💊 Residual solvents — GC

Q: How long does the test take?

The times given for the individual stages add up to approximately 2 h. The procedure comprises 6 steps.

Q: What equipment is required?

Gas chromatograph GC-FID, Headspace sampler, Capillary column DB-624, Headspace vials 20 mL, Analytical balance. Indicative cost of the core instrument (Gas chromatograph GC-FID): 150 000–300 000 PLN.

Q: Where is this test used?

Quality control of active substances (API) — batch release; Testing of finished medicinal products; Control of pharmaceutical raw materials (excipients, coating); Production process validation (drying, crystallization); Drug registration — CTD Module 3 documentation.

Q: What safety precautions apply?

Class 1 solvents (benzene, CCl₄) — carcinogenic! Work in fume hood with carbon filter.; DMSO — penetrates skin and transports substances into organism. Gloves mandatory.; Hydrogen as carrier gas — flammable, check installation tightness; Headspace vials under pressure after thermostatting — caution when opening.

Q: Which laboratory can perform this test?

The test is performed by laboratories accredited to ISO/IEC 17025. On LabCoda you can find them by the standard number Ph.Eur. 2.4.24 / ICH Q3C.

Pharma Ph.Eur. 2.4.24 / ICH Q3C

In short

Determination of residual solvents (methanol, acetone, dichloromethane, toluene, etc. The test is performed according to European Pharmacopoeia 2.4.24, ICH Q3C(R8); Class 1 solvents: Benzene (2 ppm), CCl₄ (4 ppm), 1,2-dichloroethane (5 ppm). The procedure comprises 6 steps (about 2 h in total); it is used for: Quality control of active substances (API) — batch release, Testing of finished medicinal products, Control of pharmaceutical raw materials (excipients, coating).

At a glance

Standard: European Pharmacopoeia 2.4.24, ICH Q3C(R8)
Category: Pharma
Procedure steps: 6
Total time of stages: 2 h
Class 1 solvents: Benzene (2 ppm), CCl₄ (4 ppm), 1,2-dichloroethane (5 ppm)
Class 2 solvents: DCM (600 ppm), MeOH (3000 ppm), toluene (890 ppm), ACN (410 ppm)
Class 3 solvents: Acetone, EtOH, MTBE, ethyl acetate — ≤5000 ppm total

Overview

Residual solvents are volatile organic compounds remaining in active substances (API) and finished medicinal products after synthesis, purification, and crystallization processes. ICH Q3C classifies solvents into 3 classes: class 1 — solvents to be avoided (benzene, CCl₄ — carcinogenic), class 2 — limited (DCM ≤600 ppm, methanol ≤3000 ppm, toluene ≤890 ppm), class 3 — low toxicity (acetone, ethanol — ≤5000 ppm total).

The method involves gas chromatography analysis with headspace technique (HS-GC-FID or HS-GC-MS). Sample substance is dissolved in higher boiling point solvent (DMSO, DMF, water), thermostated in headspace vial, and vapors above solution are analyzed on GC column.

Method principle

Pharmaceutical substance sample is dissolved in DMSO or water in sealed headspace vial. After thermostatting (80°C, 30–60 min), volatile solvents transfer to gas phase (headspace). Gas phase sample is automatically collected by headspace sampler and injected into gas chromatograph. Separation on capillary column (DB-624 or WAX), FID detection. Identification based on retention times, quantitative determination using calibration curve (solvent standards in DMSO).

Applications

Quality control of active substances (API) — batch release
Testing of finished medicinal products
Control of pharmaceutical raw materials (excipients, coating)
Production process validation (drying, crystallization)
Drug registration — CTD Module 3 documentation

Key parameters

Parameter	Value
Class 1 solvents	Benzene (2 ppm), CCl₄ (4 ppm), 1,2-dichloroethane (5 ppm)
Class 2 solvents	DCM (600 ppm), MeOH (3000 ppm), toluene (890 ppm), ACN (410 ppm)
Class 3 solvents	Acetone, EtOH, MTBE, ethyl acetate — ≤5000 ppm total
Technique	Headspace GC-FID (or GC-MS)
Headspace temperature	80°C / 30–60 min

Standard

Standard number: European Pharmacopoeia 2.4.24, ICH Q3C(R8)
Title (PL): Identyfikacja i kontrola rozpuszczalników resztkowych
Title (EN): Identification and control of residual solvents

Step-by-step procedure

Sample preparation

Weigh 100–500 mg substance into 20 mL HS vial. Add 5 mL DMSO. Cap with crimp. Mix by vortex.

⏱ Time: 10 min
Standard preparation

Prepare solvent standards in DMSO at 50–200% ICH limit level.

⏱ Time: 20 min
Headspace thermostatting

Place vials in HS sampler. Thermostat 80°C / 45 min with shaking.

⏱ Time: 45 min • 🌡 Temperature: 80°C
GC-FID analysis

Program: 40°C (5 min) → 10°C/min → 240°C (10 min). DB-624 column. FID detection.

⏱ Time: 30 min
Identification and calculations

Identify solvents by retention times. Calculate concentrations from calibration curve. Convert to ppm (µg/g).

⏱ Time: 10 min
Result evaluation

Compare with ICH Q3C limits. Class 1: <absolute limit. Class 2: <individual limit. Class 3: sum <5000 ppm.

⏱ Time: 5 min

Required equipment and apparatus

Equipment	Example	Indicative price
Gas chromatograph GC-FID	Agilent 8890, Shimadzu GC-2030, Thermo TRACE 1310	150 000–300 000 PLN
Headspace sampler	Agilent 7697A, PerkinElmer TurboMatrix, Shimadzu HS-20	80 000–180 000 PLN
Capillary column DB-624	Agilent DB-624, 30 m × 0.53 mm × 3 µm	2 000–4 000 PLN
Headspace vials 20 mL	Glass vials with aluminum crimp cap + septum	1–3 PLN/pc
Analytical balance	Mettler Toledo ME204	5 000–15 000 PLN

Reagents, media and consumables

Reagent	CAS	Details
DMSO (dimethyl sulfoxide)	67-68-5	Headspace grade, sample solvent (b.p. 189°C)
Class 2 solvent standards	—	Mix: DCM, MeOH, toluene, ACN, hexane, chloroform — certified CRM in DMSO
ICH class 1 standard	—	Benzene, CCl₄, 1,2-dichloroethane — low concentrations, CRM
Hydrogen (carrier gas) or helium	1333-74-0	Purity 5.0 (99.999%)

Health and safety (OHS)

Class 1 solvents (benzene, CCl₄) — carcinogenic! Work in fume hood with carbon filter.
DMSO — penetrates skin and transports substances into organism. Gloves mandatory.
Hydrogen as carrier gas — flammable, check installation tightness
Headspace vials under pressure after thermostatting — caution when opening

Frequently asked questions

Which standard describes this test?

The test is performed according to European Pharmacopoeia 2.4.24, ICH Q3C(R8) — “Identification and control of residual solvents”.

How does this method work?

Pharmaceutical substance sample is dissolved in DMSO or water in sealed headspace vial. After thermostatting (80°C, 30–60 min), volatile solvents transfer to gas phase (headspace).

What is the measuring range and accuracy?

Class 1 solvents: Benzene (2 ppm), CCl₄ (4 ppm), 1,2-dichloroethane (5 ppm); Class 2 solvents: DCM (600 ppm), MeOH (3000 ppm), toluene (890 ppm), ACN (410 ppm); Class 3 solvents: Acetone, EtOH, MTBE, ethyl acetate — ≤5000 ppm total; Technique: Headspace GC-FID (or GC-MS).

How long does the test take?