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Analytical Reference Materials
The ICH guideline classifies residual solvents by class according to toxicity. Class 1
compounds are carcino genic and pose a risk to both the consum er and the envi­
ronment. The use of these solvents must be avoided or tightly controlled. Class 2
compounds are nongenotoxic an imal carcinogens and their concentration should
be limited. Both Class 1 and 2 compounds require chromatogra phic determination
and are separated into 3 test mixes: Class 1 Mixture, Class 2 Mixtu re A, and Class 2
Mixture B. Class 3 compounds have low toxic potential. Concentration levels of up
to 0.5% are acceptabl e and, th erefore, they can be assayed by nons pecific tech­
niqu es, such as weight loss on drying. Class 2 Mixture C is not used in the second
supplement of USP 30/NF 25, bu t contains solvents that are not readily detectable
by headspace analysis. These solvents should be assayed by other appropriately val­
idated procedures.
Procedure A - Identification
Procedure A is the first step in the ident ification process and is performed on a G43
column to determine if any residual solvents are present in the sample at detectable
levels. First, Class 1 standa rd and system suitability solutions and Class 2 Mix A
standard solutions are assayed under the method-specified operating conditions to
establish system suitability. All peaks in the Class 1 system suitability solution must
have a signal-to-noise ratio not less than 3, the Class 1 standard solution mu st have
a 1,1,l -trichloroethan e respon se greater than 5, and the resolut ion of acetonitrile
and dichloromethane mu st be not less than 1 in the Class 2 Mixture A solution.
When system suitability has been achieved, the test solut ion s are assayed along with
the Class 1 and Class 2 Mixtures A and Bstandard solutions. If a peak is determined
in the sample that matches a retention time and has a greater respo nse than that of
a correspo nding reference material, then Procedure B is performed for verification
of the analyte. In the second supplemen t of USP 30/NF 25, an exemption is made
for 1,1,I-trichloroethan e, where a response greater than 150 tim es the peak
response denotes an amo unt above the percent daily exposure limit. Figures 2
th rou gh 4 (pages 3-4) illustrate the analysis of Class I, Class 2 Mixture A, and Class
2 Mixture B residu al solvent mixes by Procedure A. The resolution between ace­
tonitrile and dichloromethane was easily achieved using an Rtx®-1301 column.
Continued on page 4.
Figure 2 USP residual solvent Class 1 standard solut ion on an Rtx"-1301
column (G43).
--¥sYSTEM SUITABILITY CRITERIAMET
- .........---..1 vl.-- v "'"-_--I
4 8 10 12
Time(min)
Column: Rtx<-1301, 30m, 0.32mm 10, l.8fJm (cat.# 16092) Headspace Conditions
Sample: USP< 467> Class 1 standard solution Instrument: Tekmar HT3
(cat.# 36279) in20mL headspace vial Transfer linetemp.: 10SoC
Inj.: headspace injection(split ratio1:5),I mmsplit Valve oventemp.: 105°C
liner, Siltek' deactivated(cat.# 20972-214.1) Sampletemp.: 80°C
In], temp.: 140°C Sample equil. time: 4S min.
Carrier gas: helium, constantflow Vial pressure: 10psi
Flow rate: 2.16mL/min.,35.3cm/sec. Pressurizetime: 0.5min.
Oven temp.: 40°C for 20min.to240' C@ Loop fill pressure: 5psi
10'C/min. (holdfor20min.) Loop fill time: 2.00 min.
De!.: FlO @ 240°C Inject time: l. 00min.
USP-equivalent standards
Cont act you r Restek representative.
Product Listing
Residual Solvents - Class 1
benzene 10mg/mL l ,l-dichloroethene
carbon tetrachloride 20 l ,l ,l -trichloroethane
l ,2-dichloroethane 25
In dimethyl sulfoxide, ImL/ampul
cat. # 36279 ea.
40
50
Residual Solvents Class 2 - Mix A (15 components)
acetonitrile 2.05mg/ mL methylcyclohexane 5.90
chlorobenzene 1.80 methylene chloride 3.00
cyc lohexane 19.40 tetrahydrofuran 3.45
cis-l,2-dichloroethene 4.70 toluene 4.45
trans-l ,2-dichloroethene 4.70 m-xylene 6.51
l ,4-dioxane 1.90 o-xylene 0.98
ethylbenzene 1.84 p-xylene 1.52
methanol 15.00
In dimethylsulfoxide, l rnl./ arnpul
cat. # 36271 ~.'"-- _
Residual Solvents Class 2 - Mix B (8 comp onents)
chloroform 60pg/ mL nitromethane 50
1,2-dimethoxyethane 100 pyridine 200
n-hexane(C6) 290 tetralin 100
2-hexanone 50 trichloroethene 80
In dimethylsulfoxide,ImL/ampul
cat. # 36280 .ea.
Residual Solvents Class 2 - Mix C (8 components)
2-ethoxyethanol 800pg/mL 2-methoxyethanol (methyl
ethyleneglycol 3,100 Celosolve) 250
formamide 1,100 N-methylpyrrolidone 2,650
N,N-dimethylacetamide 5,450 sulfolane 800
N,N-dimethylformamide4,400
In dimethyl sulfoxide,I mL/ ampul
cat. # 36273 ea.
All USP singles available!
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