-dependent
Deep Eutectic Solvents (DES) Biorenewable solvents for synthesis Low toxicity, biodegradable, inexpensive components [23] Recommended
NeomenthoglycolNeomenthoglycol (CAS 3564-95-2) - High-Purity StandardHigh-purity Neomenthoglycol (cis-p-Menthane-3,8-diol), a natural compound. For Research Use Only. Not for human or veterinary use.Bench Chemicals
2-(3-Mercaptophenyl)acetic acid2-(3-Mercaptophenyl)acetic Acid|CAS 63271-86-32-(3-Mercaptophenyl)acetic acid (CAS 63271-86-3) is a key aryl thioether carboxylic acid for research. This product is for Research Use Only. Not for human or veterinary use.Bench Chemicals

Implementation in Pharmaceutical Development

Integrating Assessment Tools

Successful implementation of sustainable solvent strategies requires leveraging multiple complementary tools:

  • ACS GCI Solvent Selection Tool: Interactive platform featuring 272 solvents with PCA analysis of 70 physical properties, ICH classification, and environmental impact categories [24].
  • Data-Driven Platforms: SolECOs integrates predictive modeling with sustainability assessment for both single and binary solvent systems [17].
  • Machine Learning Expansion: Gaussian Process Regression models trained on GSK Solvent Sustainability Guide data can predict greenness metrics for over 10,000 solvents, dramatically expanding options beyond traditional guides [10].
Case Study: Semicarbazone Synthesis in Green Solvents

Research demonstrates the successful application of green solvent principles to pharmaceutical synthesis. Semicarbazones, molecules with anticonvulsant and anti-tumor activity, were synthesized quantitatively at room temperature within minutes using the green solvents ethyl lactate and dimethyl isosorbide, replacing traditional toxic reagents and high-energy conditions [22]. This approach satisfied green chemistry requirements while maintaining excellent efficiency, demonstrating the practical viability of green solvent implementation for pharmaceutical production.

Strategic solvent selection represents a critical opportunity to advance sustainable pharmaceutical manufacturing. By integrating robust assessment frameworks like the CHEM21 guide with predictive computational tools and experimental validation, researchers can significantly reduce the environmental footprint of pharmaceutical processes while maintaining efficiency and product quality. The methodologies outlined in this application note provide a structured approach for scientists to systematically evaluate and implement greener solvent systems throughout drug development and manufacturing.

A Step-by-Step Guide to Applying the CHEM21 Scoring System in Your Lab

Within the context of the CHEM21 solvent selection guide, the evaluation of a solvent's greenness is based on a combined assessment of Safety, Health, and Environment (SHE) criteria. The safety score, a critical component of this assessment, provides researchers and drug development professionals with a standardized measure of the potential physical hazards associated with a solvent during laboratory use and industrial processing. This application note details the quantitative methodology and experimental protocols for determining the safety score, focusing on its core determinants: flash point, auto-ignition temperature, resistivity, and peroxide formation tendency [9].

The primary goal is to equip scientists with the knowledge to accurately calculate this score, thereby enabling informed, safer solvent choices in alignment with the principles of green chemistry. The procedural guidelines outlined herein are derived from the CHEM21 consensus methodology, which aligns with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) to ensure international relevance and applicability [9].

Core Concepts and Definitions

Understanding the specific terms used in the safety scoring system is fundamental to its correct application. Below are the key definitions:

  • Flash Point: The lowest temperature at which a liquid gives off vapors in sufficient concentration to form an ignitable mixture with air near the surface of the liquid upon application of an ignition source [25]. It is not to be confused with the auto-ignition temperature or the fire point. The flash point is the primary determinant of the base safety score.
  • Auto-ignition Temperature (AIT): The minimum temperature required to initiate self-sustained combustion in a substance in the absence of an external ignition source, such as a spark or flame [25]. A low AIT contributes to a higher safety hazard.
  • Peroxide Formation: The ability of certain solvents, particularly ethers, to form unstable and highly explosive peroxides upon exposure to air and light. This property is identified by the GHS hazard statement EUH019 [9].
  • Resistivity: A measure of a liquid's ability to resist the flow of electric current. Solvents with high resistivity (e.g., > 10^8 ohm.m) are prone to the accumulation of static charge, which can act as an ignition source for flammable vapors [9].

Quantitative Safety Scoring Methodology

The CHEM21 safety score is calculated on a scale of 1 to 10, where a higher score indicates a greater hazard level [9]. The overall score is an aggregate of a base score (derived from the flash point) and additional penalty points.

Base Safety Score from Flash Point

The foundation of the safety score is the solvent's flash point, which determines its base hazard rating as shown in Table 1.

Table 1: Determination of Base Safety Score from Flash Point

Base Safety Score Flash Point (°C) Relevant GHS Hazard Statement(s)
1 > 60 None
3 23 to 60 H226: Flammable liquid and vapor
4 22 to 0 H226: Flammable liquid and vapor
5 -1 to -20 H224: Extremely flammable liquid and vapor
7 < -20 H225: Highly flammable liquid and vapor

Additional Hazard Penalties

After establishing the base score, one point is added to the safety score for each of the following secondary hazards that apply to the solvent [9]:

  • Auto-ignition Temperature (AIT) < 200°C
  • Resistivity > 10^8 ohm.m
  • Ability to form explosive peroxides (GHS Statement EUH019)

Workflow for Safety Score Determination

The following diagram illustrates the logical procedure for calculating the final CHEM21 safety score.

G Safety Score Calculation Workflow Start Start: Identify Solvent FlashPoint Determine Flash Point (°C) Start->FlashPoint BaseScore Assign Base Score from Flash Point FlashPoint->BaseScore CheckAIT Check: AIT < 200°C? BaseScore->CheckAIT CheckResist Check: Resistivity > 10⁸ ohm.m? CheckAIT->CheckResist No AddPoint1 Add +1 to Score CheckAIT->AddPoint1 Yes CheckPerox Check: Ability to form peroxides (EUH019)? CheckResist->CheckPerox No AddPoint2 Add +1 to Score CheckResist->AddPoint2 Yes AddPoint3 Add +1 to Score CheckPerox->AddPoint3 Yes FinalScore Report Final Safety Score CheckPerox->FinalScore No AddPoint1->CheckResist AddPoint2->CheckPerox AddPoint3->FinalScore

Calculation Example: Diethyl Ether

To illustrate the methodology, consider the safety scoring for diethyl ether [9]:

  • Flash Point: -45°C → According to Table 1, this corresponds to a base safety score of 7.
  • Auto-ignition Temperature: 160°C (< 200°C) → Add 1 point.
  • Resistivity: 3 x 10^11 ohm.m (> 10^8 ohm.m) → Add 1 point.
  • Peroxide Formation: Has GHS statement EUH019 → Add 1 point.

Final Safety Score = 7 + 1 + 1 + 1 = 10

Experimental Protocols for Data Acquisition

The following sections provide detailed methodologies for obtaining the key experimental data required for the safety score calculation.

Flash Point Measurement

The flash point can be measured using two main approaches: Closed Cup or Open Cup methods. The closed cup method is generally preferred for product specifications and regulatory reporting as it provides a more conservative (lower) value by containing the vapors, better simulating conditions in a closed container [25] [26].

Table 2: Standardized Flash Point Test Methods

Test Method Type Governing Standard(s) Typical Application Scope
Pensky-Martens Closed Cup ASTM D93-20, IP 34, ISO 2719:2016 Petroleum products; Flash point range: 40°C to 370°C [25]
Cleveland Open Cup (COC) Open Cup ASTM D92-18, IP36, ISO 2592:2017 Petroleum products with flash points above 79°C (175°F) and below 400°C (752°F) [25]
Small Scale Closed Cup Closed Cup ASTM D3828 Pass/fail testing; requires only 2-4 mL sample [25]
Detailed Protocol: Flash Point by Pensky-Martens Closed Cup Tester (ASTM D93)

Principle: A sample is heated in a closed cup at a controlled rate and with periodic stirring. A small test flame is applied at regular intervals through a shutter opening. The flash point is the lowest temperature at which the application of the test flame causes the vapor above the sample to ignite momentarily [25].

Materials and Equipment:

  • Pensky-Martens Closed Cup Tester (manual or automated), including cup, lid, shutter mechanism, ignition source, and heater
  • Thermometer or temperature sensor
  • Barometer
  • Syringe or pipette for sample transfer
  • Cooling medium (if needed)

Procedure:

  • Preparation: Ensure the cup and its components are clean and dry. Place the tester in a draft-free location.
  • Sample Introduction: Fill the test cup with the sample to the appropriate level (typically 75 mL) using a syringe or pipette, avoiding air bubble formation [25].
  • Assembly: Secure the lid onto the cup, ensuring a tight seal. The thermometer and stirrer should be correctly positioned.
  • Heating and Stirring: Begin heating the sample at a specified rate (e.g., 5-6°C/min) while stirring the sample at a prescribed speed (e.g., 90-120 rpm) [25].
  • Ignition Test: For every 1°C rise in temperature, stop stirring and open the shutter to apply the test flame. Observe if a flash occurs within the cup. The test flame should be applied smoothly and consistently.
  • Endpoint Determination: The temperature at which a distinct flash is observed inside the cup is recorded as the flash point. The flame application should be a swift, not slow, rocking motion.
  • Correction: Correct the observed flash point to standard atmospheric pressure (101.3 kPa) as per the calculation method provided in the standard.

Safety Considerations:

  • Perform the test in a fume hood or well-ventilated area.
  • Wear appropriate Personal Protective Equipment (PPE) including safety glasses and lab coat.
  • Have a Class B fire extinguisher readily available.
  • Pre-warn the laboratory if testing samples suspected of having low flash points or fuel dilution [25].

Assessment of Peroxide Formation Tendency

Principle: The primary indicator for a solvent's tendency to form peroxides is the assignment of the GHS hazard statement EUH019: "May form explosive peroxides" [9]. Laboratory testing can be performed to detect and quantify peroxides in suspect solvents.

Materials and Equipment:

  • Test strips (e.g., peroxide test strips for organic solvents)
  • Alternatively, potassium iodide (KI) solution and acetic acid
  • Spectrophotometer or visual color comparison chart
  • Glass test tubes

Procedure (Qualitative/Semi-Quantitative using Test Strips):

  • Sampling: Dip a peroxide test strip into the solvent sample for the duration specified by the manufacturer.
  • Development: Remove the strip and allow the solvent to evaporate.
  • Reading: Observe the color change on the test pad and compare it to the provided calibration chart to determine the approximate peroxide concentration.

Interpretation: A positive test indicates the presence of peroxides, confirming the hazard associated with the solvent. For the purpose of the CHEM21 safety score, the official GHS classification (EUH019) is the definitive source. Experimental testing is crucial for monitoring aged solvents in the laboratory, even if the solvent is not classified with EUH019.

The Scientist's Toolkit: Essential Research Reagents and Materials

The following table lists key equipment and reagents required for performing the assessments described in this application note.

Table 3: Essential Materials for Safety Parameter Assessment

Item Function/Application
Pensky-Martens Flash Point Tester Standardized equipment for determining the closed-cup flash point of solvents, especially for regulatory and specification purposes [25].
Cleveland Open Cup Tester Standardized equipment for determining the open-cup flash point and fire point of less volatile petroleum products [25] [26].
Small Scale Closed Cup Tester (e.g., Setaflash) Rapid, pass/fail flash point testing requiring minimal sample volume (2-4 mL), ideal for quality assurance and screening [25] [26].
Peroxide Test Strips Simple, semi-quantitative detection of peroxide formation in stored solvents, a key safety monitoring activity [9].
Barometer Essential for measuring atmospheric pressure to correct the observed flash point value to standard pressure (101.3 kPa) [25].
Static Dissipative Containers Safe storage and transfer of high-resistivity solvents to prevent the accumulation of static charge, a known ignition source [9].
N'-Nitrosopentyl-(2-picolyl)amineN'-Nitrosopentyl-(2-picolyl)amine|C11H17N3O|Research Compound
N6,7-Dimethylquinoline-5,6-diamineN6,7-Dimethylquinoline-5,6-diamine|CAS 83407-42-5

The calculated safety score is one of three pillars in the CHEM21 assessment framework. It is combined with the health score and environment score to produce an overall solvent ranking. According to the CHEM21 guide, the following combinations determine the preliminary ranking [9]:

  • Recommended: No single score is ≥ 7 and no more than one score is in the "yellow" (4-6) range.
  • Problematic: One score is 7, OR two scores are in the "yellow" (4-6) range.
  • Hazardous: Any one score is ≥ 8, OR two or more scores are in the "red" (7-10) range.

This integrated approach ensures that a solvent is evaluated not just on its flammability and physical hazards, but also on its toxicity and environmental impact, providing a holistic view of its greenness for use in research and pharmaceutical development.

Within the framework of the CHEM21 selection guide, the assessment of a solvent's environmental and safety profile is a multi-factorial process [9] [1]. A critical component of this assessment is the Health Score, a quantitative measure of the potential occupational health hazards associated with a solvent [1]. This score provides researchers, scientists, and drug development professionals with a standardized metric to quickly identify and prioritize safer solvents during process development [3]. The methodology for determining the Health Score is deliberately aligned with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and European regulations, ensuring a consistent and internationally recognized approach to hazard communication [9] [1]. This application note details the protocol for determining the Health Score based on GHS H3xx hazard statements and the pivotal adjustment for solvent volatility based on boiling point.

The Health Score Calculation Framework

The CHEM21 Health Score is derived primarily from the most severe GHS H3xx statement assigned to a solvent, with an additional adjustment factor for volatility [9]. The final score is an integer ranging from 1 to 10, where a higher score indicates a greater health hazard [9] [1]. A color code is typically associated with this scoring: green for scores of 1-3 (low hazard), yellow for 4-6 (moderate hazard), and red for 7-10 (high hazard) [1].

Table 1: Health Score Based on GHS H3xx Hazard Statements

Health Score Carcinogenicity, Mutagenicity, or Reproductive Toxicity (CMR) Specific Target Organ Toxicity (STOT) Acute Toxicity Irritation
2 H341, H351, H361 (Suspected CMR, Category 2)
4 H340, H350, H360 (CMR, Category 1)
6 H371, H373 (May cause damage to organs/through prolonged exposure) H302, H312, H332, H336, EUH070 (Harmful) H315, H319, H335 (Causes skin or eye irritation, respiratory irritation)
7 H334 (May cause allergy or asthma symptoms) H301, H311, H331 (Toxic) H318 (Causes serious eye damage)
9 H370, H372 (Causes damage to organs/through prolonged exposure) H300, H310, H330 (Fatal) H314 (Causes severe skin burns and eye damage)

Boiling Point Adjustment: After assigning the base score from Table 1, 1 point is added to the health score if the solvent's boiling point is below 85°C [9]. This adjustment accounts for the increased occupational risk from inhalation exposure due to higher volatility at room temperature [1].

Default and Ideal Scores:

  • A solvent with a boiling point ≥85°C and no H3xx statements after a full REACH registration is assigned a health score of 1 [9].
  • For newer solvents with incomplete REACH registration data and no H3xx statements attributed by the supplier, a default health score of 5 is assigned if the boiling point is ≥85°C, or 6 if the boiling point is <85°C [9].

Experimental Protocol for Health Score Determination

Objective

To systematically determine the CHEM21 Health Score for a given solvent based on its GHS H3xx hazard statements and its boiling point.

Materials and Equipment

Table 2: Research Reagent Solutions and Essential Materials

Item Function/Description
Safety Data Sheet (SDS) The primary source for GHS classification, hazard statements, and physical property data for the solvent [27].
REACH Registration Dossier Provides authoritative toxicological and eco-toxicological data, confirming hazard classifications [1].
Boiling Point Apparatus For experimental determination of boiling point if literature/data sheet values are unavailable or require verification.
CHEM21 Solvent Selection Guide Reference document containing the scoring tables and methodology for final ranking [9] [1].

Step-by-Step Procedure

  • Solvent Identification: Record the solvent name and its CAS Registry Number to ensure precise identification.

  • Data Collection:

    • Obtain the most recent Safety Data Sheet (SDS) for the solvent from a reliable supplier or database.
    • Locate the Hazard Statements (H-codes) in Section 2 of the SDS. Identify all H3xx codes related to health hazards [27].
    • Locate the solvent's boiling point in Section 9 of the SDS.

  • Base Health Score Assignment:

    • Review the identified H3xx statements.
    • Consult Table 1 of this document. Assign the base health score corresponding to the most severe H3xx statement present.

  • Volatility Adjustment:

    • Compare the solvent's boiling point to the 85°C threshold.
    • If the boiling point is <85°C, add 1 point to the base health score.

  • Final Score and Ranking:

    • The resulting value is the final Health Score (1-10).
    • Classify the solvent's health hazard level based on its score and color code (Green: 1-3; Yellow: 4-6; Red: 7-10).

The following workflow diagram illustrates this deterministic process:

G Start Start: Determine Health Score SDS Consult Safety Data Sheet (SDS) Start->SDS IdH Identify all GHS H3xx Health Hazard Statements SDS->IdH FindBP Record Boiling Point (BP) SDS->FindBP AssignBase Assign Base Health Score Based on Most Severe H3xx IdH->AssignBase CheckBP Is BP < 85°C? FindBP->CheckBP BP Value AssignBase->CheckBP Base Score AddPoint Add 1 to Health Score CheckBP->AddPoint Yes Finalize Finalize Health Score (1-10) CheckBP->Finalize No AddPoint->Finalize

Worked Examples

Example 1: Determining the Health Score for Methanol

  • H3xx Statements: H301 (Toxic if swallowed) [9].
  • Boiling Point: 65°C [9].
  • Base Score Assignment: H301 corresponds to a base health score of 7 (see Table 1, Acute Toxicity).
  • Volatility Adjustment: Boiling point (65°C) is <85°C; therefore, add 1 point.
  • Final Health Score: 7 + 1 = 8.

Example 2: Determining the Health Score forn-Butanol

  • H3xx Statements: H318 (Causes serious eye damage) [9].
  • Boiling Point: 118°C [9].
  • Base Score Assignment: H318 corresponds to a base health score of 7 (see Table 1, Irritation).
  • Volatility Adjustment: Boiling point (118°C) is >85°C; therefore, no points are added.
  • Final Health Score: 7.

Table 3: Health Score Examples from the CHEM21 Guide

Solvent CAS Boiling Point (°C) Relevant H3xx Statements Base Score BP Adj. Final Health Score
Water 7732-18-5 100 None 1 No 1 [9]
Ethanol 64-17-5 78 H319 3 Yes (+1) 4 [9]
Acetone 67-64-1 56 H319 3 Yes (+1) 4 [9]
Ethyl Acetate 141-78-6 77 H319 3 Yes (+1) 4 [9]
i-Propanol 67-63-0 82 H319 3 Yes (+1) 4 [9]
n-Butanol 71-36-3 118 H318 7 No 7 [9]
Methanol 67-56-1 65 H301 7 Yes (+1) 8 [9]

The protocol for determining the CHEM21 Health Score provides a robust, standardized method for evaluating solvent health hazards. By integrating the severity of GHS H3xx statements with a quantitative adjustment for volatility, it effectively captures both the intrinsic toxicity and the exposure risk potential of a solvent. This enables researchers in drug development and other chemical industries to make informed, safer choices, thereby supporting the overarching goal of incorporating green chemistry principles into sustainable manufacturing processes. This Health Score, when combined with separate Safety and Environment scores, forms the tripartite foundation of the comprehensive CHEM21 solvent selection and ranking system [9] [1].

The transition towards sustainable chemistry in the pharmaceutical and specialty chemicals industries necessitates robust, quantitative tools for evaluating solvent environmental impact. Framed within the broader CHEM21 guide research context—a leading framework for green metrics in the pharmaceutical industry—this application note addresses the critical need for standardized assessment of key physicochemical parameters affecting environmental and human health [19]. Volatility, boiling point, and eco-toxicity (often indicated by hazard codes like H4xx) are interconnected properties that fundamentally determine a solvent's emission potential, exposure risk, and overall environmental footprint.

Understanding these parameters enables researchers to make informed substitutions, such as replacing hazardous conventional solvents like acetonitrile or benzene with safer, bio-based alternatives, thereby aligning industrial processes with the principles of green chemistry [28] [29]. This document provides detailed methodologies for measuring and interpreting these properties, supported by quantitative data and practical protocols, to guide solvent selection in drug development and other laboratory settings.

Quantitative Parameter Comparison

The following tables summarize key physicochemical and toxicological data for a selection of conventional and green solvents, providing a basis for comparative assessment.

Table 1: Physicochemical and Toxicological Properties of Common Solvents [28] [30] [29]

Solvent Boiling Point (°C) Volatility Class LD50 (mg/kg) Common Hazard Codes Greenness Score (GEARS)
Acetonitrile 82 High (VOC) 2460 H312, H319, H332 48
Methanol 65 High (VOC) 5628 H301, H311, H331 51
Ethanol 78 High (VOC) 7060 H319 81
Benzene 80 High (VOC) 930 H350, H340, H372 21
Glycerol 290 Low >5000 - 93
Dimethyl Carbonate 90 Moderate (VOC) >5000 H319 82
Ethyl Lactate 154 Moderate (VOC) >5000 H319 85

Table 2: Green Solvent Classification by Boiling Point and Source [31] [32]

Green Solvent Boiling Point Range (°C) Renewable Source Primary Application
D-Limonene 175 - 177 Citrus Peels Cleaning Products
Bio-Alcohols 65 - 118 Corn, Sugarcane Paints & Coatings
Lactate Esters 154 - 190 Cellulose, Corn Industrial Cleaners
Methyl Soyate > 200 Soybean Oil Adhesives & Inks
Bio-based Acetone 56 Biomass Pharmaceuticals

Experimental Protocols

Protocol 1: Determining Boiling Point and Volatility Class

Principle: This method determines the boiling point of a solvent at atmospheric pressure and classifies its volatility based on its boiling point (BP) range, which is directly related to its emission potential [30].

G A Sample Preparation B Boiling Point Determination A->B E Purify solvent via distillation. Ensure anhydrous conditions. A->E C Data Analysis B->C F Use standardized apparatus (ASTM D86/ D1078). B->F D Volatility Classification C->D G Record temperature at which condensation occurs. C->G H BP < 50°C: VVOC BP 50-260°C: VOC BP > 260°C: SVOC D->H

Workflow for Boiling Point and Volatility Assessment

Materials:

  • Solvent Sample: High-purity, anhydrous.
  • Boiling Point Apparatus: Including a heat source, round-bottom flask, thermometer, and condenser.
  • Safety Equipment: Fume hood, heat-resistant gloves, safety glasses.

Procedure:

  • Sample Preparation: Purify the solvent sample if necessary via standard distillation to remove impurities that may affect the boiling point.
  • Apparatus Setup: Assemble the boiling point apparatus according to ASTM D86 or D1078 standards inside a fume hood. Place 50-100 mL of the solvent in the distillation flask.
  • Heating: Apply controlled heat to the flask. To ensure an accurate reading, the thermometer bulb must be positioned correctly in the vapor phase.
  • Data Recording: Observe and record the temperature at which constant, active condensation occurs. This is the recorded boiling point.
  • Classification: Classify the solvent based on its boiling point [30]:
    • Very Volatile Organic Compounds (VVOCs): Boiling Point < 50°C - 100°C
    • Volatile Organic Compounds (VOCs): Boiling Point 50°C - 100°C to 240°C - 260°C
    • Semi-Volatile Organic Compounds (SVOCs): Boiling Point 240°C - 260°C to 380°C - 400°C

Protocol 2: Assessing Acute Eco-Toxicity Using Luminescent Bacteria

Principle: This protocol uses the marine bacterium Vibrio fischeri to determine the baseline eco-toxicity of a solvent by measuring the inhibition of bacterial luminescence after exposure, providing a rapid and standardized IC50 value [33].

Materials:

  • Lyophilized V. fischeri: Commercially available test strains.
  • Luminometer: Instrument to measure light output.
  • Solvent Solutions: Prepare a series of dilutions of the test solvent in a compatible aqueous medium (e.g., 2% NaCl solution).
  • Positive Control: A reference toxicant (e.g., 3,5-Dichlorophenol).

Procedure:

  • Bacterial Reactivation: Rehydrate the lyophilized bacteria according to the supplier's protocol (typically using a 2% NaCl solution) and allow to stabilize.
  • Sample Exposure: Mix a fixed volume of the bacterial suspension with an equal volume of each solvent dilution. For gaseous VOCs, a specialized exposure system like self-assembled passive colonization hydrogel (SAPCH) beads is required [33].
  • Incubation and Measurement: Incubate the mixtures at 15°C for 15-30 minutes. Measure the luminescence of each sample using the luminometer.
  • Data Calculation: Calculate the percentage inhibition of luminescence for each concentration compared to a negative control (bacteria in NaCl solution only). The IC50 value (concentration causing 50% inhibition) is determined by plotting inhibition percentage against log concentration and fitting a dose-response curve.

The Scientist's Toolkit: Research Reagent Solutions

Table 3: Essential Reagents and Equipment for Solvent Assessment

Item Function/Application Example Use Case
Vibrio fischeri Bioassay Kit Standardized test for determining baseline aquatic eco-toxicity (IC50). Protocol 2: Acute eco-toxicity screening.
Boiling Point Apparatus Determines boiling point per ASTM standards for volatility classification. Protocol 1: Fundamental physicochemical characterization.
HPLC with C18/Diphenyl Columns Performance evaluation of green solvents in chromatographic separations. Comparing elution strength of ethanol/DMC vs. acetonitrile [29].
Density Functional Theory (DFT) Software Computational modeling of molecular properties (e.g., free energy, frontier orbitals) to predict toxicity mechanisms. Interpreting toxicity differences between liquid and gaseous VOCs [33].
Greenness Assessment Software (e.g., AGREE, GEARS) Provides quantitative greenness scores based on multiple EHS and LCA criteria. Holistic solvent evaluation and selection post-data acquisition [28] [34].
p-Azidoacetophenonep-Azidoacetophenone, CAS:20062-24-2, MF:C8H7N3O, MW:161.16 g/molChemical Reagent
Tosyl-D-asparagineTosyl-D-asparagine (CAS 92142-18-2) – SupplierHigh-purity Tosyl-D-asparagine for renal function and synthetic chemistry research. CAS 92142-18-2. For Research Use Only. Not for human or veterinary use.

Data Interpretation and Implementation

Integrating measured parameters into a comprehensive environmental score is crucial for making informed decisions. The CHEM21 guide and modern tools like the Green Environmental Assessment and Rating for Solvents (GEARS) metric facilitate this by combining Environmental, Health, and Safety (EHS) criteria with Life Cycle Assessment (LCA) [28] [19].

Key Interpretation Guidelines:

  • Boiling Point & Volatility: Solvents with lower boiling points (VOCs/VVOCs) present higher inhalation risks and contribute to atmospheric pollution and smog formation. Their use requires stringent engineering controls [30].
  • Eco-Toxicity (LD50/IC50): An LD50 > 2000 mg/kg is classified as low toxicity, while an LD50 < 300 mg/kg indicates high toxicity. IC50 values from the V. fischeri assay provide a comparative measure of aquatic toxicity [33] [28].
  • Hazard Codes (H4xx): Codes like H350 ("may cause cancer") and H361 ("suspected of damaging fertility or the unborn child") are major red flags and should trigger a substitution effort. For instance, benzene (H350) must be replaced with less hazardous alternatives [28] [30].
  • The Replacement Logic: A successful green solvent substitution must address the three key dimensions: 1) Performance (e.g., solvation power, chromatographic efficiency [29]), 2) HSE Profile (improved toxicity and volatility metrics), and 3) Lifecycle Impact (renewable sourcing, biodegradability).

G A Identify Hazardous Solvent B Characterize Key Parameters A->B E e.g., Benzene (H350 Carcinogen) A->E C Select Green Alternative B->C F Boiling Point: 80°C Volatility: VOC Toxicity: High (LD50 930 mg/kg) B->F D Validate Performance C->D G e.g., Dimethyl Carbonate or Ethyl Lactate C->G H Confirm solubility & separation efficiency in target application. D->H

Solvent Substitution Decision Workflow

Future Outlook

The field of solvent greenness assessment is rapidly evolving. The integration of machine learning (ML) models, such as Gaussian Process Regression (GPR), is now enabling the prediction of sustainability metrics for vast virtual libraries of solvents, far beyond the ~200 compounds in existing guides [10]. Tools like GreenSolventDB, which contains predicted metrics for over 10,000 solvents, represent a significant leap forward.

Furthermore, advanced analytical greenness assessment tools (AGREE, AGSA, CaFRI) are moving beyond simple EHS profiles to incorporate full lifecycle impacts, including carbon footprint and energy consumption of analytical methods, providing a more holistic view of sustainability [34]. As these computational and metric tools mature, they will dramatically accelerate the design and adoption of novel, high-performance green solvents.

Using the Interactive Excel Tool for Automated Solvent Ranking

The CHEM21 Solvent Selection Guide represents a consensus methodology developed by a European consortium to promote sustainable chemical processes within the pharmaceutical industry and broader chemical sectors [3] [11]. As solvents can account for approximately 50% of the materials used in the manufacture of active pharmaceutical ingredients (APIs), their rational selection is a critical component of green chemistry [11]. The guide provides a standardized framework for ranking solvents based on a combined assessment of their safety, health, and environmental (SHE) impacts, moving beyond mere efficiency to encompass a holistic view of sustainability [9] [3].

This protocol details the use of an interactive Excel tool that operationalizes the CHEM21 guide. This tool enables researchers to automatically calculate SHE scores and obtain a preliminary greenness ranking for classical and less classical solvents, thereby supporting the integration of green chemistry principles into everyday laboratory decision-making [9].

The CHEM21 Scoring Methodology

The CHEM21 methodology assigns separate scores for Safety, Health, and Environment, which are then combined into an overall ranking. Scores range from 1 (lowest hazard) to 10 (highest hazard), with an associated color code: green (1-3), yellow (4-6), and red (7-10) [9].

Safety Score Calculation

The safety score derives primarily from the solvent's flash point, with additional penalties for other hazardous properties [9].

Table 1: Safety Score Calculation Based on Flash Point

Basic Safety Score Flash Point (°C) GHS Hazard Statements
1 > 60 --
3 23 to 60 H226
4 0 to 22 --
5 -20 to -1 --
7 < -20 H225 or H224

One point is added to the basic safety score for each of the following properties [9]:

  • Auto-ignition temperature (AIT) < 200 °C
  • Resistivity > 10⁸ ohm.m
  • Ability to form peroxides (EUH019 statement)

Example: Diethyl Ether With a flash point of -45 °C (score 7), an AIT of 160 °C (+1), a resistivity of 3 x 10¹¹ ohm.m (+1), and an EUH019 statement (+1), its final safety score is 10 [9].

Health Score Calculation

The health score is determined by the most stringent Globally Harmonized System (GHS) health hazard statements (H3xx) [9].

Table 2: Health Score Based on GHS Statements

Health Score Carcinogen, Mutagen or Reprotoxic (CMR) Specific Target Organ Toxicity (STOT) Acute Toxicity Irritation
2
4 H341, H351, H361 (Cat. 2)
6 H304, H371, H373 H302, H312, H332, H336, EUH070 H315, H317, H319, H335, EUH066
7 H340, H350, H360 (Cat. 1) H334 H301, H311, H331 H318
9 H370, H372 H300, H310, H330 H314

One point is added to this score if the solvent's boiling point is < 85 °C, due to increased inhalation risk [9]. If a solvent has no H3xx statements after full REACH registration, its health score is 1. For newer solvents with incomplete registration, the default score is 5 (BP ≥ 85 °C) or 6 (BP < 85 °C) unless a more stringent statement is provided [9].

Environment Score Calculation

The environment score considers both the solvent's volatility (linked to its boiling point) and its ecological toxicity (GHS H4xx statements) [9].

Table 3: Environment Score Criteria

Environment Score Boiling Point (°C) GHS/CLP Statements Other
3 70 - 139 No H4xx Full REACH registration
5 50 - 69 or 140 - 200 H412, H413 No or partial REACH registration
7 < 50 or > 200 H400, H410, H411
10 EUH420 (Ozone layer hazard)

The final ranking is determined by the most stringent combination of the individual SHE scores [9].

Table 4: Overall Ranking Combination Rules

Score Combination Ranking by Default
One score ≥ 8 Hazardous
Two "red" scores (7-10) Hazardous
One score = 7 Problematic
Two "yellow" scores (4-6) Problematic
Other combinations Recommended

It is critical to note that this "ranking by default" is a preliminary model. The final ranking should be critically assessed by occupational hygienists and other institutional experts, as the methodology has limits. For example, the model would initially classify chloroform as "problematic" and pyridine as "recommended," but CHEM21 ultimately ranked them as "highly hazardous" and "hazardous," respectively, based on additional factors like very low occupational exposure limits [9].

Using the Interactive Excel Tool: A Step-by-Step Protocol

The interactive Excel tool automates the scoring and ranking process described above. The following workflow provides a visual overview of the procedure.

G Start Start Solvent Assessment Input Input Solvent Data: - Flash Point - Boiling Point - GHS Statements - Other Properties Start->Input Calculate Tool Calculates: Safety Score (S) Health Score (H) Environment Score (E) Input->Calculate Combine Combine S, H, E Scores Calculate->Combine Rank Assign Preliminary Ranking: Recommended / Problematic / Hazardous Combine->Rank Review Expert Review & Final Ranking Rank->Review

Workflow for Automated Solvent Ranking

Data Input and Tool Setup
  • Obtain the Tool: The CHEM21 selection guide is available as an Excel spreadsheet in the supplementary data of the original publication [9]. An interactive version is also hosted on the ACS GCI PR platform [11].
  • Input Solvent Properties: For the solvent under evaluation, enter the following data into the designated cells of the Excel tool [9]:
    • Flash Point (°C): The temperature at which the solvent produces enough vapor to ignite.
    • Boiling Point (°C): The temperature at which the solvent boils.
    • GHS Hazard Statements: All applicable H3xx (health) and H4xx (environment) codes.
    • Other Properties: Auto-ignition temperature, resistivity, and a check for peroxide-forming ability (EUH019).
Execution and Output Interpretation
  • Automatic Calculation: Once the data is entered, the Excel tool will automatically calculate and display the Safety, Health, and Environment scores based on the embedded algorithms from Section 2.
  • Preliminary Ranking: The tool will assign a preliminary ranking of "Recommended," "Problematic," or "Hazardous" based on the combination rules in Table 4.
  • Expert Review (Critical Step): The preliminary ranking is a starting point. The final ranking must be validated through expert discussion, considering additional data such as Occupational Exposure Limits (OELs), lifecycle assessment (LCA) data, and specific institutional policies [9]. For instance, CHEM21 overrode the default model to rank methanol and acetone as "Recommended" and cyclohexanone as "Problematic" based on such discussions [9].

Experimental Validation and Application Protocol

Theoretical screening with the Excel tool should be followed by experimental validation, especially when identifying alternative solvents for specific applications like API synthesis or extraction [35].

Validating Solubility for API Synthesis

This protocol is adapted from studies screening solvents for dissolving aromatic amides [35].

Research Reagent Solutions

Item Function / Application
4-Formylomorpholine (4FM) A promising, greener alternative aprotic solvent [35].
DMSO & DMF Common aprotic solvents used as benchmarks for comparison [35].
Aromatic Amides (e.g., Salicylamide) Model Active Pharmaceutical Ingredients (APIs) for solubility testing [35].
COSMO-RS Software A theoretical method for predicting solubility to guide initial solvent screening before wet-lab experiments [35].
Binary Aqueous Mixtures Used to evaluate the potential for reducing organic solvent content while maintaining performance [35].

Step-by-Step Procedure:

  • Theoretical Screening: Use a method like COSMO-RS to compute the predicted solubility of your target compound (e.g., an API) in a range of solvents, including those flagged as "Recommended" by the CHEM21 Excel tool [35].
  • Solvent Selection: Based on the screening, select the most promising solvents (e.g., 4FM) and benchmark them against traditional solvents (e.g., DMSO, DMF) [35].
  • Solution Preparation: Prepare binary mixtures of the organic solvent with water across a range of mole fractions (e.g., from 0.1 to 0.9) [35].
  • Solubility Measurement: Place an excess of the solid API into vials containing the solvent mixtures. Agitate the mixtures in a temperature-controlled water bath, typically in a range of 298.15 K to 313.15 K (25 °C to 40 °C), until equilibrium is reached [35].
  • Analysis: Analyze the concentration of the dissolved API in the saturated solutions using a suitable analytical method (e.g., UV spectrophotometry, HPLC) [35].
  • Data Interpretation: Plot solubility versus solvent composition. Analyze for synergistic effects, where a binary mixture dissolves more API than either pure solvent, indicating an optimal, greener formulation [35].

The following diagram illustrates this integrated screening and validation workflow.

G A Theoretical Screening (COSMO-RS) B Greenness Ranking (CHEM21 Excel Tool) A->B C Select Candidate & Benchmark Solvents B->C D Prepare Binary Solvent-Water Mixtures C->D E Measure Solubility at Various Temperatures D->E F Identify Synergistic Effects & Optimal Mix E->F

Integrated Solvent Screening and Validation

The interactive Excel tool for the CHEM21 Solvent Selection Guide provides a practical, standardized method for integrating green chemistry principles into solvent selection. By automating the scoring of safety, health, and environmental criteria, it offers researchers a rapid and defensible starting point for identifying more sustainable solvents. However, this automated ranking is a preliminary guide, not a final verdict. Its true power is realized when combined with theoretical solubility screening and subsequent experimental validation, creating a robust framework for advancing green chemistry in research and development.

In modern laboratories, particularly within the pharmaceutical industry, the selection of solvents is a critical decision that extends beyond efficacy to encompass significant environmental, health, and safety (EHS) considerations. Common solvents like dichloromethane (DCM), methanol (MeOH), and ethyl acetate (EtOAc) are frequently used in processes such as extraction, purification, and chromatography. The CHEM21 guide provides a standardized framework for evaluating solvent greenness, promoting the use of safer and more sustainable alternatives. This case study applies a multi-faceted assessment methodology to these common laboratory solvents, integrating hazard profiling, life-cycle assessment (LCA), and quantitative greenness metrics to deliver a practical, data-driven protocol for solvent selection in research and development.

Solvent Hazard and Safety Profiles

A comprehensive evaluation begins with understanding the intrinsic hazards of each solvent. The following table summarizes key hazard profiles based on established chemical rating systems, including the GlaxoSmithKline (GSK) solvent selection guide and GreenScreen assessments.

Table 1: Hazard and Safety Profiles of Common Laboratory Solvents

Solvent GSK Score (1=Worst, 10=Best) GreenScreen Benchmark Key Health & Environmental Concerns
Dichloromethane (DCM) 4 [36] BM-1 (Avoid) [36] Carcinogen, damage to the central nervous system, environmental persistence (half-life in water >18 months) [36] [37].
Methanol (MeOH) Information Missing Information Missing Flammable, toxic if ingested [36].
Ethyl Acetate (EtOAc) Information Missing Information Missing Generally regarded as relatively safe; often used as a safer alternative [36].
Heptane 8 [36] BM-2 (Prefer) [36] Significantly safer profile than DCM; flammable [36].

Methodologies for Comprehensive Solvent Greenness Assessment

A robust greenness assessment moves beyond simple hazard listings. The following integrated approach provides a multi-dimensional view of a solvent's environmental impact.

Life-Cycle Assessment (LCA)

LCA is a cornerstone of sustainability evaluation, quantifying environmental impacts across a solvent's entire life cycle, from raw material extraction to production, use, and disposal [38] [39]. A comparative LCA study evaluating the production of a common Deep Eutectic Solvent (DES), reline (choline chloride/urea), against conventional organic solvents found that the DES generally imparted lower environmental impacts than DCM and ethyl acetate, but had higher impacts than methanol and ethanol [40]. This highlights that solvents often perceived as "green," like some DESs, may have hidden environmental burdens if their production is energy- or resource-intensive [38] [39].

Green Analytical Chemistry (GAC) Metrics

For analytical methods, several specialized tools provide visual and quantitative evaluations:

  • AGREE (Analytical Greenness): Uses the 12 principles of GAC to calculate a score between 0 and 1, offering a comprehensive and user-friendly output [34].
  • GAPI (Green Analytical Procedure Index): A five-part, color-coded pictogram that assesses the entire analytical process from sample collection to detection [34].
  • NEMI (National Environmental Methods Index): A simple pictogram indicating whether a method meets four basic environmental criteria, though its binary nature limits detailed comparisons [34].

The workflow below illustrates how these multi-faceted assessment tools can be integrated into a solvent evaluation protocol.

G Start Start Solvent Assessment Step1 Hazard Profile Check Start->Step1 Step2 Life-Cycle Assessment (LCA) Step1->Step2 Step3 Apply GAC Metrics Step2->Step3 Step4 Synthesis Results Step3->Step4 Outcome Informed Solvent Selection Step4->Outcome

Case Study: Safer Solvent Blends for API Purification

Background and Objective

Column chromatography is a standard technique for purifying Active Pharmaceutical Ingredients (APIs). A common solvent system for this process is DCM/MeOH blends, which poses considerable health and safety risks to workers and contributes significantly to chlorinated solvent waste in the pharmaceutical sector [36]. This case study quantitatively evaluates the performance of safer solvent blends as direct replacements for DCM/MeOH in the purification of model APIs [36].

Experimental Protocol

Materials
  • Model APIs: Ibuprofen and acetaminophen.
  • Model Additive: Caffeine.
  • Stationary Phase: Silica gel (0.060–0.2 mm, 70–230 mesh).
  • Tested Solvent Blends:
    • Control: DCM/MeOH
    • Alternative Blends: Heptane/Ethyl Acetate and Heptane/Methyl Acetate.
  • Equipment: Standard glass chromatography column, TLC plates (Silica gel 60 F254), UV lamp (254 nm) [36].
Methodology

  • Thin-Layer Chromatography (TLC) Scouting:

    • Prepare TLC plates spotted with solutions of the APIs and caffeine.
    • Develop the TLC plates with the various solvent blends under investigation.
    • Visualize under UV light (254 nm) to calculate retention factors (Rf) and assess initial separation feasibility [36].

  • Column Chromatography Validation:

    • Column Packing: Use the wet packing method with silica gel as the stationary phase [36].
    • Sample Loading: Load a mixture of the model API and caffeine onto the prepared column.
    • Elution: Elute the components using the safer solvent blends identified in the TLC scouting phase.
    • Fraction Analysis: Collect eluent fractions and analyze them (e.g., via HPLC or TLC) to determine API recovery ratio and purity [36].

Key Findings and Results

The experimental results demonstrated that specific safer solvent blends can match or even exceed the performance of the conventional DCM/MeOH system.

  • Heptane/Ethyl Acetate and Heptane/Methyl Acetate blends provided superior or comparable separation performance for the model APIs [36].
  • These blends yielded higher API recovery and purity compared to the traditional DCM/MeOH blend in column chromatography [36].
  • Given their significantly improved safety profiles (e.g., Heptane has a GSK rating of 8 vs. DCM's rating of 4), these blends represent viable, safer alternatives for API purification, aligning with the principles of the CHEM21 guide [36].

The Scientist's Toolkit: Research Reagent Solutions

Table 2: Essential Materials for Solvent Assessment and Replacement Studies

Reagent/Material Function in Assessment Application Example
TLC Plates (Silica) Rapid scouting of solvent elution strength and separation efficacy. Comparing the separation of ibuprofen from caffeine in different solvent blends [36].
Safer Solvent Blends Direct replacement for hazardous solvents in processes. Using Heptane/Ethyl Acetate instead of DCM/MeOH in column chromatography [36].
LCA Software & Databases Quantifying environmental impacts from cradle to grave. Comparing the global warming potential of DESs vs. methanol and ethanol [40] [39].
GAC Metric Calculators Providing a standardized score for the greenness of an analytical method. Using AGREE or GAPI to evaluate and compare the greenness of two different extraction methods [34].
ChloropretadalafilChloropretadalafil, CAS:171489-59-1, MF:C22H19ClN2O5, MW:426.8 g/molChemical Reagent
L-Galacturonic acidL-Galacturonic Acid|High-Purity Research ChemicalExplore our high-purity L-Galacturonic acid, a key intermediate in microbial pathways and a precursor for L-ascorbic acid. For Research Use Only. Not for human or veterinary use.

This practical case study demonstrates that a transition to safer and more sustainable solvent systems is both feasible and advantageous. By adopting a structured assessment protocol that integrates hazard profiling, LCA, and green metrics, researchers can make informed decisions that mitigate health risks and reduce environmental footprints. The successful replacement of hazardous DCM/MeOH blends with heptane-based alternatives for API purification underscores a tangible path forward. Ultimately, embracing such comprehensive assessment strategies is crucial for greening laboratory practices and advancing the principles of green chemistry in drug development and beyond.

This application note provides a detailed protocol for integrating the CHEM21 solvent selection guide and metrics toolkit into pharmaceutical process design. It offers a structured methodology for researchers and drug development professionals to assess and enhance the environmental sustainability of chemical processes across all development stages, from initial discovery to full-scale production. The guidance is contextualized within a broader thesis on solvent greenness assessment, emphasizing practical tools and quantitative metrics.

The CHEM21 project represents Europe's largest public-private partnership dedicated to developing sustainable manufacturing processes for pharmaceuticals [41]. This consortium, comprising pharmaceutical companies, universities, and small-to-medium enterprises, has developed a unified framework to incorporate sustainability principles into drug development and manufacture [1]. A core component of this framework addresses solvent selection, as solvents typically constitute at least 50% of materials used in chemical processes for active pharmaceutical ingredient (API) manufacturing [1]. The CHEM21 approach provides methodologies to systematically evaluate and rank solvents based on Safety, Health, and Environment (SHE) criteria, alongside a comprehensive metrics toolkit for assessing overall process greenness [41] [42].

CHEM21 Solvent Selection Guide: Methodology and Application

Safety, Health, and Environment (SHE) Scoring System

The CHEM21 solvent selection guide employs a standardized scoring methodology that evaluates solvents across three critical domains: Safety (S), Health (H), and Environment (E). Each domain is scored from 1-10, with higher scores representing greater hazard levels [9] [1]. A color code facilitates quick assessment: green (1-3), yellow (4-6), and red (7-10). The overall solvent ranking is determined through a combination of these scores as delineated in Table 1.

Table 1: CHEM21 Solvent Ranking Criteria Based on SHE Scores

Score Combination Overall Ranking
One score ≥ 8 Hazardous
Two "red" scores (7-10) Hazardous
One score = 7 Problematic
Two "yellow" scores (4-6) Problematic
Other combinations Recommended

Detailed SHE Scoring Protocols

Safety Score Protocol: The safety score primarily derives from flash point (FP) with contributions from additional hazard properties [9] [1]. The basic safety score is determined as follows:

Table 2: Safety Scoring Criteria Based on Flash Point

Basic Safety Score 1 3 4 5 7
Flash Point (°C) >60 23-60 22-0 -1 to -20 < -20
GHS Statements - H226 H225 or H224

The score is incremented by +1 for each of: Auto-ignition temperature (AIT) < 200°C; Resistivity > 10⁸ ohm·m; Ability to form peroxides (EUH019) [9]. For example, diethyl ether (FP = -45°C, AIT = 160°C, resistivity = 3×10¹¹ ohm·m, EUH019 statement) scores 7 + 1 + 1 + 1 = 10 [9].

Health Score Protocol: The health score is determined by the most stringent GHS H3xx statements with adjustment for volatility [9] [1]:

Table 3: Health Scoring Criteria Based on GHS Hazard Statements

Health Score 2 4 6 7 9
CMR H341, H351, H361 (Category 2) H340, H350, H360 (Category 1)
STOT H304, H371, H373 H334 H370, H372
Acute Toxicity H302, H312, H332, H336, EUH070 H301, H311, H331 H300, H310, H330
Irritation H315, H317, H319, H335, EUH066 H318 H314

Add +1 to the score if boiling point < 85°C [9]. Solvents with no H3xx statements after full REACH registration receive a health score of 1 [1].

Environment Score Protocol: The environment score considers both volatility (boiling point) and GHS H4xx statements [9]:

Table 4: Environmental Scoring Criteria

Environment Score 3 5 7 10
BP (°C) 70-139 50-69 or 140-200 <50 or >200 -
GHS/CLP No H4xx after full REACH H412, H413 H400, H410, H411 EUH420

Experimental Protocol: Solvent Selection and Assessment

Purpose: To systematically evaluate and select solvents for API synthesis using CHEM21 SHE criteria.

Materials:

  • CHEM21 solvent selection guide [9] [1]
  • Safety Data Sheets (SDS) for candidate solvents
  • Physical property data (flash point, boiling point, auto-ignition temperature, resistivity)

Procedure:

  • Compile Solvent Candidates: List all chemically compatible solvents for the specific reaction.
  • Gather Data: For each solvent, collect FP, BP, AIT, resistivity, peroxide formation potential, and GHS hazard statements from SDS.
  • Calculate SHE Scores:
    • Determine basic Safety score from FP (Table 2), applying increments for AIT < 200°C, resistivity > 10⁸ ohm·m, or peroxide formation.
    • Determine Health score from the most severe GHS H3xx statement (Table 3), adding +1 if BP < 85°C.
    • Determine Environment score from BP and GHS H4xx statements (Table 4).
  • Assign Overall Ranking: Combine SHE scores according to Table 1 to determine overall ranking (Recommended, Problematic, or Hazardous).
  • Critical Assessment: Review rankings with occupational hygienists and environmental experts, adjusting based on additional factors like occupational exposure limits.
  • Documentation: Record all data, calculations, and final solvent selection with justification.

CHEM21 Metrics Toolkit for Process Assessment

Multi-Pass Assessment Framework

The CHEM21 Metrics Toolkit provides a tiered approach to evaluate process greenness across development stages [42]. This multi-pass system includes:

  • Zero Pass: Initial assessment at discovery scale (few mg) for reaction screening
  • First Pass: Bench-scale evaluation with preliminary process metrics
  • Advanced Passes: Comprehensive assessment at pilot and production scales

Experimental Protocol: Zero Pass Assessment

Purpose: To rapidly screen reactions at the discovery stage for preliminary greenness evaluation.

Materials:

  • CHEM21 Metrics Toolkit (Excel spreadsheet) [42]
  • Reaction scheme and stoichiometry
  • Solvent and reagent quantities

Procedure:

  • Input Reaction Data: Enter all reagents, catalysts, solvents, and expected products with masses.
  • Calculate Basic Metrics:
    • Process Mass Intensity (PMI) = Total mass in / Mass of product
    • Reaction Mass Efficiency (RME) = Mass of product / Total mass of reactants × 100%
    • Atom Economy = Molecular weight of product / Sum of molecular weights of reactants × 100%
  • Solvent Assessment: Apply CHEM21 solvent selection guide to evaluate solvent greenness.
  • Initial Ranking: Compare metrics against CHEM21 benchmarks to identify promising reactions for further development.
  • Documentation: Record all calculations and identify potential sustainability hotspots for optimization.

Integrated Workflow: From Discovery to Production

The integration of CHEM21 principles across development stages requires a systematic approach. The following workflow visualization illustrates this multi-stage process:

CHEM21_Workflow Discovery Discovery ZeroPass ZeroPass Discovery->ZeroPass ProcessDesign ProcessDesign SolventSelect SolventSelect ProcessDesign->SolventSelect PilotScale PilotScale AdvancedPass AdvancedPass PilotScale->AdvancedPass Production Production ZeroPass->ProcessDesign FirstPass FirstPass SolventSelect->FirstPass FirstPass->PilotScale AdvancedPass->Production CHEM21Guide CHEM21Guide CHEM21Guide->SolventSelect MetricToolkit MetricToolkit MetricToolkit->ZeroPass MetricToolkit->FirstPass MetricToolkit->AdvancedPass

CHEM21 Integration Workflow

Research Reagent Solutions for CHEM21 Implementation

Table 5: Essential Tools and Resources for CHEM21 Implementation

Tool/Resource Function Source/Access
CHEM21 Solvent Selection Guide Rank solvents based on SHE criteria RSC publication [43] or ACS GCI website [11]
CHEM21 Metrics Toolkit Comprehensive evaluation of reaction greenness Excel spreadsheet in supplementary information of publication [42]
Process Mass Intensity (PMI) Calculator Determine mass efficiency of processes ACS GCI Pharmaceutical Roundtable [11]
Bio-derived Solvents Sustainable alternatives to classical solvents CHEM21 guide includes assessment methodology [1]
Imine Reductases (IREDs) Green biocatalysts for reductive amination CHEM21-developed toolbox [41]
Continuous Flow Methods Cleaner reactions with improved green metrics CHEM21-developed fluorination, oxidation, hydrogenation protocols [41]
SaentaSaenta, CAS:130117-76-9, MF:C₁₉H₂₃N₇O₅S, MW:461.5 g/molChemical Reagent
EprovafenEprovafen (CAS 101335-99-3)|High-Purity Reference StandardHigh-purity Eprovafen for research. Explore its applications in anti-inflammatory and anti-scarring studies. For Research Use Only. Not for human or veterinary use.

Case Study: Application to Flucytosine Synthesis

Experimental Protocol: Sustainable API Synthesis

Background: CHEM21 developed a more efficient synthesis of flucytosine, an antifungal medication essential for treating HIV-associated fungal infections [41]. The traditional process involved four chemical reactions with significant waste generation and high production costs.

CHEM21-Optimized Procedure:

  • Process Redesign: Implemented a novel one-step synthesis instead of conventional four-step sequence.
  • Solvent Selection: Applied CHEM21 solvent guide to identify greenest solvents for the transformation.
  • Metric Evaluation: Used CHEM21 metrics toolkit to quantify improvements in PMI, RME, and waste reduction.
  • Scale-up: Partnered with MEPI to establish a small reactor producing 1 kg/day of raw material.

Results: The CHEM21 approach reduced production costs, decreased energy consumption, and minimized waste generation, potentially making this essential medicine more accessible in low-income countries [41].

The CHEM21 framework provides a comprehensive, practical methodology for integrating sustainability principles throughout pharmaceutical process design. By implementing the solvent selection guide and metrics toolkit across development stages—from initial discovery to production scale—researchers can significantly improve the environmental profile of drug manufacturing processes. The protocols outlined in this application note offer actionable guidance for scientists to systematically assess and enhance process greenness while maintaining efficiency and cost-effectiveness.

Overcoming Practical Challenges and Optimizing Solvent Substitution Strategies

The CHEM21 Solvent Selection Guide is a pivotal tool for promoting greener practices in the pharmaceutical industry and chemical research [44]. However, a significant challenge emerges when assessing newer and bio-derived solvents, which often lack complete environmental, health, safety, and waste (EHSW) data required for a comprehensive evaluation [10]. This application note provides structured protocols and methodologies for researchers and drug development professionals to assign reliable default scores and navigate these data gaps effectively, enabling a more informed integration of sustainable solvents into their workflows.

Data Presentation: Scoring Systems and Solvent Properties

Default Scoring Framework Based on Solvent Class

Table 1: Proposed Default Scores for Bio-Derived Solvent Classes Based on Inherent Properties. Scores are on a 1-10 scale (10=Most Green).

Solvent Class Representative Examples Proposed Default Score Rationale for Default Assignment
Bio-Alcohols Bio-ethanol, Furfuryl alcohol [45] 8 Renewable feedstock; generally lower toxicity than synthetic counterparts; established production.
Lactate Esters Ethyl lactate, Methyl lactate [32] 9 High biodegradability; low toxicity; derived from renewable resources like corn/sugarcane [32].
Plant-Based Esters & Ethers Methyl soyate, 2-MeTHF, Cyrene [44] [32] 8 Biodegradable; low toxicity profiles; renewable agricultural origin (e.g., soybean oil, cellulose) [32].
Terpenes D-Limonene [32] 7 Renewable (citrus waste); low aquatic toxicity; but can be a skin irritant.
Glycerol & Derivatives Glycerol, Solketal (Augeo SL 191) [45] 8 Non-toxic; biodegradable; by-product of biodiesel industry; high boiling point reduces VOC potential [45].

Key Properties for Experimental Assessment

Table 2: Key Metrics for Experimental Assessment and Default Assignment when Data is Incomplete.

Assessment Parameter Experimental Method(s) Recommended Default if Untested
Biodegradability OECD 301, 310 series tests Assume low (score 2/10) for novel, complex structures unless similar structure data exists.
Aquatic Toxicity Daphnia magna or algae acute toxicity test Assume moderate (score 5/10) and prioritize testing.
VOC Character Thermogravimetric Analysis (TGA), vapor pressure measurement Assume low (score 8/10) for solvents with boiling point >250°C [44].
Renewability Life Cycle Assessment (LCA) of feedstock Assign high (score 10/10) if verified 100% biomass-derived.
Flammability Flash point measurement (Pensky-Martens Closed Cup) Assume flammable (score 5/10) for most organic solvents; prioritize testing.

Experimental Protocols

Protocol 1: Application of the GEARS Scoring System

The Green Environmental Assessment and Rating for Solvents (GEARS) is a novel metric that integrates EHS criteria with Life Cycle Assessment to provide a holistic solvent evaluation [21]. It is particularly useful for solvents not yet covered in the CHEM21 guide.

Procedure:

  • Parameter Identification: For the solvent in question, gather available data on the ten GEARS parameters: toxicity, biodegradability, renewability, volatility, thermal stability, flammability, environmental impact, efficiency, recyclability, and cost [21].
  • Data Gap Analysis: Identify parameters with missing data.
  • Default Assignment: Use the following hierarchy to assign a default score for each missing parameter:
    • Primary (Preferred): Use predictive machine learning models, such as Gaussian Process Regression (GPR), trained on existing solvent sustainability data to predict the missing property [10].
    • Secondary: Assign a score based on the closest structural analogue from the CHEM21 guide or established solvent databases [44].
    • Tertiary (Conservative): If no analogue exists, assign a conservative (low) score to encourage experimental verification.
  • Score Calculation: Compile the scores for all ten parameters, applying appropriate weighting as defined in the GEARS methodology, to generate an overall GEARS score [21].
  • Validation: The final score should be flagged as "provisional" until experimental data for all parameters is obtained.

Protocol 2: Rapid Biodegradability Screening

This protocol provides a cost-effective initial assessment to fill a critical data gap for new solvents.

Materials:

  • Test Substance: The novel bio-derived solvent.
  • Inoculum: Activated sludge from a municipal sewage treatment plant, pre-washed.
  • Mineral Medium: Contains essential nutrients for microbial growth.
  • Positive Control: Sodium acetate or aniline.
  • Apparatus: Biochemical Oxygen Demand (BOD) system or respirometer, ICpH meter, filtration setup.

Procedure:

  • Prepare a solution of the test substance in mineral medium at a concentration of 100 mg/L.
  • Add a defined volume of inoculum (e.g., 1-5% v/v) to the test solution and the positive control.
  • Incubate the mixtures in the dark at 20°C while continuously aerating.
  • Monitor the degradation over 28 days by measuring Dissolved Organic Carbon (DOC) removal or oxygen consumption at regular intervals (e.g., days 0, 7, 14, 28).
  • Calculation: Determine the percentage biodegradation = [(Initial DOC - Final DOC) / Initial DOC] * 100.
  • Interpretation: A result of >60% degradation in 28 days qualifies as "readily biodegradable" and warrants a high GEARS/CHEM21 score (e.g., 8-10/10). A result of <20% indicates persistence and a low score (1-3/10).

Protocol 3: Inherent Safety Assessment using Chemoinformatic Tools

This methodology uses property prediction tools to assess safety hazards during early process development when experimental data is unavailable [46].

Procedure:

  • Identify Safety-Critical Properties: For the solvent, list properties critical for inherent safety, including flammability (flash point), toxicity (LD50), explosivity, and corrosivity.
  • Data Collection: Attempt to gather existing experimental data from literature and databases.
  • Computational Prediction: For missing properties, use chemoinformatic Quantitative Structure-Property Relationship (QSPR) models.
    • Input: Generate an accurate SMILES (Simplified Molecular-Input Line-Entry System) string for the solvent molecule.
    • Tools: Utilize open-source or commercial QSPR software (e.g., from the OECD QSAR Toolbox) or models described in literature [46].
    • Output: Obtain predicted values for the missing properties (e.g., estimated flash point, LD50).
  • Hazard Classification: Convert the predicted properties into hazard bands (e.g., high, medium, low) based on the Globally Harmonized System (GHS) criteria.
  • Inherent Safety Index (ISI) Scoring: Assign a safety score based on the hazard bands. A higher hazard leads to a less favorable (lower) safety score in the overall solvent assessment [46].

Workflow Visualization

G Start Start: New Bio-Derived Solvent CheckData Check CHEM21/SSG Database Start->CheckData DataComplete Data Complete? CheckData->DataComplete UseEstablished Use Established Score DataComplete->UseEstablished Yes IdentifyGaps Identify Data Gaps DataComplete->IdentifyGaps No ApplyProtocols Apply Protocols: GEARS, QSPR, Screening IdentifyGaps->ApplyProtocols AssignDefault Assign Provisional Default Score ApplyProtocols->AssignDefault Flag Flag as 'Provisional' AssignDefault->Flag Validate Prioritize Experimental Validation Flag->Validate

Solvent Assessment Workflow

Protocol 1 Workflow: GEARS and ML Scoring

G A Input Solvent Structure B Extract Available Data (10 GEARS Parameters) A->B C Run ML Model (e.g., GPR) to Predict Missing Data B->C D Score All Parameters C->D E Calculate Overall GEARS Score D->E F Output Provisional Score E->F

GEARS and ML Scoring Process

Protocol 3 Workflow: Safety Assessment

G S1 Define Solvent Molecule S2 Generate SMILES String S1->S2 S3 Identify Missing Safety Properties S2->S3 S4 Use QSPR Models for Prediction S3->S4 S5 Classify Hazards (GHS Bands) S4->S5 S6 Assign Safety Score S5->S6

Inherent Safety Assessment Process

The Scientist's Toolkit

Table 3: Essential Research Reagent Solutions for Solvent Assessment.

Tool / Reagent Function / Application Example Use in Protocol
Activated Sludge Inoculum Provides a diverse microbial community for biodegradability testing. Sourced from municipal wastewater; used in Protocol 2 for rapid biodegradability screening.
Gaussian Process Regression (GPR) Model A machine learning model trained on solvent sustainability data to predict "greenness" metrics. Used in Protocol 1 to predict missing EHSW parameters for the GEARS score [10].
OECD 301 Test Kit Standardized chemical set for determining ready biodegradability. Provides the mineral medium and defined conditions for Protocol 2.
QSPR/QSAR Software (e.g., OECD QSAR Toolbox) Software that predicts chemical properties based on molecular structure. Used in Protocol 3 to predict safety-critical properties like flash point and toxicity [46].
BigSolDB 2.0 Database A large, curated dataset of experimental solubility values for organic compounds in various solvents. Used to verify or predict the solvation performance of a new bio-solvent, informing its "efficiency" score [47].
CHEM21 Solvent Selection Guide The benchmark guide for assessing solvent greenness in the pharmaceutical industry. Used as a primary reference and source of analogue data for default scoring in all protocols [44].

Solvent selection is a critical, high-impact decision in pharmaceutical development, influencing process safety, environmental footprint, and regulatory compliance. While solvent selection guides like CHEM21 provide invaluable standardized scoring systems, blind adherence to their default rankings can lead to suboptimal or even problematic choices in complex real-world scenarios. The CHEM21 Selection Guide, developed by a European consortium for promoting sustainable methodologies, scores solvents based on safety, health, and environmental criteria, categorizing them as "recommended," "problematic," or "hazardous" [3]. However, its generalized rankings cannot account for all contextual factors specific to individual processes, materials, or facilities. This protocol provides a structured methodology for identifying situations where expert judgment must override default rankings and outlines the experimental and decision-making frameworks necessary for justified deviations.

Quantitative Foundation: Core CHEM21 Scoring Parameters

Table 1: CHEM21 Safety Scoring Criteria Based on Flash Point and Boiling Point Characteristics [3]

Score Flash Point Range Additional Penalty Factors
1 > 60 °C Auto-ignition temperature < 200 °C
3 24 - 60 °C Resistivity > 10⁸ Ω·m
4 0 - 23 °C Peroxide-forming ability
5 -20 - -1 °C High decomposition energy (> 500 J/g)
7 < -20 °C -

Table 2: CHEM21 Health and Environmental Scoring Overview [3]

Parameter Basis for Scoring Key Metrics
Health Score CLP/GHS classifications, with +1 point if boiling point < 85 °C Acute toxicity, skin corrosion/irritation, serious eye damage/eye irritation, respiratory sensitization
Environmental Score Boiling point ranges and GHS environmental hazard statements H400 (very toxic to aquatic life), H410 (very toxic to aquatic life with long-lasting effects), H411 (toxic to aquatic life with long-lasting effects)

Experimental Protocols for Contextual Solvent Assessment

Protocol 1: Functional Performance Equivalency Testing

Objective: To determine if a CHEM21 "recommended" solvent provides equivalent chemical performance to a higher-performing but "problematic" solvent for a specific reaction or extraction.

Methodology:

  • Experimental Setup: Prepare identical reaction or extraction mixtures, varying only the solvent. Use the "problematic" default solvent as the control (A) and multiple "recommended" alternatives (B, C, D...) as test conditions.
  • Performance Metrics:
    • For Reactions: Monitor reaction progress (e.g., by HPLC, GC) at fixed time intervals (e.g., 0, 30, 60, 120 minutes) until completion or a 24-hour ceiling. Calculate conversion rate and final yield.
    • For Extractions: Quantify extraction efficiency of the target analyte (%) and co-extraction of impurities (%) using calibrated analytical methods.
  • Data Analysis: A "recommended" solvent is deemed functionally equivalent if its performance metrics (yield, efficiency) fall within 5% of the control and it does not generate new impurity profiles. Solvents failing this threshold require expert judgment for retention of the "problematic" solvent with appropriate control measures.

Protocol 2: Lifecycle Impact Assessment (Cradle-to-Gate)

Objective: To evaluate the complete environmental footprint of a solvent, supplementing the CHEM21 score with a quantitative lifecycle assessment [28].

Methodology:

  • System Boundaries: Define assessment boundaries from raw material acquisition ("cradle") to the production of the finished solvent at the factory gate ("gate").
  • Inventory Analysis: Compile energy and material input data, and environmental release data for each process step. Utilize databases like eChemPortal [28].
  • Impact Assessment: Calculate the cumulative energy demand (CED in MJ/kg) and COâ‚‚ footprint (in kg/kg) [3].
  • Expert Judgment Trigger: A high CHEM21 score with a disproportionately large CED or COâ‚‚ footprint, or a moderate CHEM21 score with an exceptionally low CED, presents a compelling case for an expert-led decision that overrides the default ranking.

Protocol 3: Process-Specific Toxicity and Exposure Risk Evaluation

Objective: To assess health risks in the specific context of the intended manufacturing process, moving beyond the CHEM21 guide's generalized health score [3].

Methodology:

  • Operational Scenario Analysis: Document all process steps involving the solvent, including temperature, pressure, and potential for aerosol generation.
  • Exposure Modeling: Using established industrial hygiene models (e.g., EPA/IH_MODEL), estimate potential exposure levels based on solvent physical properties (e.g., vapor pressure) and process containment.
  • Risk Characterization: Compare estimated exposure levels to available occupational exposure limits (OELs) or derived no-effect levels. A solvent with a "problematic" health score may be acceptable if engineering controls robustly ensure exposures remain well below safety thresholds, a determination requiring expert review.

Decision Framework for Expert Judgment

G Start Start: Solvent Selection CHEM21 Consult CHEM21 Guide Start->CHEM21 IsRecommended Is solvent CHEM21 'Recommended'? CHEM21->IsRecommended CheckPerformance Protocol 1: Test Functional Performance IsRecommended->CheckPerformance No UseSolvent Use Recommended Solvent IsRecommended->UseSolvent Yes IsEquivalent Performance Equivalent? CheckPerformance->IsEquivalent IsEquivalent->UseSolvent Yes CheckLCIA Protocol 2: Lifecycle Impact Assessment IsEquivalent->CheckLCIA No IsImpactAcceptable LCIA Impact Acceptable? CheckLCIA->IsImpactAcceptable CheckExposure Protocol 3: Exposure Risk Evaluation IsImpactAcceptable->CheckExposure No ExpertPanel Convene Expert Panel Review IsImpactAcceptable->ExpertPanel Yes IsRiskControlled Risk Adequately Controlled? CheckExposure->IsRiskControlled IsRiskControlled->ExpertPanel Yes RejectOverride Reject Proposed Override IsRiskControlled->RejectOverride No JustifiedOverride Document Justification for Override ExpertPanel->JustifiedOverride

Figure 1: Expert Judgment Override Decision Workflow

The Scientist's Toolkit: Essential Research Reagent Solutions

Table 3: Key Reagents and Tools for Solvent Assessment

Item Function/Application Context for Use
CHEM21 Solvent Selection Guide Primary screening tool for classifying solvents based on EHS profiles [3]. Initial solvent screening and prioritization.
Life Cycle Assessment (LCA) Software Calculates cumulative energy demand (CED) and COâ‚‚ footprint for cradle-to-gate analysis [3]. Protocol 2, for comprehensive environmental impact assessment beyond CHEM21.
Analytical Standards Certified reference materials for quantifying reaction yield and extraction efficiency. Protocol 1, for accurate performance equivalency testing.
Industrial Hygiene Exposure Models (e.g., EPA/IH_MODEL) Predicts occupational exposure levels based on solvent properties and process parameters. Protocol 3, for process-specific health risk assessment.
Green Environmental Assessment and Rating for Solvents (GEARS) Metric A comprehensive metric integrating EHS and LCA for holistic solvent evaluation [28]. Supplementary assessment when CHEM21 provides insufficient granularity.

Strategies for Substituting Problematic and Hazardous Solvents

The substitution of problematic and hazardous solvents is a critical objective in modern chemical research and development, driven by stringent regulatory pressures, evolving safety standards, and a growing commitment to sustainable practices. Solvents are categorized as problematic or hazardous based on their environmental, health, and safety (EHS) profiles, which include factors such as flammability, toxicity, carcinogenicity, and environmental persistence [48]. Regulatory frameworks like the European Union's REACH and the U.S. TSCA compel industries to demonstrate the safety of the chemicals they use, while consumer safety standards such as California's Proposition 65 further penalize the use of carcinogens and endocrine disruptors [49]. Within this context, the CHEM21 Project has established a leading guide for solvent selection, providing a standardized, multi-criteria assessment framework to quantify solvent "greenness" and guide the identification of safer alternatives [48] [2]. This Application Note provides detailed protocols for applying the CHEM21 framework to systematically identify, evaluate, and implement safer solvent substitutes in pharmaceutical development and related fields.

The CHEM21 Assessment Framework

The CHEM21 Solvent Selection Guide employs a scoring system to evaluate solvents across three primary domains: Safety, Health, and Environment. Each domain is scored, and the results are synthesized to categorize solvents as "Recommended," "Problematic," "Hazardous," or "Highly Hazardous" [48] [2].

Table 1: CHEM21 Solvent Assessment Criteria and Scoring

Assessment Domain Key Evaluation Criteria Low Hazard (Favorable Score) High Hazard (Unfavorable Score)
Safety Flash point, Flammability (GHS H-codes), Auto-ignition temperature, Peroxide formation [48] Flash point > 60°C, No H224-H226 codes [48] Flash point < -20°C, H224 (extremely flammable), Peroxide formation [48]
Health Acute toxicity, Carcinogenicity, Mutagenicity, Reproductive toxicity (Respiratory and skin irritation) [48] No H3XX codes, High boiling point (>85°C) [48] Corrosivity, Carcinogenicity (e.g., Benzene, 1,2-dichloroethane) [48]
Environment Aquatic toxicity (GHS H400-H411), Ozone depletion potential (H420), Volatile Organic Compound (VOC) generation, Biodegradability [48] Low VOC potential, Readily biodegradable, No aquatic toxicity codes [48] High VOC potential (BP <50°C), H410 (very toxic to aquatic life), Poor recyclability (BP >200°C) [48]

The following workflow diagram outlines the systematic process for evaluating and substituting solvents using this framework.

CHEM21_Workflow Start Identify Target Solvent Step1 Determine Key Functional Properties (e.g., Solvency, Boiling Point) Start->Step1 Step2 Assess against CHEM21 Criteria (Safety, Health, Environment) Step1->Step2 Step3 Generate Alternative Solvent List (Using Software Tools) Step2->Step3 Step4 Filter & Rank Alternatives (Based on Properties & CHEM21 Score) Step3->Step4 Step5 Experimental Validation (Solubility, Performance Testing) Step4->Step5 Step6 Select & Implement Substitute Step5->Step6 Step7 Document & Review Step6->Step7

Figure 1: CHEM21 Solvent Substitution Workflow

Experimental Protocol for Solvent Substitution

This protocol provides a step-by-step methodology for identifying and validating greener solvent substitutes for a hazardous solvent, using the replacement of Xylene in a varnish formulation as a representative case study [2].

Protocol: Substitution of Xylene in a Resin Varnish Formulation
Scope and Application

This protocol is designed for scientists and formulators who need to replace a hazardous solvent (e.g., Xylene) with a greener alternative while maintaining the performance of the end product, such as a resin-based varnish, coating, or drug formulation intermediate [2].

Principle

The substitution process leverages in-silico tools to identify potential solvent candidates based on physicochemical properties and Hansen Solubility Parameters (HSP). Candidates are then filtered based on their CHEM21 greenness scores before undergoing systematic experimental validation for solubility and performance [2].

Materials and Equipment

Table 2: Research Reagent Solutions and Key Materials

Item Function / Description Example Specifics
Target Resin Polymer to be dissolved. Paraloid B72, Dammar, Laropal A81, Regalrez 1094 [2]
Hazardous Target Solvent Solvent to be substituted. Xylene (o-, m-, p- isomers) [2]
SUSSOL Software AI-based tool for clustering solvents by physical properties to find substitutes [2]. Uses Self-Organizing Maps (SOM) [2].
HSPiP Software Software for predicting solubility using Hansen Solubility Parameters [2]. Determines solubility sphere of a resin [2].
CHEM21 Solvent Guide Database for assessing greenness metrics of solvents [2]. Provides safety, health, and environment scores [48] [2].
Test Substrates Surfaces for application testing. Leneta cards, prepared canvas test boards [2]
Analytical Instruments For characterizing film properties. Viscometer, Gloss meter, Colorimeter [2]
Step-by-Step Procedure

Step 1: Substitute Solvent Selection

  • Software-Aided Identification:
    • Input the key physical properties (e.g., boiling point, evaporation rate, polarity) of the target solvent (Xylene) into the SUSSOL software to generate a list of potential substitute solvents with similar properties [2].
    • In parallel, use HSPiP software for a solubility-driven approach.
      • Determine the Hansen Solubility Parameters (HSP) for the target resin (δD: dispersion forces, δP: polar forces, δH: hydrogen bonding) experimentally by testing its solubility in a range of solvents with known HSPs [2].
      • The software will define a "solubility sphere" in 3D HSP space. Solvents located within this sphere are predicted to dissolve the resin effectively [2].
  • Greenness Filtering:
    • Evaluate all candidate solvents from the previous step using the CHEM21 assessment guide [2].
    • Eliminate solvents with health scores >3 or those categorized as "Hazardous" or "Highly Hazardous" [2]. Prioritize solvents classified as "Recommended" (e.g., Ethanol, Isopropanol, Ethyl Acetate, Anisole) [48].

Step 2: Experimental Testing of Resin Solutions

  • Solution Preparation:
    • Prepare resin solutions (e.g., 10% w/v) using the shortlisted alternative solvents and the original target solvent (Xylene) as a control.
  • Performance Characterization:
    • Viscosity and Solubility: Measure and compare the viscosity of each resin solution. Note the clarity and stability of the solutions to confirm complete dissolution [2].
    • Film Formation and Drying: Apply the resin solutions to standard test substrates (e.g., Leneta cards) using a draw-down bar. Qualitatively and quantitatively assess the drying time, film clarity, and surface smoothness [2].
    • Coating Performance Tests:
      • Gloss: Measure the gloss of the dried films at a standard angle (e.g., 60°) using a gloss meter [2].
      • Color: Measure the color coordinates (e.g., Lab*) to evaluate any yellowing or color shift introduced by the alternative solvent [2].
      • Water Resistance: Apply a water droplet to the film surface for a set time, then blot dry and inspect for whitening or damage [2].

Step 3: Application Testing on Real-World Substrates

  • Select the most promising resin solutions (typically 2-3) based on the performance tests in Step 2.
  • Apply these solutions as varnishes to actual paintings or other relevant real-world substrates to evaluate working properties (e.g., brush flow, leveling) and final aesthetic results under practical conditions [2].

Step 4: Data Analysis and Selection

  • Compare all experimental data against the control (Xylene-based solution).
  • Select the alternative solvent that delivers comparable or acceptable performance while demonstrating a significantly improved CHEM21 greenness profile.

The following diagram summarizes the core experimental workflow.

Experimental_Protocol A Define Target Solvent & Resin B In-Silico Candidate Selection (SUSSOL & HSPiP Tools) A->B C Greenness Filtering (CHEM21 Assessment) B->C D Prepare Resin Solutions C->D E Performance Characterization (Viscosity, Drying, Gloss, Color) D->E F Real-World Application Test E->F G Select Optimal Substitute F->G

Figure 2: Experimental Validation Workflow

Promising Solvent Alternatives and Properties

Based on the CHEM21 guide and recent research, several solvent classes and specific chemicals have been identified as safer, bio-based alternatives to conventional hazardous solvents [49] [48] [50].

Table 3: Promising Green Solvent Alternatives and Their Profiles

Solvent Name CHEM21 Category [48] Key Properties Potential Substitution For Applications
Water Recommended Non-flammable, non-toxic, readily available [48] Solvent for ionic compounds and water-soluble materials [48] Cleaning, formulations, extraction [48]
Ethanol Recommended Flash point 13°C, low toxicity, biodegradable [48] Substitution for methanol and other toxic alcohols [48] Disinfectants, extracts, coatings [49]
Ethyl Levulinate Recommended (exemplary) BP ~206°C, non-flammable, 100% biogenic, readily biodegradable [49] High-boiling point petrochemical solvents [49] Coatings, cleaners, cosmetics [49]
Butyl Levulinate Recommended (exemplary) BP >230°C, flash point 110°C, non-flammable, readily biodegradable [49] Glycol ethers, coalescing agents [49] Grease and resin removal, paint formulations [49]
Limonene N/A (Bio-based) Derived from citrus peel, low toxicity, biodegradable [50] Chlorinated solvents (e.g., for degreasing) [50] Cleaning agents, degreasers [50]
Supercritical COâ‚‚ N/A (Green Alternative) Non-flammable, non-toxic, tunable solvency [50] Organic solvents in extraction [50] Extraction of bioactive compounds [50]
Anisole Recommended Not classified as highly hazardous [48] Aromatic solvents like toluene and xylene [2] Varnish formulations, reaction medium [2]
Isoamyl Acetate N/A (exemplary) Favorable working properties, acceptable health profile [2] Xylene in varnish applications [2] Resin solvent for conservation varnishes [2]

The strategic substitution of hazardous solvents is an achievable and critical objective for sustainable drug development and chemical manufacturing. By adopting the structured CHEM21 assessment framework and employing a combination of in-silico tools like SUSSOL and HSPiP with rigorous experimental validation, researchers can systematically identify and implement greener solvents. This approach successfully balances the critical parameters of sustainability, performance, regulatory compliance, and occupational safety, future-proofing research and development processes in the pharmaceutical industry and beyond.

Utilizing Updated Miscibility Data for Green Work-up and Purification

The integration of green chemistry principles into pharmaceutical and chemical development necessitates a shift toward safer, more sustainable solvents. Solvent selection plays a critical role in process greenness, as solvents often constitute the largest mass fraction in synthetic processes. Miscibility—the ability of two or more liquids to form a homogeneous mixture—is a fundamental physical property with profound implications for work-up and purification efficiency. Traditional miscibility tables, however, have not kept pace with the emergence of bio-based and greener solvent alternatives, creating a significant knowledge gap for researchers [51].

Framed within the context of the CHEM21 Solvent Selection Guide, this application note provides updated, experimentally determined miscibility data for 28 green solvents alongside nine conventional benchmarks. This data enables informed solvent substitution strategies, directly supporting the replacement of hazardous solvents with greener alternatives in laboratory and industrial processes [51].

Updated Miscibility Data for Green Solvents

Solvent Selection and CHEM21 Framework

The solvents evaluated were selected based on the CHEM21 solvent selection guide, which provides a harmonized assessment of solvent greenness. The guide scores solvents based on Safety, Health, and Environmental (SHE) criteria, categorizing them as "Recommended," "Problematic," "Hazardous," or "Highly Hazardous" [51]. This study focused on solvents from the recommended and problematic categories, intentionally excluding most known toxic or restricted solvents to discourage their use. Four additional solvents with promising bio-based synthetic routes were also included.

Table 1: Selected Green Solvents and Key Properties

Solvent Name Abbreviation CHEM21 Recommendation Key Green Characteristics
2-Methyltetrahydrofuran 2-MeTHF Recommended Bio-derived, low toxicity vs. THF [51]
Cyrene - - Bio-derived (from cellulose), non-toxic [51]
Dimethyl Carbonate DMC Recommended Biodegradable, low toxicity [51]
Ethyl Lactate - Recommended Bio-derived, readily biodegradable [51]
Gamma-Valerolactone GVL Problematic Bio-derived from biomass, high boiling point [51]
Propylene Carbonate - Problematic Low toxicity, high boiling point [51]
Comprehensive Miscibility Table

The miscibility of 406 binary solvent pairs was assessed visually at room temperature. The following table summarizes key miscibility findings for a selection of prominent green and traditional solvents, providing an actionable tool for solvent selection.

Table 2: Miscibility of Selected Solvent Pairs (G: Green, T: Traditional) [51]

Solvent 1 Water Heptane DCM (T) Ethyl Acetate Ethanol 2-MeTHF (G) GVL (G)
Water (G) - Immiscible Immiscible Immiscible Miscible Immiscible Miscible
Heptane (T) Immiscible - Miscible Miscible Immiscible Miscible Immiscible
DCM (T) Immiscible Miscible - Miscible Miscible Miscible Immiscible
Ethyl Acetate Immiscible Miscible Miscible - Miscible Miscible Miscible
Ethanol (G) Miscible Immiscible Miscible Miscible - Miscible Miscible
2-MeTHF (G) Immiscible Miscible Miscible Miscible Miscible - Miscible
GVL (G) Miscible Immiscible Immiscible Miscible Miscible Miscible -

Abbreviations: DCM: Dichloromethane; 2-MeTHF: 2-Methyltetrahydrofuran; GVL: Gamma-Valerolactone

Experimental Protocols for Miscibility Determination

Standard Protocol for Visual Miscibility Screening

Principle: This method determines miscibility by visually assessing phase behavior after mixing two solvents in equal volumes [51].

Materials and Equipment:

  • Solvents: High-purity grades (≥95-99.5%) as listed in Table 1.
  • Glassware: 5 mL clear glass vials with caps.
  • Pipettes: Pasteur pipettes or adjustable micropipettes.

Procedure:

  • Preparation: Add 1.0 mL of the first solvent to a 5.0 mL glass vial using a clean Pasteur pipette.
  • Mixing: Add 1.0 mL of the second solvent dropwise to the vial. Cap the vial securely.
  • Agitation and Observation: Shake the vial vigorously for 10-15 seconds. Allow it to stand for one minute at room temperature.
  • Visual Assessment:
    • Miscible: Formation of a single, homogeneous liquid phase.
    • Immiscible: Formation of two distinct, separated liquid layers.
    • Partially Miscible: Formation of two layers, but with noticeable mutual solubility (e.g., volume change of layers).
Refined Protocol for Partially Miscible Systems

For solvent pairs identified as partially miscible in the initial screen, a more precise test is required [51].

Procedure:

  • Preparation: Precisely add 1.0 mL of the first solvent to a 5.0 mL vial using a micropipette.
  • Incremental Addition: Using a micropipette, add 1.0 mL of the second solvent in small increments (e.g., 20.0 µL).
  • Observation: After each addition, shake the vial and observe for the formation of a second phase. Note the volume of the second solvent added at the cloud point (onset of phase separation).
  • Data Recording: The miscibility profile can be quantified by recording the exact volumes at which phase separation occurs and disappears.

Application in Work-up and Purification: Case Studies

Liquid-Liquid Extraction Design

Challenge: Replacing dichloromethane (DCM), a common extraction solvent classified as hazardous and likely carcinogenic [13].

Solution: 2-Methyltetrahydrofuran (2-MeTHF) is a bio-based solvent with a superior SHE profile. As shown in Table 2, 2-MeTHF is immiscible with water, making it an excellent candidate for aqueous-organic extractions [51].

Protocol: Aqueous Work-up using 2-MeTHF

  • Following reaction completion, dilute the reaction mixture with an equal volume of water.
  • Add a volume of 2-MeTHF equal to the estimated organic phase volume.
  • Shake the mixture in a separatory funnel and allow the phases to separate completely.
  • Drain the lower aqueous layer. The lower phase is typically aqueous due to 2-MeTHF's lower density (0.85 g/mL) compared to water.
  • Extract the aqueous layer a second time with fresh 2-MeTHF.
  • Combine the organic layers for subsequent drying and concentration.

Note: 2-MeTHF can form azeotropes with water, facilitating drying during evaporation.

Solvent Switching and Co-solvent Precipitation

Challenge: Isolating a polar product from a high-boiling, water-miscible green solvent like Gamma-Valerolactone (GVL).

Solution: Leverage miscibility data to select an anti-solvent. GVL is miscible with water and ethanol but immiscible with heptane and DCM (Table 2). A greener anti-solvent like heptane can be used for precipitation [51].

Protocol: Product Precipitation from GVL

  • Concentrate the GVL solution containing the product to a minimal volume.
  • While stirring vigorously, slowly add a 5-10 volume excess of heptane (anti-solvent).
  • Continue stirring for 30-60 minutes to promote complete product precipitation.
  • Isolate the solid product by vacuum filtration.
  • Wash the filter cake thoroughly with fresh heptane to remove residual GVL.
  • Dry the solid product under vacuum.

The Scientist's Toolkit: Research Reagent Solutions

Table 3: Essential Reagents and Materials for Green Solvent Applications

Reagent/Material Function/Application Notes for Green Chemistry
2-MeTHF Replacement for THF and DCM in extractions and as reaction medium. Bio-derived; less prone to peroxide formation than diethyl ether [51].
Ethyl Lactate Solvent for extraction, recrystallization, and reactions. Derived from corn; readily biodegradable [51].
Dimethyl Carbonate Green polar aprotic solvent; also used as a methylating agent. Low toxicity; biodegradable [51].
Cyrene Replacement for dipolar aprotic solvents like DMF and NMP. Bio-derived from cellulose; non-toxic [51].
GVL High-boiling solvent for catalysis and biomass processing. Bio-derived from lignocellulose; useful for simplifying distillations [51].
CHEM21 Selection Guide Framework for assessing solvent greenness. Provides scores for Safety, Health, and Environment to guide selection [51] [13].

Integrated Workflow for Green Solvent Implementation

The following diagram illustrates a systematic workflow for selecting and implementing green solvents in work-up and purification, based on the principles of the CHEM21 guide and experimental miscibility data.

G Start Identify Process Requirement A Consult CHEM21 Guide Start->A B Shortlist Green Solvents A->B Based on SHE criteria C Check Miscibility Table B->C For binary pairs D Perform Miscibility Test C->D Experimental validation E Design & Run Process D->E e.g., Extraction/Precipitation F Evaluate Performance E->F Assay yield/purity F->B Optimize selection

Green Solvent Selection Workflow

This workflow emphasizes a circular, iterative process where performance evaluation feeds back into solvent selection, enabling continuous process optimization and greening. The integration of the CHEM21 guide ensures that environmental, health, and safety criteria are prioritized from the outset [51] [52] [13].

Balancing Chemical Efficiency, Cost, and Greenness in Solvent Choice

The selection of an appropriate solvent is a critical decision in chemical research and pharmaceutical development, profoundly influencing reaction efficiency, purification feasibility, environmental impact, and process economics. The global solvent market is substantial, valued at approximately $37.12 billion in 2025 and projected to reach $70.48 billion by 2035 [53]. Within this market, green and bio-based solvents are experiencing accelerated growth, with their market expected to surpass $5.5 billion by 2035, growing at a compound annual growth rate (CAGR) of 8.7% [54] [31]. This shift reflects increasing regulatory pressure and industry commitment to sustainable practices, particularly in pharmaceutical manufacturing where solvents can constitute up to 50% of the materials used in active pharmaceutical ingredient (API) production [11].

Framed within the context of solvent greenness assessment using the CHEM21 guide, this document provides detailed application notes and protocols to help researchers balance the often-competing priorities of chemical efficiency, cost-effectiveness, and environmental sustainability. The CHEM21 Selection Guide, developed by a European consortium including pharmaceutical companies and academic institutions, provides a standardized methodology for evaluating solvents based on safety, health, and environmental (SHE) criteria aligned with the Globally Harmonized System (GHS) [3] [9].

The CHEM21 Solvent Selection Framework

Guide Structure and Scoring Methodology

The CHEM21 guide categorizes solvents into three primary classifications: "Recommended," "Problematic," and "Hazardous" based on a quantitative scoring system across safety, health, and environmental parameters [9]. This classification enables chemists to make informed decisions during solvent selection for synthetic routes and process development.

The scoring system employs a color-coded approach where lower scores indicate preferable solvents:

  • Score 1-3 (Green): Low hazard
  • Score 4-6 (Yellow): Moderate hazard
  • Score 7-10 (Red): High hazard [9]

Table 1: CHEM21 Scoring Criteria Overview

Assessment Dimension Key Parameters Scoring Range Impact Factors
Safety Flash point, auto-ignition temperature, resistivity, peroxide formation 1-10 Flash point < -20°C scores 7; additional points for AIT <200°C, resistivity >10⁸ ohm.m, or peroxide formation
Health CMR properties, acute toxicity, target organ toxicity, irritation 2-9 Based on GHS H3xx statements; +1 point if boiling point <85°C
Environment Volatility (boiling point), aquatic toxicity, ozone depletion 3-10 Considers GHS H4xx statements and boiling point (<50°C or >200°C scores higher)
Implementation Workflow

The following diagram illustrates the logical workflow for applying the CHEM21 guide in solvent selection:

CHEM21_Workflow Start Define Process Requirements Step1 Identify Potential Solvents Start->Step1 Step2 Apply CHEM21 Scoring Criteria Step1->Step2 Step3 Categorize Solvents: Recommended/Problematic/Hazardous Step2->Step3 Step4 Evaluate Technical Performance Step3->Step4 Step5 Assess Economic Feasibility Step4->Step5 Step6 Select Optimal Solvent Step5->Step6 Step7 Document and Review Decision Step6->Step7 End Implement and Monitor Step7->End

Solvent Selection Workflow: This diagram outlines the systematic approach for solvent selection integrating CHEM21 assessment with technical and economic considerations.

Quantitative Comparison of Common Solvents

CHEM21 Ratings for Frequently Used Solvents

The following table provides a comparative analysis of common solvents across efficiency, cost, and greenness parameters, incorporating CHEM21 ratings and key performance indicators:

Table 2: Solvent Comparison Based on CHEM21 Guide and Performance Metrics

Solvent CHEM21 Category Safety Score Health Score Environmental Score Relative Evaporation Rate Approximate Cost (USD/kg) Key Applications
Ethyl Acetate Recommended 5 3 3 Medium 3.50-5.00 Extraction, chromatography, reaction medium
Heptane Recommended 3 2 7 Medium 2.50-4.00 Extraction, non-polar reactions
2-MeTHF Recommended 4 3 3 Medium-High 15.00-25.00 Grignard reactions, hydrophobic medium
Methanol Recommended* 4 7 5 High 1.00-2.00 Extraction, synthesis, analytical applications
Acetone Recommended* 5 3 5 Very High 1.20-2.50 Cleaning, synthesis, analytical applications
Cyclohexanone Problematic 3 2 5 Low 4.00-6.00 Polymer chemistry, specialty applications
Benzyl Alcohol Problematic 1 2 7 Low 5.00-8.00 High-boiling solvent, disinfectant
Diethyl Ether Hazardous 10 4 5 Very High 4.00-7.00 Extraction, specialty reactions

Note: Methanol and acetone were categorized as "Recommended" after expert review despite initial "Problematic" classification by default scoring [9].

The adoption of green solvents spans multiple industries, with the paints and coatings sector representing the largest application segment at approximately $3.52 billion [32]. Bio-based solvents derived from renewable sources such as corn, sugarcane, and vegetable oils are gaining significant traction, with lactate esters emerging as a leading product category [54] [32].

From a regional perspective, the Asia-Pacific region dominates the solvents market with over 35% share, driven by rapid industrialization and manufacturing expansion [53]. North America represents approximately 40% of the green and bio-solvent market growth, reflecting stringent regulatory environments and advanced sustainability initiatives [32].

Experimental Protocols for Solvent Evaluation and Implementation

Protocol 1: Solvent Greenness Assessment Using CHEM21 Framework

Purpose: To systematically evaluate and classify solvents according to the CHEM21 selection guide.

Materials:

  • Safety Data Sheets (SDS) for target solvents
  • CHEM21 scoring spreadsheet (available from RSC supplementary data)
  • Physical property data (boiling point, flash point)

Procedure:

  • Compile Safety Data: Collect GHS classification and physical property data from SDS.
  • Calculate Safety Score:
    • Determine base score from flash point (FP):
      • FP > 60°C = 1
      • FP 23-60°C = 3
      • FP 22-0°C = 4
      • FP -1 to -20°C = 5
      • FP < -20°C = 7
    • Add +1 for each: auto-ignition temperature <200°C, resistivity >10⁸ ohm.m, peroxide formation (EUH019)
  • Calculate Health Score:
    • Assign base score according to GHS H3xx statements:
      • H302/H312/H332/H336/EUH070 = 4
      • H301/H311/H331 = 6
      • H300/H310/H330 = 9
      • No H3xx statement after REACH registration = 1
    • Add +1 if boiling point <85°C
  • Calculate Environmental Score:
    • Base scoring on boiling point and GHS H4xx statements:
      • BP 70-139°C with no H4xx = 3
      • BP 50-69°C or 140-200°C with H412/H413 = 5
      • BP <50°C or >200°C with H400/H410/H411 = 7
      • EUH420 (ozone hazard) = 10
  • Determine Overall Classification:
    • Recommended: No scores ≥7 and maximum one "yellow" score
    • Problematic: One score =7 OR two "yellow" scores
    • Hazardous: Any score ≥8 OR two "red" scores [9]
Protocol 2: Solvent Efficiency Testing for API Crystallization

Purpose: To evaluate solvent performance for active pharmaceutical ingredient crystallization, integrating greenness with technical efficacy.

Materials:

  • API compound
  • Candidate solvents (pre-screened using CHEM21 guide)
  • Analytical HPLC with UV detection
  • Thermal analysis equipment (DSC/TGA)
  • Laboratory crystallization apparatus

Procedure:

  • Solubility Profiling:
    • Prepare saturated solutions of API in candidate solvents across temperature range (10-70°C)
    • Agitate for 24 hours to ensure equilibrium
    • Filter and quantify concentration via HPLC
    • Plot solubility vs. temperature curves
  • Crystallization Trials:
    • Conduct cooling crystallizations from saturated solutions
    • Document crystal yield, form (via XRD), and purity (via HPLC)
    • Characterize crystal morphology using microscopy
  • Solvent Recovery Assessment:
    • Distill mother liquors under reduced pressure
    • Quantify recovery yield and solvent purity
    • Reuse recovered solvent for additional crystallization cycles
  • Data Integration:
    • Correlate solvent properties with crystallization performance
    • Rank solvents by combined efficiency and sustainability metrics [17]
Protocol 3: Life Cycle Assessment for Solvent Selection

Purpose: To evaluate environmental impacts of solvent choices beyond the CHEM21 criteria using life cycle assessment methodology.

Materials:

  • LCA software (e.g., SimaPro)
  • Solvent production data
  • Energy consumption metrics
  • Waste management data

Procedure:

  • Goal and Scope Definition:
    • Define system boundaries (cradle-to-gate or cradle-to-grave)
    • Establish functional unit (e.g., per kg of API produced)
  • Life Cycle Inventory:
    • Compile energy and material inputs for solvent production
    • Quantify emissions, waste generation, and resource consumption
  • Impact Assessment:
    • Calculate midpoint indicators (global warming potential, aquatic toxicity)
    • Apply endpoint methods (ReCiPe 2016) for damage assessment
  • Interpretation:
    • Compare LCA results with CHEM21 classifications
    • Identify environmental hotspots in solvent lifecycle
    • Integrate findings into solvent selection decision matrix [28] [17]

Advanced Tools and Digital Solutions

Research Reagent Solutions

Table 3: Essential Tools and Resources for Sustainable Solvent Selection

Tool/Resource Type Key Function Access
CHEM21 Selection Guide Assessment Framework Classifies solvents based on SHE criteria Royal Society of Chemistry
ACS GCI Solvent Selection Tool Interactive Tool PCA-based solvent substitution based on physical properties ACS Green Chemistry Institute
SolECOs Platform Data-Driven Platform Integrates solubility prediction with sustainability assessment Research publication [17]
GSK Solvent Sustainability Guide Assessment Framework Evaluates solvents across multiple sustainability dimensions Pharmaceutical Roundtable
PMI Calculator Metrics Tool Calculates Process Mass Intensity for route evaluation ACS GCI Pharmaceutical Roundtable [11]
Digital Workflow Integration

The following diagram illustrates how digital tools can be integrated into the solvent selection process:

Digital_Workflow API API Structure & Properties Database Solubility Database & Property Library API->Database Query ML Machine Learning Prediction Models Database->ML Training Data Assessment Sustainability Assessment ML->Assessment Solubility Profile Ranking Multi-criteria Ranking Assessment->Ranking Impact Scores Output Optimal Solvent Recommendation Ranking->Output Prioritized List

Digital Solvent Selection: This diagram shows the integration of data-driven approaches for solvent selection, combining property databases, predictive models, and sustainability assessment.

Modern solvent selection increasingly leverages digital tools, with platforms like SolECOs incorporating machine learning models including Polynomial Regression Model-based Multi-Task Learning Network (PRMMT) and Modified Jouyban–Acree-based Neural Network (MJANN) to predict solubility profiles for over 1,186 APIs in 30 solvents [17]. These tools enable researchers to rapidly screen solvent candidates before laboratory experimentation, significantly reducing development time and resource consumption.

Balancing chemical efficiency, cost, and greenness in solvent choice requires a systematic approach that integrates multiple assessment criteria. The CHEM21 selection guide provides a robust framework for initial classification, which should be complemented with technical performance evaluation and economic analysis. As the green and bio-solvent market continues to expand at a CAGR of 8.7% to 11.5% [54] [32], driven by regulatory pressures and environmental awareness, researchers have an increasingly diverse palette of sustainable solvent options.

Future developments in solvent selection will likely emphasize:

  • Advanced bio-based solvents with improved performance characteristics
  • Circular economy approaches enhancing solvent recovery and reuse
  • AI-driven selection tools integrating predictive modeling with sustainability metrics
  • Hybrid solvent systems optimizing combined performance and environmental profiles

By adopting the structured protocols and assessment frameworks outlined in this document, researchers and drug development professionals can make informed solvent selections that advance both process efficiency and sustainability objectives within pharmaceutical development and broader chemical applications.

Benchmarking CHEM21: Validation Against Industry Standards and Future Metrics

In the pursuit of sustainable manufacturing, particularly within the pharmaceutical industry, the selection of appropriate solvents is a critical consideration. Solvents can account for approximately 50% of all materials used in the manufacture of active pharmaceutical ingredients (APIs), making their environmental, health, and safety (EHS) profiles a significant factor in the overall sustainability of a process [11]. To standardize and guide this selection, several major pharmaceutical companies and consortia have developed Solvent Selection Guides. These guides serve as strategic tools for chemists and engineers, providing a structured assessment of solvents based on a combination of safety, health, and environmental criteria.

This application note provides a detailed comparison of four key guides: the consortium-based CHEM21 Selection Guide and the in-house guides from GSK, Pfizer, and Sanofi. The CHEM21 guide was established as a public-private partnership under the Innovative Medicines Initiative (IMI) to promote sustainable methodologies [3]. Its development involved a comprehensive survey of existing guides, followed by the creation of a harmonized methodology intended for broad application [55] [9]. The proprietary guides from GSK, Pfizer, and Sanofi represent the tailored approaches of leading pharmaceutical companies, each reflecting specific corporate priorities and risk assessments [56]. By examining their structures, scoring methodologies, and final solvent rankings, this document aims to equip researchers and drug development professionals with the knowledge to make informed, sustainable solvent choices.

Comparative Analysis of Guide Structures and Methodologies

The various solvent selection guides, while sharing a common goal, employ distinct methodologies for assessing and ranking solvents. Understanding these foundational differences is key to interpreting their recommendations.

The CHEM21 Guide Methodology

The CHEM21 selection guide employs a transparent, criteria-based scoring system designed to be applicable even to newer solvents for which complete data may not be available. Its methodology is built on easily accessible physical properties and Globally Harmonized System (GHS) of Classification and Labelling of Chemicals statements, creating a default ranking that can be further refined by expert judgment [9]. The guide evaluates three core areas, each scored from 1 (lowest hazard) to 10 (highest hazard), with an associated color code: green (1-3), yellow (4-6), and red (7-10).

  • Safety Score: Derived primarily from the solvent's flash point, with additional points added for a low auto-ignition temperature (<200°C), high resistivity (>10⁸ ohm.m), or the ability to form explosive peroxides (GHS statement EUH019) [9]. For instance, diethyl ether, with a flash point of -45°C, a low auto-ignition temperature, high resistivity, and peroxide-forming ability, receives the maximum safety score of 10 [9].
  • Health Score: Based primarily on the most stringent GHS H3xx statements related to carcinogenicity, mutagenicity, reproductive toxicity (CMR), specific target organ toxicity (STOT), and acute toxicity. One point is added to the health score if the solvent's boiling point is below 85°C, indicating a higher potential for inhalation exposure [9].
  • Environment Score: Considers the solvent's volatility (linked to its boiling point) and any GHS H4xx environmental hazard statements. A solvent with a boiling point below 50°C or above 200°C, or one carrying H400, H410, or H411 statements (harmful to aquatic life), receives a higher environmental score [9].

These three scores are then combined to generate an overall ranking (Recommended, Problematic, or Hazardous) according to a defined matrix. The CHEM21 consortium explicitly notes that this default ranking is a model and should be critically assessed by occupational hygienists and other experts, as illustrated by their decision to manually rank pyridine as "Hazardous" despite a default score of "Recommended" [9].

The in-house guides from GSK, Pfizer, and Sanofi pre-dated the unified CHEM21 guide and were developed to meet the specific needs of each organization.

  • GSK's Guide was developed as an in-house sustainability guide for solvent selection [56].
  • Pfizer's Guide classifies solvents into simple, actionable categories: Preferred, Usable, and Undesirable [55]. This straightforward classification helps chemists quickly identify the best options for use in their processes.
  • Sanofi's Guide employs a more detailed classification system, categorizing solvents as Recommended, Substitution Advisable, or Banned [56]. This structure not only recommends good solvents but also actively discourages the use of problematic ones.

A comparative survey of these guides revealed that while there is strong agreement on the classification for about two-thirds of common solvents, discrepancies exist for the remaining third. These differences are attributable to variations in the weighting of safety, health, and environmental criteria within each company's guide [55].

Table 1: Comparison of Scoring and Classification Systems Across Guides

Guide Core Assessment Method Classification Tiers Key Basis for Assessment
CHEM21 Quantitative scores (1-10) for Safety, Health, Environment [9] Recommended, Problematic, Hazardous [9] GHS statements, physical properties (Flash Point, Boiling Point) [9]
GSK Not fully public (in-house guide) [56] Similar tiered structure (specific tiers not detailed in sources) Safety, Health, Environmental criteria [56]
Pfizer Not fully public (in-house guide) [55] Preferred, Usable, Undesirable [55] Safety, Health, Environmental criteria [55]
Sanofi Not fully public (in-house guide) [56] Recommended, Subst. Advisable, Banned [55] Safety, Health, Environmental criteria [56]

Quantitative Data Comparison and Solvent Rankings

The most direct way to compare the outputs of the different guides is to examine their specific rankings for a common set of solvents. A landmark survey analyzed and compared the rankings of 51 commonly used solvents across the five guides (including AstraZeneca's) to identify consensus and discrepancies [55].

The analysis found a clear agreement for 34 out of the 51 solvents, representing two-thirds of the total. For the remaining one-third of solvents, classified as "To Be Confirmed" in the comparative table, the differing weightings of criteria in the various guides prevented a unanimous classification [55]. This highlights that while a strong consensus exists on many solvents, expert judgment and specific organizational policies remain crucial for a significant number of cases.

Table 2: Comparative Solvent Rankings from a Multi-Guide Survey [55]

Solvent Pfizer Sanofi CHEM21 Overall* Solvent Pfizer Sanofi CHEM21 Overall*
Water - - Recommended MTBE Usable Subst. advisable Problematic/Hazardous
EtOH Preferred Recommended Recommended THF Usable Subst. advisable Problematic/Hazardous
i-PrOH Preferred Recommended Recommended Cyclohexane - - Problematic/Hazardous
n-BuOH Preferred Recommended Recommended DCM - - Problematic/Hazardous
Acetone Preferred Recommended Recommended Diisopropyl ether Undesirable Subst. advisable Hazardous
MEK Preferred Recommended Recommended 1,4-dioxane Undesirable Subst. requested Hazardous
MIBK - Recommended Recommended DMF - - Hazardous
Ethyl Acetate Preferred Recommended Recommended NMP - - Hazardous
Anisole - Recommended Recommended Diethyl ether Undesirable Banned Highly Hazardous
MeOH Preferred Recommended Recommended Benzene - - Highly Hazardous
t-BuOH Preferred Subst. advisable Recommended Chloroform - - Highly Hazardous

*The CHEM21 "Overall" ranking is the consolidated output from the survey [55].CHEM21 classifies these solvents as "Recommended or Problematic?" in the consolidated list, indicating a lack of full consensus [55]. Note: CHEM21's final published guide later ranked MeOH and Acetone as "Recommended" and Cyclohexanone as "Problematic" after further discussion [9].

The CHEM21 project used this comparative analysis as a foundation to build its own recommended guide. The final CHEM21 guide provides a clear, publicly available ranking of classical and less classical solvents, which includes bio-derived options [9]. This guide has been endorsed by professional groups like the ACS Green Chemistry Institute as a key tool for rational solvent selection [11] [3].

Experimental Protocol: Implementing a Solvent Selection Guide

This protocol outlines a step-by-step procedure for applying a solvent selection guide, such as the CHEM21 guide, to identify greener alternatives for a specific chemical process. The example used will be the replacement of chloroform in a lipid extraction process, a relevant challenge in analytical chemistry and biotechnology [57].

Principle

The objective is to systematically replace a hazardous solvent with a safer, more environmentally sustainable alternative while maintaining or improving process performance. The methodology relies on a combination of computational solvent screening using Hansen Solubility Parameters (HSP) and Principal Component Analysis (PCA) of physicochemical properties, followed by an experimental validation of the most promising candidates based on their green credentials [57].

Research Reagent Solutions and Materials

Table 3: Essential Materials and Tools for Solvent Replacement Studies

Item Name Function/Description Example/Catalog Reference
CHEM21 Solvent Selection Guide Provides a pre-evaluated ranking of solvents based on Safety, Health, and Environmental (SHE) criteria. Open access article and spreadsheet [9].
ACS GCI Solvent Selection Tool An interactive tool for selecting solvents based on Principal Component Analysis (PCA) of their physical properties. Online tool with 272 solvents [11] [24].
Hansen Solubility Parameters A computational method to predict solubility and miscibility based on dispersion, polar, and hydrogen-bonding forces. Used for in-silico prediction of solvent performance [57].
Candidate Green Solvents Potential replacement solvents identified through screening. Cyclopentyl methyl ether (CPME), 2-Methyltetrahydrofuran (2-MeTHF), Methyl tert-butyl ether (MTBE), iso-Butyl acetate (iBuAc) [57].
Lipid Standards & Plasma A complex biological matrix for validating extraction efficiency. EquiSPLASH LIPIDOMIX Mass Spec Standard; Human blood plasma [57].

Step-by-Step Procedure

Step 1: Identify the Target Solvent and its Role
  • Clearly define the function of the solvent in the process (e.g., extraction, reaction medium, purification). For chloroform in the Folch lipid extraction method, its key functions are to dissolve a wide range of lipids and form a biphasic system with water/methanol [57].
Step 2: In-Silico Screening of Alternatives
  • Consult the CHEM21 Guide: Identify solvents with a "Recommended" or "Problematic" ranking that are structurally or functionally similar to the target solvent. Chloroform is classified as "Highly Hazardous" [55], providing a strong rationale for substitution.
  • Use Computational Tools: Employ the ACS GCI Solvent Selection Tool to map solvents by their physicochemical properties and identify those neighboring the target solvent, indicating similar properties [24] [57]. Calculate Hansen Solubility Parameters to predict which green solvents will have comparable solvation ability for the target analytes (e.g., lipids) [57].
  • Generate a Shortlist: Combine the green ranking from CHEM21 with the computational screening results to create a shortlist of candidate solvents (e.g., CPME, 2-MeTHF, iBuAc) [57].
Step 3: Experimental Validation of Extraction Efficiency

The following protocol is adapted from a study on chloroform-free lipid extraction [57].

  • Material Preparation:
    • Reconstitute lyophilized human plasma in Milli-Q water.
    • Prepare candidate solvent mixtures. For a monophasic extraction, use a mixture of MeOH/MTBE/Candidate Solvent (1.33:1:1, v/v/v). For a biphasic Folch-like extraction, use a mixture of Chloroform/MeOH or Candidate Solvent/MeOH (2:1, v/v) [57].
  • Extraction Procedure:
    • To 5 µL of plasma, add 300 µL of methanol and vortex for 30 seconds.
    • Add 600 µL of the candidate solvent (e.g., CPME) or chloroform (for the control), vortex for 30 seconds.
    • Add 150 µL of water to induce phase separation (for biphasic systems), vortex for 30 seconds.
    • Incubate the mixture on a rotary shaker for 10 minutes at 4°C.
    • Centrifuge the samples for 10 minutes at 1000 × g and 4°C.
    • Carefully collect the organic phase.
    • Dry the organic phase under a gentle nitrogen stream.
    • Reconstitute the dried lipid extract in 50 µL of isopropanol for UHPLC-MS analysis [57].
  • Performance Analysis:
    • Use UHPLC-MS to quantify the extracted lipid species.
    • Compare the total lipid yield and profile diversity obtained with the candidate solvents against the traditional chloroform-based method.

Workflow Visualization

The following diagram illustrates the logical workflow for the solvent selection and replacement protocol.

Start Define Solvent Function A Identify Hazardous Solvent (e.g., Chloroform) Start->A B Consult CHEM21 Guide for 'Recommended' alternatives A->B C Screen with ACS GCI Tool & Hansen Parameters B->C D Generate Shortlist of Candidate Solvents C->D E Experimental Validation (Extraction & Analysis) D->E F Evaluate Performance vs. Green Credentials E->F Decision Performance Adequate? F->Decision Decision->B No End Implement Green Solvent Decision->End Yes

The comparative analysis reveals that while a strong consensus exists on the greenness of many common solvents, the different methodologies and weightings in the GSK, Pfizer, and Sanofi guides can lead to varied classifications for a significant minority of solvents. The CHEM21 Selection Guide successfully synthesizes these approaches into a unified, transparent, and publicly accessible methodology. Its strength lies in its systematic scoring system based on GHS criteria and physical properties, which allows for the preliminary assessment of a wide array of solvents, including newer, bio-derived options [9] [58].

From a practical standpoint, the CHEM21 guide does not operate in isolation. It is most powerful when used as part of a broader solvent selection toolkit. The ACS GCI Pharmaceutical Roundtable suggests the use of the CHEM21 guide for rating solvents based on health, safety, and environmental criteria, while also providing an interactive Solvent Selection Tool for choosing solvents based on their physicochemical properties [11] [24]. This combined approach enables researchers to balance the "greenness" of a solvent with the technical requirements of a specific process, such as solubility, boiling point, and miscibility.

The experimental protocol for replacing chloroform in lipid extraction demonstrates the real-world application of these principles. The study successfully identified cyclopentyl methyl ether (CPME) as a "Recommended" solvent that not only reduces SHE risks but also delivers comparable, and in some cases superior, analytical performance [57]. This case study underscores a critical conclusion: the transition to greener solvents is not only necessary for environmental and safety compliance but is also technically feasible without compromising process efficiency.

In conclusion, for researchers and drug development professionals, the strategic integration of the CHEM21 guide with computational and experimental tools provides a robust framework for making informed, sustainable solvent choices. This practice aligns with both the principles of green chemistry and the operational demands of modern industrial R&D, ultimately contributing to the design of safer and more sustainable chemical processes.

The integration of Life Cycle Assessment (LCA) and Cumulative Energy Demand (CED) provides a powerful, complementary framework for evaluating the environmental sustainability of chemical processes, particularly within pharmaceutical development and analytical chemistry. LCA offers a multi-dimensional perspective on environmental impacts, assessing factors from global warming potential to ecosystem quality and human health [59]. CED delivers a focused quantitative metric for total energy resource consumption throughout a product's life cycle, from raw material extraction to end-of-life disposal [60] [61]. Within the context of the CHEM21 guide for solvent greenness assessment, these tools move evaluations beyond simple solvent selection to a holistic understanding of process sustainability, identifying hidden environmental trade-offs and enabling informed decision-making for greener drug development [62].

Theoretical Foundations and Methodology

The LCA Framework

Life Cycle Assessment is a standardized methodology (ISO 14040/14044) structured into four distinct phases [62]:

  • Goal and Scope Definition: This critical first step establishes the study's purpose, the functional unit (e.g., 1 kg of an Active Pharmaceutical Ingredient (API)), and the system boundaries (e.g., "cradle-to-gate" for API synthesis or "cradle-to-grave" for full product life cycle).
  • Life Cycle Inventory (LCI): This involves compiling a detailed account of all energy and material inputs (feedstocks, solvents, electricity) and environmental outputs (emissions, waste) associated with the defined system. Data is sourced from commercial databases like ecoinvent or through direct measurement [59] [62].
  • Life Cycle Impact Assessment (LCIA): The inventory data is translated into potential environmental impacts using standardized metrics. Key categories include [59] [62]:
    • Global Warming Potential (GWP) in kg COâ‚‚-equivalents.
    • Ecosystem Quality (EQ) and Human Health (HH) impacts.
    • Natural Resource (NR) depletion.
  • Interpretation: Results are analyzed to identify environmental "hotspots," assess data quality, and provide actionable conclusions for reducing the overall environmental footprint.

Cumulative Energy Demand (CED)

CED is a pivotal indicator within LCA that aggregates the total primary energy harvested from nature to provide a product or service. It accounts for direct and indirect energy use across all life cycle stages, providing a direct measure of resource efficiency [63]. In the context of energy-producing technologies, CED is fundamental for calculating the Energy Payback Time (EPBT)—the time required for a system to generate the same amount of primary energy that was consumed throughout its life cycle [61]. For example, a study on utility-scale solar photovoltaic systems in the U.S. showed EPBTs ranging from 0.5 to 1.2 years, demonstrating a highly efficient energy return [61].

The CHEM21 Context and Complementary Use

The CHEM21 guide is a prominent resource for selecting greener solvents, traditionally relying on metrics like safety, health, and environmental profiles. Integrating LCA and CED complements this guide by providing a systems-level perspective. While CHEM21 helps identify inherently safer solvents, LCA and CED evaluate the broader consequences of their production, use, and disposal, ensuring that a solvent choice with a good green chemistry profile does not inadvertently create high energy demands or other life cycle impacts [62]. This combined approach is essential for a genuine sustainability assessment in pharmaceutical research.

Application Notes: Protocols for Sustainability Assessment

Protocol 1: LCA for Evaluating API Synthesis Routes

This protocol outlines a comparative LCA for pharmaceutical routes, using the synthesis of the antiviral drug Letermovir as a case study [59].

  • Workflow Diagram:

G Start Start: Define Goal & Scope FU Functional Unit: 1 kg of Letermovir API Start->FU LCIData Life Cycle Inventory (LCI) - Reagents - Solvents - Energy FU->LCIData DataCheck Data Availability Check (ecoinvent database) LCIData->DataCheck Retrosynth Retrosynthetic Analysis & Proxy Data Generation DataCheck->Retrosynth Missing Data Impact Impact Assessment (LCIA) GWP, HH, EQ, NR DataCheck->Impact Data Available Retrosynth->Impact Hotspot Hotspot Identification Impact->Hotspot Compare Compare Route Variants Hotspot->Compare Optimize Optimize Synthesis Compare->Optimize

  • Objective: To identify the most environmentally sustainable synthesis route for a target molecule by quantifying and comparing life cycle impacts.
  • Functional Unit: 1 kg of Letermovir API [59].
  • Key Steps:
    • Goal and Scope: Define a cradle-to-gate system boundary encompassing all synthesis steps from raw material extraction to the final API.
    • Inventory Creation: Compile a detailed bill of materials and energy flows for each synthesis step. A critical challenge is the limited availability of LCI data for specific fine chemicals and catalysts; one study found only 20% of required chemicals in the ecoinvent database [59].
    • Address Data Gaps: Employ an iterative retrosynthetic approach to model and build life cycle inventory data for missing chemicals by tracing them back to available precursor data [59].
    • Impact Calculation: Use LCIA methods (e.g., ReCiPe 2016) to calculate endpoint impacts on Human Health (HH), Ecosystem Quality (EQ), Natural Resources (NR), and Global Warming Potential (GWP) [59].
    • Interpretation: Identify environmental "hotspots" (e.g., specific reaction steps, reagents, or solvents) and use these insights to benchmark and optimize the synthesis route.
  • Case Study Insight: The LCA of Letermovir synthesis revealed that a Pd-catalyzed Heck cross-coupling was a significant environmental hotspot, providing a clear target for optimization [59].

Protocol 2: CED Analysis for Process and Technology Evaluation

This protocol uses CED to assess the total energy burden of a process or technology, applicable to both chemical processes and equipment manufacturing.

  • Workflow Diagram:

G A Define System & EoL Scenarios B Material Production (Raw Material Extraction) A->B C Manufacturing & Assembly (Unit Processes) B->C D Use Phase (Energy Consumption) C->D E End-of-Life (EoL) (Recycling, Landfilling) D->E F Sum CED per Stage E->F G Calculate EPBT if applicable F->G

  • Objective: To quantify the total life cycle energy demand of a product or process, enabling the calculation of energy payback times and the evaluation of energy-related benefits from lightweighting or recycling.
  • Key Steps:
    • System Definition: Establish a cradle-to-grave system, including explicit End-of-Life (EoL) scenarios (e.g., open-loop recycling vs. closed-loop recycling) [60].
    • Inventory Analysis: Quantify energy flows for each unit process: raw material extraction, manufacturing, use phase, and EoL treatment.
    • CED Aggregation: Sum the primary energy demand across all life cycle stages.
    • EPBT Calculation (for energy systems): Calculate Energy Payback Time as EPBT = (CED of system) / (Annual primary energy generation by system) [61].
  • Case Study Insight 1 (Gear Manufacturing): A CED analysis compared a conventional steel gear with a novel hybrid metal-composite gear. In a scenario with comprehensive closed-loop recycling, the hybrid gear showed a 28.82% lower CED than the full steel gear, demonstrating the profound impact of EoL strategies on energy sustainability [60].
  • Case Study Insight 2 (Solar PV): A cradle-to-grave LCA of U.S. utility-scale solar PV systems reported a CED of below 0.1 MJoil-eq per MJ of electricity generated, resulting in a short EPBT of 0.5 to 1.2 years [61].

Protocol 3: Greenness Assessment for Analytical Methods

This protocol employs metric-based tools to evaluate and improve the environmental performance of analytical methods used in pharmaceutical quality control.

  • Objective: To minimize the environmental footprint of analytical techniques like HPLC by using standardized greenness assessment metrics.
  • Key Tools:
    • Analytical Method Greenness Score (AMGS): A comprehensive metric evaluating solvent energy, toxicity (EHS), and instrument energy consumption [64].
    • AGREE (Analytical GREEnness): Uses a circular pictogram and a score (0-1) based on the 12 principles of Green Analytical Chemistry (GAC) [34] [64].
    • Modified GAPI (MoGAPI): A visual, color-coded pictogram assessing the entire analytical process [34].
  • Implementation Workflow:
    • Method Profiling: Document the entire analytical procedure, including sample preparation, solvent volumes, reagent hazards, energy consumption, and waste generation.
    • Metric Application: Calculate scores using one or more tools (e.g., AMGS, AGREE). For example, AstraZeneca uses AMGS to trend data and drive continuous improvement [64].
    • Interpretation and Optimization: Use the scores to identify weaknesses (e.g., high waste volume, toxic solvents) and guide re-design (e.g., solvent substitution, method miniaturization) [34] [64].

Data Presentation and Comparative Analysis

Quantitative Data from Case Studies

Table 1: Comparative CED and Environmental Impact Data from LCA Studies

System Studied Methodology Key Quantitative Results Main Conclusion
Hybrid Metal-Composite Gears [60] CED, Cradle-to-Grave CED of hybrid gear vs. full steel gear: • Open-loop scenario: +12.58% • Closed-loop scenario: -28.82% End-of-life recycling is critical for realizing the energy savings potential of lightweight composite designs.
Utility-Scale Solar PV (US) [61] LCA/CED, Cradle-to-Grave • CED: <0.1 MJoil-eq/MJgenerated • EPBT: 0.5 - 1.2 years • GHG: 10-36 g CO₂-eq/kWh PV systems are low-carbon and energy-efficient, with a rapid energy payback.
Wind Electricity (Europe) [65] LCA, Cradle-to-Grave • GHG: 14.9 g CO₂-eq/kWh (European mix) • GHG: 18.1 g CO₂-eq/kWh (Swiss mix) Wind energy has one of the lowest impacts on climate change among power generation technologies.
SULLME Analytical Method [34] Multi-Metric (MoGAPI, AGREE, AGSA, CaFRI) • AGREE Score: 0.56 • Combined Score: ~60/100 (Avg. of tools) The method showed strengths in miniaturization but weaknesses in waste management and reagent safety.

Table 2: Greenness Assessment Tools for Analytical Chemistry

Tool Name Type of Output Key Assessment Criteria Advantages Limitations
AMGS [64] Numerical Score Solvent energy, EHS, instrument energy. Holistic, developed for chromatography. Constraints include non-inclusion of additives.
AGREE [34] [64] Pictogram & Score (0-1) 12 principles of GAC. Comprehensive, visual, easy to compare. Can be subjective; may not cover pre-analytical steps.
MoGAPI [34] Color-coded Pictogram Entire analytical process steps. Visual, detailed stage-by-stage analysis. Lacks a single overall score; some subjectivity.
AGREEprep [34] Pictogram & Score Sample preparation only. Targeted evaluation of a high-impact stage. Must be used with another tool for full method assessment.
CaFRI [34] Numerical Score Carbon footprint, energy, transport. Addresses climate impact specifically. A newer tool, less established.

The Scientist's Toolkit: Essential Reagents and Materials

Table 3: Key Research Reagent Solutions in Sustainable Chemistry

Item/Category Function in Research Sustainability Considerations
Bio-based Solvents (e.g., from sugarcane) [62] Replace petrochemical solvents in extraction, reaction media, and chromatography. Can reduce fossil resource depletion and GWP, but LCA is needed to check for impacts from agriculture (land/water use).
Cradle-to-Gate LCI Databases (e.g., ecoinvent) [59] [62] Provide life cycle inventory data for energy, materials, and chemicals. Essential for credible LCA; a key limitation is missing data for novel or complex chemicals.
Solid Phase Transfer Catalysts (e.g., Cinchonidine-derived) [59] Enable asymmetric synthesis for chiral API manufacturing. Biomass-derived catalysts can reduce dependency on scarce metal catalysts, but their own LCA must be evaluated.
Carbon Fiber Reinforced Plastic (CFRP) [60] Lightweight composite material for equipment (e.g., hybrid gears). Reduces weight and energy use in the use phase (e.g., automotive). High CED in production is offset if effective EoL recycling is implemented.
Pd-based Catalysts [59] Facilitate key cross-coupling reactions (e.g., Heck reaction). Often an environmental "hotspot" in LCA due to the high impact of precious metal mining and processing. Guides research towards catalyst recycling or alternative methodologies.

{# The %Greenness Metric and Other Emerging Quantitative Assessments

In modern pharmaceutical research and development, the selection of solvents is increasingly guided by the imperative to adopt sustainable and environmentally responsible practices. The concept of "solvent greenness" has evolved from a qualitative notion to a field rich with quantitative metrics that enable researchers to make informed, data-driven decisions. These metrics evaluate solvents based on a complex interplay of environmental impact, human health effects, and safety considerations, moving beyond mere functional performance to encompass the full lifecycle impact of chemical choices. Frameworks such as the CHEM21 Selection Guide have emerged as pivotal tools, providing standardized methodologies for assessing and comparing solvents within pharmaceutical applications [3] [13]. This document provides detailed application notes and experimental protocols for implementing these quantitative greenness assessments, specifically framed within the context of the CHEM21 guide research, to support researchers, scientists, and drug development professionals in integrating sustainability into their analytical and process development workflows.

The CHEM21 Selection Guide Framework

The CHEM21 Solvent Selection Guide represents a comprehensive consensus-based approach for evaluating solvent greenness, developed by a European consortium to promote sustainable methodologies in the pharmaceutical industry and related chemical sectors. This guide classifies solvents into three primary categories—Recommended, Problematic, and Hazardous—based on integrated assessments of safety, health, and environmental (SHE) impacts aligned with the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) [3].

The scoring methodology employs a multi-factor evaluation system. The safety score primarily considers flash point and boiling point characteristics, with additional penalties for properties such as low auto-ignition temperature (<200°C), high resistivity (>10⁸ Ω·m), peroxide-forming potential, or high energy of decomposition (>500 J/g). The health score utilizes GHS hazard classifications, with an additional point applied for solvents with boiling points below 85°C due to increased exposure risks. The environmental score incorporates factors including environmental toxicity to aquatic and insect populations, broader ecological impacts, carbon footprint, and recycling potential, with scoring heavily influenced by boiling point ranges [3].

Table 1: CHEM21 Scoring Criteria for Solvent Classification

Assessment Dimension Key Evaluation Parameters Score Range
Safety Flash point, boiling point, auto-ignition temperature, peroxide formation, decomposition energy 1 (high flash point >60°C) to 7 (very low flash point <-20°C)
Health GHS hazard classifications, boiling point (<85°C adds 1 point) Based on CLP/GHS system with modifiers
Environmental Aquatic toxicity, soil impact, air emissions, biodegradability, carbon footprint, recycling potential 3, 5, or 7 based on boiling point and toxicity

This framework provides drug development professionals with a standardized methodology for comparing solvent options during analytical method development and process design, enabling the identification of safer alternatives to traditional hazardous solvents such as dichloromethane, N,N-dimethylformamide (DMF), and N-methyl-2-pyrrolidone (NMP) [3] [13].

Emerging Greenness Assessment Metrics

While the CHEM21 guide provides a robust foundational framework, the landscape of greenness assessment has expanded to include several specialized metrics that offer complementary perspectives on solvent sustainability. These emerging tools provide quantitative, often score-based evaluations that enable more nuanced comparisons between solvent systems.

AGREE (Analytical GREEnness) Metric

The AGREE metric employs a comprehensive 0-1 scoring system that evaluates 10 distinct principles of green analytical chemistry, providing a combined total greenness score along with detailed sub-scores for individual assessment criteria. This tool has been effectively applied to analytical methods such as the AQbD-driven RP-HPLC determination of irbesartan in nanoparticles, where it demonstrated high greenness performance for methods utilizing ethanol-sodium acetate mobile phases [66].

GAPI (Green Analytical Procedure Index)

GAPI utilizes a qualitative color-coded pictogram system to assess environmental impacts across a method's entire lifecycle, from sample collection to final disposal. This tool has been implemented in the sustainability assessment of stability-indicating chromatographic methods for pharmaceutical compounds including metronidazole and nicotinamide, providing visual representation of environmental performance [66].

Analytical Eco-Scale

This metric employs a penalty-points approach based on hazardous reagent usage, energy consumption, and waste generation, with higher final scores indicating greener analytical procedures. The eco-scale has been used to evaluate methods employing eco-friendly solvents such as ethanol and water, demonstrating alignment with United Nations Sustainable Development Goals (UN-SDGs) [66].

Life Cycle Assessment (LCA) Approaches

Comprehensive LCA methodologies, such as the ReCiPe 2016 framework, evaluate environmental impacts across multiple categories including carbon footprint, water usage, and ecotoxicity. These approaches have been integrated into advanced solvent selection platforms like SolECOs, which incorporates 23 distinct LCA indicators to provide multidimensional sustainability rankings for solvent candidates in pharmaceutical crystallization processes [17].

Table 2: Comparison of Emerging Greenness Assessment Metrics

Metric Assessment Approach Output Format Key Application Context
AGREE Evaluates 10 principles of green analytical chemistry Score 0-1 with sub-scores HPLC method development; AQbD frameworks
GAPI Pictogram-based lifecycle assessment Color-coded diagram (green/yellow/red) Pharmaceutical analysis; stability-indicating methods
Analytical Eco-Scale Penalty points for hazardous materials, energy, waste Numerical score (higher = greener) Method validation; sustainability reporting
LCA (ReCiPe) Multi-indicator environmental impact assessment 23 separate impact category scores Process design; solvent selection platforms
GSK Solvent Framework Safety, health, environmental criteria Categorical ranking Pharmaceutical manufacturing; early process development

Experimental Protocols for Greenness Assessment

Protocol 1: CHEM21 Solvent Evaluation Workflow

Purpose: To systematically evaluate and classify solvents using the CHEM21 selection guide criteria for use in pharmaceutical development.

Materials and Equipment:

  • Safety Data Sheets (SDS) for target solvents
  • CHEM21 scoring template (spreadsheet or software)
  • Physical property data (flash point, boiling point)
  • GHS classification information

Procedure:

  • Data Collection: Compile complete physical property data including boiling point, flash point, auto-ignition temperature, and resistivity for each solvent candidate.
  • Safety Assessment: Calculate safety score based on flash point categories: award 1 point for >60°C, 3 points for 24-60°C, 4 points for 0-23°C, 5 points for -20 to -1°C, and 7 points for <-20°C. Add additional points for specific hazards: auto-ignition temperature <200°C (+1), resistivity >10⁸ Ω·m (+1), peroxide formation potential (+1), or decomposition energy >500 J/g (+1).
  • Health Assessment: Determine health score using GHS hazard statements and classifications. Apply base scores according to H-codes: H360, H361, H370, H371 receive highest scores. Add 1 point for solvents with boiling point <85°C due to increased exposure risk.
  • Environmental Assessment: Calculate environmental score based on boiling point ranges and GHS environmental hazard statements: 3 points for boiling point 70-139°C without H4xx codes; 5 points for boiling point 50-69°C or 140-200°C with H412/H413; 7 points for boiling point <50°C or >200°C with H400/H410/H411.
  • Classification: Combine scores to categorize solvents as "Recommended" (low overall impact), "Problematic" (moderate concern), or "Hazardous" (significant issues requiring substitution).
  • Documentation: Record all scores with justifications and source references for audit and continuous improvement purposes.

Protocol 2: AGREE Metric Implementation for HPLC Methods

Purpose: To quantitatively assess the greenness of HPLC methods using the AGREE metric software.

Materials and Equipment:

  • AGREE calculator software (available online)
  • Complete method parameters (mobile phase composition, flow rate, column dimensions, injection volume, analysis time, sample preparation details)
  • Safety and hazard information for all reagents

Procedure:

  • Method Characterization: Document all method parameters including mobile phase composition (exact percentages), flow rate (mL/min), column specifications (dimensions, particle size), injection volume (μL), analysis time (minutes), and sample preparation requirements.
  • Reagent Classification: Identify GHS hazard codes for all chemicals used in the method including mobile phase components, additives, standards, and sample preparation reagents.
  • Software Input: Enter collected data into the AGREE calculator, addressing all 10 assessment principles: (1) need for hazardous reagents, (2) waste generation, (3) energy consumption, (4) operator safety, (5) total chemical usage, (6) waste toxicity, (7) recyclability, (8) sample throughput, (9) miniaturization potential, and (10) operator training requirements.
  • Score Interpretation: Analyze the output circular diagram which displays scores for each principle (closer to center = better performance) and the overall composite score (0-1 scale).
  • Method Optimization: Use comparative results to identify opportunities for improving method greenness through solvent substitution, waste reduction, or energy optimization.
  • Validation Reporting: Include AGREE scores in method validation documentation alongside traditional validation parameters.

Protocol 3: Computational Solvent Screening Using SolECOs Platform

Purpose: To identify optimal green solvents for pharmaceutical crystallization processes using data-driven screening.

Materials and Equipment:

  • SolECOs platform access
  • API molecular structure (SMILES notation or molecular file)
  • Target solubility and crystallization parameters
  • Process temperature range

Procedure:

  • API Characterization: Input API molecular structure using SMILES notation or upload molecular structure file. Define key molecular descriptors if available.
  • Process Parameters: Set target process conditions including temperature range, desired yield, and any crystallization-specific requirements (polymorph control, crystal size distribution).
  • Sustainability Preferences: Select relevant sustainability assessment criteria from available options (GSK framework, ReCiPe indicators, CHEM21 alignment).
  • Solvent Database Screening: Execute screening against platform's database of 30 common solvents and binary mixtures with over 30,000 solubility data points for 1186 APIs.
  • Result Analysis: Review ranked solvent recommendations based on integrated assessment of predicted solubility and sustainability performance.
  • Experimental Verification: Validate computational predictions through limited laboratory experiments focusing on top-ranked solvent candidates.

Visualization of Assessment Workflows

CHEM21_Workflow Start Start CHEM21 Assessment DataCollection Collect Solvent Data (Physical Properties, GHS) Start->DataCollection SafetyScore Calculate Safety Score (Flash Point, Hazards) DataCollection->SafetyScore HealthScore Calculate Health Score (GHS Classifications) SafetyScore->HealthScore EnvScore Calculate Environmental Score (Boiling Point, Ecotoxicity) HealthScore->EnvScore Classification Classify Solvent (Recommended/Problematic/Hazardous) EnvScore->Classification Documentation Document Results and Justifications Classification->Documentation End Assessment Complete Documentation->End

Figure 1: CHEM21 Solvent Assessment Workflow

Greenness_Integration Start Start Method Development DefineATP Define Analytical Target Profile (ATP) Start->DefineATP MethodOpt Method Optimization Using DoE and AQbD DefineATP->MethodOpt GreenAssess Greenness Assessment (Multiple Metrics) MethodOpt->GreenAssess Compare Compare Greenness Scores Across Methods GreenAssess->Compare Select Select Optimal Method (Balancing Performance & Greenness) Compare->Select End Validated Green Method Select->End

Figure 2: Integrated Greenness Assessment in Method Development

The Scientist's Toolkit: Essential Research Reagents and Materials

Table 3: Essential Research Reagents for Greenness Assessment

Reagent/Material Function/Purpose Application Context
CHEM21 Selection Guide Standardized solvent evaluation framework Primary solvent screening and classification
AGREE Calculator Software Quantitative greenness scoring for analytical methods HPLC/UPLC method development and validation
SolECOs Platform Data-driven solvent selection with sustainability ranking Pharmaceutical crystallization process development
GSK Solvent Sustainability Framework Industrial solvent assessment guidelines Manufacturing process design and optimization
ReCiPe 2016 LCA Methodology Comprehensive environmental impact assessment Lifecycle analysis and environmental reporting
EAT (HPLC Environmental Assessment Tool) Instrument-specific environmental impact evaluation Laboratory equipment selection and operation

The quantitative assessment of solvent greenness has evolved from a theoretical concept to an essential component of sustainable pharmaceutical development. The CHEM21 Selection Guide provides a robust foundational framework, while emerging metrics such as AGREE, GAPI, and LCA-based approaches offer complementary perspectives that enable comprehensive sustainability evaluation. The integration of these tools with Analytical Quality by Design (AQbD) principles and data-driven platforms like SolECOs represents a significant advancement in green chemistry implementation. By adopting the protocols and assessments detailed in this document, researchers and drug development professionals can systematically incorporate sustainability considerations into their methodological choices, contributing to the pharmaceutical industry's progress toward reduced environmental impact while maintaining scientific rigor and regulatory compliance.

Within the framework of green chemistry, the selection of an appropriate solvent is a critical determinant of a process's overall environmental sustainability. Solvents can account for at least half of the material mass used in a typical chemical process, amplifying their impact on waste generation, operator safety, and ecological footprint [1]. The CHEM21 Solvent Selection Guide, developed by a consortium of academic and industrial institutions, provides a standardized methodology to rank solvents based on a combined assessment of Safety, Health, and Environment (SHE) criteria [9] [1]. This guide classifies solvents into categories such as "Recommended," "Problematic," and "Hazardous," facilitating informed decision-making for chemists [1]. This application note validates the practical implementation of the CHEM21 guide through detailed case studies on nitration and α-halogenation reactions, demonstrating how solvent choice influences both reaction efficiency and green metrics.

The CHEM21 Solvent Selection Guide: A Framework for Assessment

The CHEM21 guide employs a transparent scoring system, where Safety, Health, and Environment are each assigned a score from 1 (best) to 10 (worst), visualized with a green-amber-red color code [9] [1].

  • Safety Score: Primarily derived from a solvent's flash point, with penalties for low auto-ignition temperature (<200°C), high resistivity (>10⁸ ohm.m, indicating electrostatic charging risk), and the ability to form explosive peroxides [9]. For example, diethyl ether's safety score of 10 results from its very low flash point (-45°C) combined with all three additional hazards [9].
  • Health Score: Based predominantly on the GHS hazard statements (e.g., H3xx codes for CMR properties, acute toxicity, irritation), with an added penalty for high volatility (boiling point <85°C) [9].
  • Environment Score: Considers both the solvent's volatility (linked to boiling point) and its GHS environmental hazard statements (H4xx), such as aquatic toxicity [9].

These three scores are combined to produce an overall ranking. Solvents like Ethyl Acetate (EtOAc) and Ethanol (EtOH) are typically "Recommended," whereas solvents like Dimethylformamide (DMF) are considered "Problematic" or "Hazardous" due to health concerns [9] [13].

Case Study 1: Solvent Influence in Nitration Reactions

Experimental Protocol: Nitration of Benzothiophene and Cinnamic Acid

Objective: To evaluate the efficiency and greenness of nitration reactions in various solvents classified under the CHEM21 guide. Reaction Scheme:

  • Substrate: Benzothiophene or Cinnamic Acid.
  • Nitrating Agent: Fe(NO₃)₃·9Hâ‚‚O.
  • Solvents Screened: Acetic acid (AcOH), Acetonitrile (ACN), Cyclopentyl methyl ether (CPME), Dichloromethane (DCM), Dimethyl carbonate (DMC), Ethanol (EtOH), Ethyl acetate (EtOAc), and Water (Hâ‚‚O) [67].

Procedure:

  • Reaction Setup: Charge a round-bottom flask with the substrate (e.g., 1.0 mmol benzothiophene) and Fe(NO₃)₃·9Hâ‚‚O (1.2 equiv). Add the chosen solvent (5 mL) to the mixture [67].
  • Reaction Execution: Stir the reaction mixture at room temperature (or elevated temperature if required) and monitor by TLC or LC-MS until completion [67].
  • Work-up: Upon completion, dilute the mixture with water (10 mL) and extract the product with a suitable "Recommended" solvent like EtOAc (3 × 10 mL). Combine the organic layers, dry over anhydrous MgSOâ‚„, and concentrate under reduced pressure [67].
  • Purification & Analysis: Purify the crude residue by flash chromatography. Identify the product by ¹H NMR (400 MHz) and GC-MS. Calculate the isolated yield [67].

Key Findings and Data Analysis

The nitration reactions proceeded efficiently across several solvents, but the greenness profile varied significantly. The following table summarizes the performance of each solvent in the nitration reaction, its CHEM21 ranking, and the calculated Process Mass Intensity (PMI)—a key green metric defined as the total mass of materials used per mass of product obtained [67].

Table 1: Solvent Performance in Nitration Reactions

Solvent CHEM21 Ranking [9] Isolated Yield (%) [67] Process Mass Intensity (PMI) [67]
Ethyl Acetate (EtOAc) Recommended 90 21.4
Ethanol (EtOH) Recommended 85 23.1
Dimethyl Carbonate (DMC) Recommended 88 22.0
Cyclopentyl Methyl Ether (CPME) Recommended 82 24.5
Water (Hâ‚‚O) Recommended 78 25.8
Acetonitrile (ACN) Problematic 90 21.4
Acetic Acid (AcOH) Problematic 80 26.3
Dichloromethane (DCM) Hazardous 92 20.5

The data demonstrates that EtOAc, EtOH, and DMC achieved an optimal balance, delivering high yields and low PMI while maintaining a "Recommended" status [67]. Although DCM yielded the lowest (best) PMI, its "Hazardous" classification renders it unsuitable from a green chemistry perspective [67] [9]. This underscores the principle that reaction efficiency must be evaluated alongside SHE criteria.

Case Study 2: Solvent Influence in α-Halogenation Reactions

Experimental Protocol: α-Bromination of Propiophenone

Objective: To assess the greenness of a common α-halogenation reaction in different solvents. Reaction Scheme:

  • Substrate: Propiophenone.
  • Brominating Agent: Pyridinium Hydrobromide Perbromide (PHPB).
  • Solvents Screened: EtOAc, DMC, EtOH, ACN, DCM, CPME [67].

Procedure:

  • Reaction Setup: Dissolve propiophenone (1.0 mmol) in the chosen solvent (5 mL) in a round-bottom flask. Add Pyridinium Hydrobromide Perbromide (PHPB, 0.55 equiv) to the stirring solution [67].
  • Reaction Execution: Stir the mixture at room temperature. Monitor the reaction by TLC until the starting material is consumed [67].
  • Work-up: Quench the reaction by adding a saturated aqueous solution of sodium thiosulfate (10 mL). Transfer the mixture to a separatory funnel, extract with EtOAc (3 × 10 mL), and combine the organic phases. Wash the combined extracts with brine, dry over anhydrous MgSOâ‚„, and concentrate [67].
  • Purification & Analysis: Purify the crude product via flash chromatography. Characterize the α-brominated product using ¹H NMR and GC-MS, and determine the isolated yield [67].

Key Findings and Data Analysis

The α-halogenation reaction was successful in all tested solvents, but again, the greenness profiles were distinct.

Table 2: Solvent Performance in α-Halogenation Reactions

Solvent CHEM21 Ranking [9] Isolated Yield (%) [67] Process Mass Intensity (PMI) [67]
Ethyl Acetate (EtOAc) Recommended 95 12.6
Dimethyl Carbonate (DMC) Recommended 92 13.5
Ethanol (EtOH) Recommended 90 14.2
Cyclopentyl Methyl Ether (CPME) Recommended 85 16.1
Acetonitrile (ACN) Problematic 95 12.6
Dichloromethane (DCM) Hazardous 98 11.9

Consistent with the nitration case study, EtOAc and DMC emerged as the top performers, delivering excellent yields and favorable PMIs while adhering to the "Recommended" CHEM21 status [67]. The high yield in DCM was offset by its significant health and environmental hazards, reinforcing the importance of a multi-criteria assessment.

Integrated Workflow for Green Solvent Selection

The following diagram illustrates a systematic workflow for selecting a green solvent for a given reaction, integrating the principles of the CHEM21 guide and experimental validation.

G Start Define Synthetic Objective Step1 Screen CHEM21 'Recommended' Solvents (e.g., EtOAc, EtOH, DMC, CPME, Water) Start->Step1 Step2 Perform Small-Scale Reactions in Selected Solvents Step1->Step2 Step3 Analyze Yield and Conversion Step2->Step3 Step4 Calculate Green Metrics (PMI, %Greenness) Step3->Step4 Step5 Optimal Balance Found? Step4->Step5 Step6 Select Optimal Solvent Step5->Step6 Yes Alternative Evaluate 'Problematic' Solvents if Performance is Inadequate Step5->Alternative No Alternative->Step2 Re-evaluate with new data

Green Solvent Selection Workflow

This workflow encourages chemists to begin their screening with solvents from the "Recommended" category, only considering "Problematic" or "Hazardous" solvents if no suitable green alternative provides adequate reactivity [9] [11].

The Scientist's Toolkit: Research Reagent Solutions

The following table details key reagents and materials essential for conducting and evaluating these green chemistry experiments.

Table 3: Essential Research Reagents and Materials

Item Function/Description Green Chemistry Consideration
Fe(NO₃)₃·9H₂O A non-toxic, easy-to-handle, and cheap metallic nitrate salt used as a nitrating agent [67]. Safer alternative to traditional mixed acids (HNO₃/H₂SO₄), reducing environmental impact [67].
Pyridinium Hydrobromide Perbromide (PHPB) A stable, solid brominating agent used for α-halogenation of ketones [67]. Facilitates accurate dosing, potentially minimizing waste compared to molecular bromine.
Recommended Solvents (EtOAc, EtOH, DMC) Reaction media with favorable SHE profiles [9]. Lower EHS scores in the CHEM21 guide, reducing process hazard and environmental footprint [67] [9].
CHEM21 Solvent Guide A published guide and interactive tool for solvent selection based on Safety, Health, and Environment criteria [9] [11]. Enables quantitative and standardized assessment of solvent greenness, promoting safer choices.
Process Mass Intensity (PMI) Calculator A tool (e.g., from ACS GCI) to calculate the total mass used in a process per mass of product [11]. A key green metric; lower PMI indicates higher material efficiency and less waste [67] [11].

Advanced Mechanochemical Nitration as a Solvent-Free Alternative

Pushing the boundaries of green synthesis, recent advances demonstrate mechanochemical nitration as a powerful solvent-minimized alternative. A 2025 study reported using a saccharin-derived reagent (NN) under liquid-assisted grinding (LAG) conditions, where minimal solvent (e.g., Hexafluoroisopropanol - HFIP) is used to facilitate the reaction in a ball mill [68]. This protocol achieved efficient nitration of various alcohols and arenes with high yields and excellent functional group tolerance, significantly enhancing green metrics by drastically reducing or eliminating the need for bulk reaction solvents [68].

These case studies provide validated experimental protocols confirming that "Recommended" solvents such as Ethyl Acetate, Ethanol, and Dimethyl Carbonate can successfully replace hazardous solvents like Dichloromethane in synthetically important nitration and halogenation reactions without compromising efficiency [67]. The following practices are recommended for researchers:

  • Primary Screening: Always initiate solvent screening with the CHEM21 "Recommended" list [9] [11].
  • Holistic Analysis: Base solvent selection on a combination of SHE criteria, reaction yield, and process metrics (e.g., PMI), not on yield alone [67] [13].
  • Embrace Innovation: Consider emerging technologies, such as mechanochemistry, which can obviate the need for bulk solvents altogether [68].

Adherence to these principles and the application of the CHEM21 guide empower scientists in both academic and industrial settings to make informed decisions that advance the goals of green and sustainable chemistry.

The global shift towards sustainable industrial processes is fundamentally reshaping the solvents market. Green solvents, characterized by their low toxicity, biodegradability, and origin from renewable resources, are increasingly replacing traditional petroleum-derived solvents due to growing regulatory pressures and environmental concerns [31]. The global green solvents market, valued at approximately USD 2.2 billion in 2024, is projected to surpass USD 5.5 billion by 2035, growing at a compound annual growth rate (CAGR) of around 8.7% [31]. Another analysis posits an even larger market size, estimating it will grow from USD 5.81 billion in 2025 to USD 11.54 billion by 2035 at a CAGR of 7.1% [69]. This growth is primarily fueled by stringent government regulations limiting volatile organic compound (VOC) emissions and incentivizing the adoption of sustainable chemicals [31].

The Asia-Pacific region leads this market expansion, driven by rapid industrialization, a growing manufacturing base, and increasing governmental focus on environmental sustainability [31] [69]. Key application segments include paints and coatings, adhesives and sealants, pharmaceuticals, and personal care products [31] [69]. Despite the positive outlook, the market faces challenges such as higher production costs compared to conventional solvents and occasional performance limitations in specific applications, necessitating continued research and development [31].

Table 1: Global Green Solvents Market Outlook

Attribute Details
2024 Market Size USD 2.2 Billion [31]
2025 Market Size USD 5.81 Billion [69]
2035 Projected Market Size USD 5.51 - 11.54 Billion [31] [69]
Forecast CAGR (2025-2035) 7.1% - 8.7% [31] [69]
Key Growth Driver Stringent environmental regulations and demand for eco-friendly products [31]
Major Challange Higher production cost and complex production process [31] [69]

Defining Green Solvents: Principles and Assessment Frameworks

The CHEM21 Solvent Selection Guide

A cornerstone for assessing solvent sustainability is the CHEM21 Solvent Selection Guide, developed by a consortium of pharmaceutical companies and academics [9] [11]. This guide provides a standardized methodology to rank solvents based on safety, health, and environmental (SHE) criteria, offering a practical tool for researchers to make informed choices.

The guide employs a traffic-light system (Recommended, Problematic, Hazardous) derived from a quantitative scoring system across three domains [9]:

  • Safety Score (1-10): Primarily based on flash point, with contributions from auto-ignition temperature, resistivity, and peroxide formation potential.
  • Health Score (1-10): Derived from Globally Harmonized System (GHS) hazard statements (H3xx), considering carcinogenicity, mutagenicity, reproductive toxicity (CMR), and other health hazards, with an adjustment for boiling point.
  • Environment Score (1-10): Accounts for volatility (boiling point), potential for recycling, and GHS environmental hazard statements (H4xx).

The final ranking is determined by the most stringent combination of these scores, providing a clear, at-a-glance assessment for chemists [9].

Emerging Metrics: %Greenness

Beyond the CHEM21 guide, new quantitative metrics are emerging. The %Greenness (%G) metric offers an alternative, consolidated classification of a solvent's environmental profile [67]. This parameter synthesizes published data on a solvent's properties and hazards into a single percentage value, facilitating direct comparison. Furthermore, the Price-Affected Greenness (%PAfG) metric incorporates commercial price, acknowledging that economic viability is a critical factor in solvent selection for industrial applications [67]. In comparative studies, solvents like ethyl acetate (EtOAc), dimethyl carbonate (DMC), and ethanol (EtOH) have demonstrated high performance with a favorable balance of greenness and cost impact [67].

Categories and Properties of Promising Green Solvents

Bio-Based Solvents

Bio-based solvents are derived from renewable biomass sources such as corn, sugarcane, cellulose, and vegetable oils [31]. They represent a drop-in solution for replacing many conventional solvents. Key examples include:

  • 2-Methyltetrahydrofuran (2-MeTHF): Derived from furfural and levulinic acid, it is a promising alternative to tetrahydrofuran (THF). It offers lower water miscibility, higher stability, and a higher boiling point (80°C). Its low toxicity and lack of mutagenicity support its safe use, though its high flammability requires careful handling [70].
  • Cyclopentyl Methyl Ether (CPME): Produced via an atom-economical process, CPME is characterized by a high boiling point (106°C), low freezing point (-140°C), and exceptional stability against peroxide formation. Its low vaporization energy facilitates easy recovery and reuse via distillation [70].
  • D-Limonene: Sourced from citrus peels, this solvent is widely used in cleaning products and as a fragrance. The segment for D-Limonene is expected to see massive growth, driven by its application in food & beverages and cleaning goods [69].
  • Lactate Esters (e.g., Ethyl Lactate): These solvents, derived from renewable resources, are biodegradable, recyclable, and non-corrosive. Their demand is growing in various end-use industries, including their use as thickening agents in cosmetics [69].

Table 2: Properties of Key Bio-Based and Neoteric Solvents

Solvent Category Boiling Point (°C) Key Advantages Considerations
2-MeTHF [70] Bio-based Ether 80 Higher stability than THF; low water miscibility High flammability
CPME [70] Bio-based Ether 106 High peroxide stability; easy recovery -
D-Limonene [69] Plant Metabolite ~176 Pleasant odor; high solvency power Derived from citrus, a potential allergen
Ethyl Lactate [69] Lactate Ester ~154 Biodegradable; non-toxic; excellent solvent power -
Cyrene [70] Bio-based Ketone 226 High boiling point; low toxicity; derived from cellulose High viscosity
Deep Eutectic Solvent (DES) [71] Neoteric Varies Tunable properties; biodegradable; low cost Potential high viscosity; complex characterization

Neoteric Solvents

Neoteric ("new") solvents are a class of innovative liquids with unique properties that distinguish them from molecular organic solvents.

  • Deep Eutectic Solvents (DESs): DESs are formed by the fusion of a hydrogen-bond acceptor (e.g., quaternary ammonium salt) and a hydrogen-bond donor (e.g., amine, acid) [71]. This mixture results in a significant melting point depression, creating a liquid at room temperature. DESs are celebrated for being low-cost, easy to prepare, and often exhibiting low toxicity and high biodegradability. Their properties are highly tunable by varying the components, making them "designer solvents" for specific applications [71].
  • Cyrene (Dihydrolevoglucosenone): This solvent is obtained from cellulose through a pyrolysis and hydrogenation process [70]. It is a highly polar, dipolar aprotic solvent seen as a potential green alternative to solvents like DMF and NMP. Cyrene boasts a high boiling point (226°C), is biodegradable, and shows low ecotoxicity and no mutagenicity [70].

Application Notes and Experimental Protocols

Protocol 1: Nitration of Benzothiophene in Green Solvents

Application: Synthesis of nitroaromatic compounds, important building blocks in pharmaceuticals and agrochemicals [67].

Objective: To evaluate the performance of green solvents in the nitration of benzothiophene using an iron nitrate catalyst.

Materials:

  • Benzothiophene
  • Iron(III) nitrate nonahydrate (Fe(NO~3~)~3~·9H~2~O)
  • Green solvents for screening: Ethyl Acetate (EtOAc), Dimethyl Carbonate (DMC), Ethanol (EtOH), Cyclopentyl Methyl Ether (CPME) [67]

Procedure:

  • In a round-bottom flask, dissolve benzothiophene (1.0 mmol) in the selected green solvent (5 mL).
  • Add Fe(NO~3~)~3~·9H~2~O (1.2 mmol) to the reaction mixture.
  • Reflux the mixture with stirring at the solvent's boiling point for 4-6 hours. Monitor reaction progress by TLC or GC-MS.
  • Upon completion, cool the reaction mixture to room temperature.
  • Dilute with water (10 mL) and extract the product with the same green solvent (3 x 5 mL).
  • Combine the organic layers, dry over anhydrous magnesium sulfate, and filter.
  • Remove the solvent under reduced pressure using a rotary evaporator to obtain the crude nitrated product.
  • Purify the product via column chromatography or recrystallization.

Assessment: In this reaction, EtOAc demonstrated the best performance, offering high yield and superior green metrics as calculated by the %Greenness (%G) metric [67].

Protocol 2: Asymmetric Catalysis in 2-MeTHF

Application: Synthesis of chiral molecules for pharmaceutical development using metal catalysis, organocatalysis, or biocatalysis [70].

Objective: To exploit the hydrophobic nature and stability of 2-MeTHF for asymmetric transformations.

Materials:

  • Chiral catalyst (e.g., metal complex, organocatalyst)
  • Substrates
  • 2-MeTHF (anhydrous)
  • Aqueous work-up solutions

Procedure:

  • In an inert atmosphere glovebox or under nitrogen, add the chiral catalyst (0.5-2 mol%) and substrates (1.0 mmol) to a reaction vial.
  • Add anhydrous 2-MeTHF (2-5 mL) to dissolve the reactants.
  • Stir the reaction at the required temperature (from room temperature to 80°C) for the specified time.
  • After completion, cool the mixture and add a saturated aqueous ammonium chloride solution (5 mL).
  • Due to its partial miscibility with water, the separation of the organic (2-MeTHF) and aqueous layers is clean and efficient.
  • Extract the aqueous layer with additional 2-MeTHF (2 x 5 mL).
  • Combine the organic phases, dry, and concentrate under reduced pressure.
  • Determine the enantiomeric excess (ee) of the product by chiral HPLC or GC.
  • The recovered 2-MeTHF can be dried and recycled for subsequent runs, reducing waste.

The Scientist's Toolkit: Research Reagent Solutions

Table 3: Essential Materials for Green Solvent Research

Item / Reagent Function / Application Notes
CHEM21 Solvent Selection Guide [9] [11] Framework for ranking solvents based on Safety, Health, and Environment (SHE) criteria. The definitive starting point for solvent selection. An interactive version is available from ACS GCI.
2-MeTHF [70] Bio-based ethereal solvent for Grignard reactions, metal-catalyzed cross-couplings, and asymmetric synthesis. Superior to THF: higher b.p., lower water solubility. Must be stabilized to prevent peroxide formation.
CPME [70] Bio-based ethereal solvent for reactions requiring high temperature and low peroxide formation. Ideal for Williamson ether synthesis, Boc protections, and as a reaction/extraction medium.
Cyrene [70] Bio-based dipolar aprotic solvent替代 for DMF and NMP in polymer chemistry, nanomaterial synthesis, and cycloadditions. High boiling point allows high-temperature reactions. Check stability with strong nucleophiles/bases.
DES Kits [71] Pre-measured components (e.g., Choline Chloride + Urea/Glycerol) for preparing Deep Eutectic Solvents. Enables rapid screening of different DES formulations for specific catalytic or extraction processes.
Ethyl Lactate [69] Bio-based solvent for extraction, chromatography, and as a reaction medium for esterifications and polymerizations. Excellent for removing oils, greases, and inks; considered safe for food-contact applications.

Integrated Workflow for Solvent Selection and Assessment

The following workflow diagrams the decision-making process for integrating green solvents into research and development, based on the CHEM21 guide and application data.

G Start Start: Need for a Solvent Step1 Consult CHEM21 Guide for Initial Ranking Start->Step1 Step2 Is a 'Recommended' solvent suitable? Step1->Step2 Step3 Proceed with 'Recommended' Solvent (e.g., EtOH, EtOAc, CPME) Step2->Step3 Yes Step4 Evaluate 'Problematic' or New Bio-based/Neoteric Options Step2->Step4 No Step7 Optimize & Scale-Up (Consider Recycling & Cost) Step3->Step7 Step5 Test in Model Reaction (Apply %Greenness Metric) Step4->Step5 Step6 Assess Technical Performance (Yield, Reaction Rate, etc.) Step5->Step6 Step6->Step7 End Implement Green Solvent Step7->End

Diagram 1: Solvent Selection Workflow

G Traditional Traditional Solvent Sub1 Polar Aprotic (e.g., DMF, NMP) Traditional->Sub1 Sub2 Ethereal (e.g., THF, Diethyl Ether) Traditional->Sub2 Sub3 Chlorinated (e.g., DCM) Traditional->Sub3 GSub1 Cyrene Sub1->GSub1 Replace with GSub2 2-MeTHF or CPME Sub2->GSub2 Replace with GSub3 Ethyl Lactate or DES Sub3->GSub3 Replace with Green Green Substitute

Diagram 2: Common Solvent Substitutions

The landscape of green solvents is dynamic and promising, offering viable and sustainable alternatives to traditional petrochemical solvents. Frameworks like the CHEM21 Solvent Selection Guide provide a critical, evidence-based foundation for making informed choices [9] [11], while new metrics like %Greenness offer refined tools for quantitative comparison [67]. The successful application of bio-based solvents like 2-MeTHF, CPME, and Cyrene, along with neoteric solvents like DESs, across diverse chemical reactions—from nitration and halogenation to asymmetric catalysis—demonstrates their robust capabilities [67] [70]. As regulatory pressure mounts and the global market continues its expansion, the adoption and further innovation of green solvents will be integral to advancing sustainable chemistry in pharmaceutical development and industrial manufacturing.

Conclusion

The CHEM21 Solvent Selection Guide provides a robust, harmonized, and practical framework for integrating sustainability into chemical research and development. By systematically evaluating solvents across Safety, Health, and Environmental criteria, it empowers scientists to make informed choices that significantly reduce the ecological footprint of their processes, which is especially critical in pharmaceutical development. The future of green solvent assessment lies in the continued integration of tools like CHEM21 with life-cycle analysis data, the development of novel bio-based solvents, and the adoption of digital selection platforms. For biomedical and clinical research, embracing this holistic approach to solvent selection is not just an operational improvement but a fundamental step toward achieving more sustainable and responsible drug development pipelines, ultimately aligning scientific innovation with global environmental goals.

References