N-dimethylformamide (DMF) is an extremely important non-polar polar solvent in pharmaceutical production, but its toxicity and environmental hazards are also prominent. Therefore, its application and recycling are essential management aspects for pharmaceutical enterprises.

Part 1: Application of DMF in pharmaceutical production

Due to its unique physical and chemical properties, DMF plays multiple key roles in drug synthesis and purification.

Application field   Specific function and reason     Typical process steps

Chemical reaction solvent  Top polar non-polar solvent, which can dissolve most organic compounds and inorganic salts well, promoting SN2 reactions, coupling reactions, condensation reactions, etc. API (raw material drug) synthesis steps, especially palladium-catalyzed coupling reactions (such as Buchwald-Hartwig amide formation), acylation reactions, acylation reactions.

Crystallization and recrystallization solvent    Excellent solubility and moderate boiling point, making it often used as a single solvent or a component of a mixed solvent system, for API purification, purification and obtaining specific crystal forms.       Final purification steps of API.

Solvent for peptides and proteins    Can dissolve protecting amino acids, being a classic solvent for solid-phase peptide synthesis.       Peptide drugs (such as liraglutide, semaglutide) synthesis.

Chromatography purification eluent       Used in preparative chromatography as a strong polar eluent, especially for separating compounds with high polarity. Separation and purification of high-value API at pilot or small-scale.

Separation extraction solvent    Used for extracting organic products from aqueous phase (liquid-liquid extraction).     Post-reaction treatment.

Core advantages: versatile, efficient dissolution ability.

Core disadvantages: reproductive toxicity, liver toxicity, classified as a high-risk solvent (ICH Q3C Class 2 solvent, limit 880 ppm), and prone to causing water and environmental pollution.

Part 2: DMF recycling technology and strategies

Due to the large amount, high value, and high hazard of DMF, its recycling is not only an environmental protection requirement but also has significant economic benefits. Pharmaceutical enterprises must establish a closed-loop management system.

1. General recycling principles

• Source control: Try to reduce the amount of DMF used or find greener alternative solvents (such as N-methylpyrrolidone NMP, dimethyl sulfoxide DMSO, etc., each with their own advantages and disadvantages) during the process development stage.

• Classification collection: Different process steps may produce DMF waste liquid containing different impurities, so it is necessary to collect them as much as possible in different qualities and categories to improve the recovery efficiency and quality of the recovered products.

• Pre-treatment: Before recycling, the waste liquid needs to undergo simple pre-treatment such as filtration and decolorization to remove solid particles and some pigments.

2. Main recycling process technologies

The following are the most widely used and reliable several DMF recycling technologies in the pharmaceutical industry:

Technology   Principle Advantages   Disadvantages and challenges       Applicable scenarios

Continuous/Reduced-pressure distillation     Utilize the boiling point difference between DMF and impurities (water, low-boiling-point solvents, high-boiling-point impurities) for separation.      Technically mature, equipment universal, high recovery purity (up to 99.9% or more).    High energy consumption (DMF boiling point is high, 153℃); prone to thermal decomposition, prolonged heating may generate impurities such as dimethylamine; special treatment is required for co-boiling systems (such as DMF-water).     The most mainstream method, suitable for waste liquids with relatively simple and stable impurities. Often combined with dehydration steps.

Molecular sieve adsorption dehydration + distillation First use molecular sieves, calcium oxide, etc. as adsorbents to reduce the water content in the waste DMF to an extremely low level (<0.1%), then perform distillation to remove other organic impurities.     Lower energy consumption than direct water removal; protects DMF, reduces thermal decomposition; high recovery quality.    Molecular sieves require regular regeneration, increasing operational complexity; For highly water-containing waste liquids, the cost of adsorbents is high. The preferred combined process for treating DMF waste liquids with high water content.

Thin-film evaporation / Strip film evaporation: The material forms an extremely thin liquid film on the heating surface and is rapidly evaporated and separated under vacuum. The residence time is extremely short (at the second level), particularly suitable for heat-sensitive materials to prevent DMF decomposition; the evaporation efficiency is high. The equipment investment is relatively high; the processing capacity is usually not as large as that of traditional distillation towers; it may be limited for high-viscosity materials. Treating DMF waste liquids containing thermally unstable products or high-boiling-point polymer impurities.

Pervaporation membrane separation: Selective permeation of the DMF-water mixture by hydrophilic/hydrophobic membranes for dehydration. Operation at normal temperature, energy-saving; no phase change, no chemical additives; deep dehydration is possible. The membrane module cost is high and needs to be replaced regularly; the flux is limited, suitable for a specific concentration range; high pre-treatment requirements (anti-fouling and blocking prevention). As an efficient and energy-saving dehydration unit, integrated with the distillation system, used for pre-concentration or deep dehydration of waste DMF.

3. Typical recovery process flow (taking complex waste liquids as an example)

A modern DMF recovery workshop may adopt the following combined process:

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Waste DMF collection tank → Filtration pretreatment → **Pervaporation membrane dehydration unit** (reducing water content from ~20% to <1%) → **Membrane evaporator** (removing most high-boiling-point tar-like impurities) → **Precision distillation tower** (further separating low-boiling-point solvents to obtain over 99.5% pure product) → After inspection is qualified, it is returned to production.

4. Quality control and reuse of recovered materials

•      Strict quality inspection: The recovered DMF must establish strict internal quality control standards, including purity (GC), moisture (KF method), color, acidity, content of specific impurities (such as dimethylamine), etc. The most crucial aspect is to assess its impact on subsequent chemical reactions (such as whether it contains catalytic poisons).

•      Graded reuse: Based on the inspection results, implement a graded reuse system:

o Optimal grade: Used for final API crystallization or key synthesis steps.

o Qualified grade: Used for intermediate synthesis or initial reaction steps.

o Downgraded use: For rinsing, extraction, etc., non-core purposes.

•      Certification and verification: Under GMP conditions, the recovery process and the quality of the recovered solvent must undergo complete process validation and stability assessment, and be included in the drug registration documents (such as DMF or MA), subject to review by regulatory authorities (such as FDA, EMA, NMPA).

Summary and trends

1. Application: DMF is an indispensable “universal solvent” in pharmaceutical synthesis, especially in the production of advanced intermediates and APIs.

2. Reuse necessity: Due to safety, environmental protection, and cost pressures, recycling is a mandatory choice.

3. Technical core: Distillation is the foundation, membrane evaporation is the protection, and membrane technology is the direction of energy conservation. The combined process is the key to solving complex waste liquids, improving recovery rates and quality.

4. Management core: Quality originates from design. Recovery is not a simple “boil it”, but a full life cycle quality management system from process development planning, to waste liquid classification management, to precise separation and strict quality inspection.

For pharmaceutical enterprises, investing in the construction of an advanced DMF recovery system is not only a fulfillment of social responsibility, but also a strategic investment that can bring long-term economic returns and supply chain security.