Residual solvents in pharmaceutical products are defined as organic volatile compounds that are used or produced in the manufacturing of drug substances or excipients, or in the preparation of drug products, or from packaging and storage. Residual solvents are sometimes crucial in the synthesis of drug substances. Oftentimes, residual solvents are necessary to ameliorate the quality of drug substances or excipients. However, they are pitfalls and have no therapeutic value. Therefore, if the residual solvents are not completely removed by practical manufacturing methodologies, they must be evaluated and justified.

Pharmaceutical products should contain low levels of residual solvents as determined by safety data. If the presence of residual solvents in pharmaceutical products exceeds tolerance limits as determined by safety data, they may be harmful to the human health and to the environment. That’s the reason that residual solvents testing becomes one of the important parts of quality control in pharmaceuticals.

The USP <467> method sets the concentration limit for each solvent. Solvents are grouped according to their toxicity levels and potential adverse effects.

• Class 1 solvents (known to cause unacceptable toxicities or to have environmental effects) will be avoided in the manufacturing process of drug substances, excipients, or pharmaceutical products unless their use can be strongly justified in a risk-benefit assessment.

Solvent Concentration
Limit (ppm)
Concern
Benzene 2 Carcinogen
Carbon tetrachloride 4 Toxic and environmental hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethene 8 Toxic
1,1,1-Trichloroethane 1500 Environmental hazard

 

• Class 2 solvents (associated with less severe toxicity) will be limited in order to protect patients from potential adverse effects.

Solvent PDE
(mg/day)
Concentration
Limit (ppm)
Acetonitrile 4.1 410
Chlorobenzene 3.6 360
Chloroform 0.6 60
Cumene 0.7 70
Cyclohexane 38.8 3880
1,2-Dichloroethene 18.7 1870
1,2-Dimethoxyethane 1.0 100
N,N-Dimethylacetamide 10.9 1090
N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380
2-Ethoxyethanol 1.6 160
Ethylene glycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3000
2-Methoxyethanol 0.5 50
Methylbutylketone 0.5 50
Methylcyclohexane 11.8 1180
Methylene chloride 6.0 600
N-Methylpyrrolidone 5.3 530
Nitromethane 0.5 50
Pyridine 2.0 200
Sulfolane 1.6 160
Tetrahydrofuran 7.2 720
Tetralin 1.0 100
Toluene 8.9 890
Trichloroethylene 0.8 80
Xylene* 21.7 2170
* Usually 60% m-xylene, 14% p-xylene, 9% o-xylene with 17% ethyl benzene.

• Class 3 solvents (less toxic) will be used where practical, because they pose a lower risk to human health. Residual solvents concentration of 50 mg per day or less, corresponding to 5000 ppm, would be acceptable without justification.

Acetic acid Heptane
Acetone Isobutyl acetate
Anisole Isopropyl acetate
1-Butanol Methyl acetate
2-Butanol 3-Methyl-1-butanol
Butyl acetate Methylethylketone
tert-Butylmethyl ether Methylisobutylketone
Formic acid 2-Methyl-1-propanol
Dimethyl sulfoxide Pentane
Ethanol 1-Pentanol
Ethyl acetate 1-Propanol
Ethyl ether 2-Propanol
Ethyl formate Propyl acetate

 

Gas Chromatography with valve-and-loop headspace analysis is recommended for identi­fication and quanti­fication of residual solvents in pharmaceutical samples. Based on Good Manufacturing Practices, measuring residual solvents is mandatory for the release testing of all active pharmaceutical ingredients.

Three analytical procedures are used for identifi­cation and quantifi­cation of the residual solvents:

• Procedure A screens for and confi­rms the solvents’ presence.

• Procedure B confi­rms the solvents’ identity.

• Procedure C is required to quantify the amount of residual solvents present.

The determination of residual solvents in drug substances, excipients or drug products is known to be one of the most difficult and demanding analytical tasks in the pharmaceutical industry. Many pharmaceutical products must be analyzed for residual solvents at different stages of their development (raw materials, intermediate products, and final product).

Whitehouse Laboratories, LLC is equipped with multiple Gas Chromatography instruments, most of which have headspace capabilities for residual solvents testing, and analysts with more than 2 decades of combined experience analyzing pharmaceutical products for residual solvents.

By: Conchita Mendoza – Manager, HPLC / GC Services